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44 Study Matches
A Study of LY4101174 in Participants With Recurrent, Advanced or Metastatic Solid Tumors
The purpose of this study is to find out whether the study drug, LY4101174, is safe, tolerable and effective in participants with advanced, or metastatic solid tumors. The study is conducted in two parts - phase Ia (dose-escalation, dose-optimization) and phase Ib (dose-expansion). The study will last up to approximately 4 years.
* Have one of the following solid tumor cancers:
* Cohort A1: urothelial carcinoma, triple negative breast cancer, non-small cell lung cancer, esophageal cancer, pancreatic cancer, ovarian cancer, cervical cancer (squamous cell carcinoma), head and neck squamous cell carcinoma or prostate cancer
* Cohort A2/B1/B2: urothelial carcinoma
* Cohort C1: triple negative breast cancer
* Cohort C2: non-small cell lung cancer
* Cohort C3: ovarian or fallopian tube cancer
* Cohort C4: cervical cancer
* Cohort C5: head and neck squamous cell carcinoma
* Prior Systemic Therapy Criteria:
* Cohort A1/C1-5: Individual has received all standard therapies for which the participant was deemed to be an appropriate candidate by the treating investigator; OR there is no standard therapy available for the disease. There is no restriction on number of prior therapies
* Cohort A2/B1/B2: Individual must have received at least one prior regimen in the advanced or metastatic setting. There is no restriction on number of prior therapies.
* Prior enfortumab vedotin specific requirements:
* Cohorts A1/A2/C1-5: prior treatment with enfortumab vedotin is allowed, but not required
* Cohort B1: individual must be enfortumab vedotin naive in the advanced/metastatic setting
* Cohort B2: individual must have received enfortumab vedotin in the metastatic/advanced setting.
* Measurability of disease
* Cohort A1: measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST 1.1)
* Cohorts A2, B1, B2, C1-5: measurable disease required as defined by RECIST v1.1
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Have adequate archival tumor tissue sample available or undergo a screening biopsy if allowed per country specific regulations
Exclusion Criteria:
* Individual with known or suspected uncontrolled CNS metastases
* Individual with uncontrolled hypercalcemia
* Individual with uncontrolled diabetes
* Individual with evidence of corneal keratopathy or history of corneal transplant
* Any serious unresolved toxicities from prior therapy
* Significant cardiovascular disease
* Current of history of intestinal obstruction in the previous 3 months
* Recent thromboembolic event or bleeding disorder
* Prolongation of QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 ms
* History of pneumonitis/interstitial lung disease
* History of Grade ≥3 skin toxicity when receiving enfortumab vedotin
* Individuals who are pregnant, breastfeeding or plan to breastfeed during study or within 30 days of last dose of study intervention
DRUG: LY4101174
Prostate Cancer, Esophageal Cancer, Non-Small Cell Lung Cancer, Pancreatic Cancer, Bladder Cancer, Ovarian Cancer, Cervical Cancer, Head and Neck Squamous Cell Carcinoma, Triple Negative Breast Cancer, Advanced Solid Tumor, Breast - Female, Breast - Male, Cervix, Esophagus, Larynx, Lip, Oral Cavity and Pharynx, Lung/Thoracic, Ovary, Pancreas, Prostate, Urinary Bladder, Metastatic Solid Tumor, Recurrent Solid Tumor, Urinary Bladder Neoplasm, Renal Pelvis Cancer
Dinutuximab With Chemotherapy, Surgery and Stem Cell Transplantation for the Treatment of Children With Newly Diagnosed High Risk Neuroblastoma
This phase III trial tests how well the addition of dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor, radiation, stem cell transplantation, and immunotherapy works for treating children with newly diagnosed high-risk neuroblastoma. Dinutuximab is a monoclonal antibody that binds to a molecule called GD2, which is found on the surface of neuroblastoma cells, but is not present on many healthy or normal cells in the body. When dinutuximab binds to the neuroblastoma cells, it helps signal the immune system to kill the tumor cells. This helps the cells of the immune system kill the cancer cells, this is a type of immunotherapy. When chemotherapy and immunotherapy are given together, during the same treatment cycle, it is called chemoimmunotherapy. This clinical trial randomly assigns patients to receive either standard chemotherapy and surgery or chemoimmunotherapy (chemotherapy plus dinutuximab) and surgery during Induction therapy. Chemotherapy drugs administered during Induction include, cyclophosphamide, topotecan, cisplatin, etoposide, vincristine, and doxorubicin. These drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing or by stopping them from spreading. Upon completion of 5 cycles of Induction therapy, a disease evaluation is completed to determine how well the treatment worked. If the tumor responds to therapy, patients receive a tandem transplantation with stem cell rescue. If the tumor has little improvement or worsens, patients receive chemoimmunotherapy on Extended Induction. During Extended Induction, dinutuximab is given with irinotecan, temozolomide. Patients with a good response to therapy move on to Consolidation therapy, when very high doses of chemotherapy are given at two separate points to kill any remaining cancer cells. Following, transplant, radiation therapy is given to the site where the cancer originated (primary site) and to any other areas that are still active at the end of Induction. The final stage of therapy is Post-Consolidation. During Post-Consolidation, dinutuximab is given with isotretinoin, with the goal of maintaining the response achieved with the previous therapy. Adding dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor, radiation, stem cell transplantation, and immunotherapy may be better at treating children with newly diagnosed high-risk neuroblastoma.
studyfinder@utsouthwestern.edu
ALL
to 30 Years old
PHASE3
This study is NOT accepting healthy volunteers
NCT06172296
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Inclusion Criteria:
* Patients must be enrolled on APEC14B1 and have consented to testing through the Molecular Characterization Initiative (MCI), prior to enrollment on ANBL2131
* ≤ 30 years at the time of initial diagnosis with high-risk disease
* Must have a diagnosis of neuroblastoma (NBL) or ganglioneuroblastoma (nodular) verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamines
* Newly diagnosed, high risk neuroblastoma (HRNBL) defined as one of the following:
* Any age with International Neuroblastoma Risk Group (INRG) Stage L2, MS, or M and MYCN amplification
* Age ≥ 547 days and INRG stage M regardless of biologic features (clinical MYCN testing not required prior to enrollment)
* Any age initially diagnosed with INRG Stage L1 MYCN amplified NBL who have progressed to stage M without systemic chemotherapy
* Age ≥ 547 days of age initially diagnosed with INRG Stage L1, L2, or MS who have progressed to stage M without systemic chemotherapy (clinical MYCN testing not required prior to enrollment)
* Patients must have a BSA ≥ 0.25 m\^2
* No prior anti-cancer therapy except as outlined below:
* Patients initially recognized to have high-risk disease treated with topotecan/cyclophosphamide initiated on an emergent basis and within allowed timing, and with consent
* Patients observed or treated with a single cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (e.g., as per ANBL0531, ANBL1232 or similar) for what initially appeared to be non-high-risk disease but subsequently found to meet the criteria
* Patients who received localized emergency radiation to sites of life threatening or function-threatening disease prior to or immediately after establishment of the definitive diagnosis
* Human immunodeficiency virus (HIV) -infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* A serum creatinine based on age/sex derived from the Schwartz formula for estimating glomerular filtration rate (GFR) utilizing child length and stature data published by the CDC or
* a 24-hour urine creatinine clearance ≥ 70 mL/min/1.73 m\^2 or
* a GFR ≥ 70 mL/min/1.73 m\^2. GFR must be performed using direct measurement with a nuclear blood sampling method or direct small molecule clearance method (iothalamate or other molecule per institutional standard) Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age
* Serum glutamic pyruvic transaminase (SGPT) (Alanine aminotransferase \[ALT\]) ≤ 10 x ULN\*
* Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
* Shortening fraction of ≥ 27% by echocardiogram, or ejection fraction of ≥ 50% by echocardiogram or radionuclide angiogram
* Ability to tolerate Peripheral Blood Stem Cell (PBSC) Collection:
No known contraindication to PBSC collection. Examples of contraindications might be a weight or size less than the collecting institution finds feasible, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure
Exclusion Criteria:
* Patients who are 365-546 days of age with INRG Stage M and MYCN non amplified NBL, irrespective of additional biologic features
* Patients ≥ 547 days of age with INRG Stage L2, MYCN non-amplified NBL, regardless of additional biologic features
* Patients with known bone marrow failure syndromes
* Patients on chronic immunosuppressive medications (e.g., tacrolimus, cyclosporine, corticosteroids) for reasons other than prevention/treatment of allergic reactions and adrenal replacement therapy are not eligible. Topical and inhaled corticosteroids are acceptable
* Patients with a primary immunodeficiency syndrome who require ongoing immune globulin replacement therapy
* Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required prior to enrollment for female patients of childbearing potential
* Lactating females who plan to breastfeed their infants
* Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, food and drug administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
A Study Using Nivolumab, in Combination With Chemotherapy Drugs to Treat NasopharyngealCarcinoma (NPC)
This phase II trial tests effects of nivolumab in combination with chemotherapy drugs prior to radiation therapy patients with nasopharyngeal carcinoma (NPC). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as gemcitabine and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Researchers want to find out what effects, good and/or bad, adding nivolumab to chemotherapy has on patients with newly diagnosed NPC. In addition, they want to find out if children with NPC may be treated with less radiation therapy and whether this decreases the side effects of therapy.
* Patients must be ≤ 21 years of age at the time of study enrollment
* Newly diagnosed American Joint Committee on Cancer (AJCC) stage II-IV nasopharyngeal carcinoma (NPC)
* Patients must have had histologic verification of the malignancy at original diagnosis
* Although submission of tumor tissue for the molecular characterization initiative is not required for eligibility, it is strongly recommended
* Patients must have had histologic verification of the malignancy at original diagnosis
* Although submission of tumor tissue for the molecular characterization initiative is not required for eligibility, it is strongly recommended
* Patients must have a Lansky (for patients ≤ 16 years of age) or Karnofsky (for patients \> 16 years of age) performance status score of ≥ 60%
* Peripheral absolute neutrophil count (ANC) ≥ 1000/uL (within 7 days prior to start of protocol therapy)
* Platelet count ≥ 100,000/uL (transfusion independent) (within 7 days prior to start of protocol therapy)
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m\^2 or (within 7 days prior to start of protocol therapy)
* A serum creatinine based on age/gender (within 7 days prior to start of protocol therapy) Age: Maximum serum creatinine (mg/dL)
1 month to \< 6 months: 0.4 mg/dL (male); 0.4 mg/dL (female) 6 months to \< 1 year: 0.5 mg/dL (male); 0.5 mg/dL (female)
1 to \< 2 years: 0.6 mg/dL (male); 0.6 mg/dL (female) 2 to \< 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female) 6 to \< 10 years 1 mg/dL (male); 1 mg/dL (female) 10 to \<13 years: 1.2 mg/dL (male); 1.2 mg/dL (female) 13 to \< 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)
≥ 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and (within 7 days prior to start of protocol therapy)
* Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase \[ALT\]) ≤ 135 U/L\* (within 7 days prior to start of protocol therapy)
* Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
* Shortening fraction of ≥ 27% by echocardiogram, or
* Ejection fraction of ≥ 50% by radionuclide angiogram
* No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry \> 94% if there is clinical indication for determination
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months and T-cell count above the lower limit of normal are eligible for this trial
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
Exclusion Criteria:
* Patients who received prior radiotherapy to the head or neck
* Patients who received prior chemotherapy or radiation for the treatment of any cancer in the last 3 years. These patients must also be in remission
* Patients with a diagnosis of immunodeficiency
* Patients with an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive agents). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Note: Patients with well-controlled asthma and no need for systemic steroids for the treatment of asthma in the last 12 months will not be excluded
* Patients with a condition requiring systemic treatment with either corticosteroids (\> 0.25 mg/kg (10 mg) daily prednisone equivalent) within 14 days or other immunosuppressive medications within 30 days of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses \> 0.25 mg/kg (10 mg) daily prednisone equivalent, are permitted in the absence of active autoimmune disease
* Patients with a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
* Patients with detectable viral load of human immunodeficiency virus (HIV), hepatitis B or hepatitis C, or active tuberculosis
* Patients who have undergone solid organ or allogeneic hematopoietic transplant at any time
* Due to risks of fetal and teratogenic adverse events as seen in animal studies, a negative pregnancy test must be obtained in females of childbearing potential, defined as females who are post-menarchal. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Females of childbearing potential that are sexually active must agree to either practice 2 medically accepted highly-effective methods of contraception at the same time or abstain from heterosexual intercourse from the time of signing the informed consent through 5 months after the last dose of nivolumab, 6 months after the last dose of gemcitabine, and 14 months after the last dose of cisplatin, whichever is longer
* Males of childbearing potential that are sexually active must agree to either practice a medically accepted highly-effective methods of contraception or abstain from heterosexual intercourse from the time of signing the informed consent through 3 months after the last dose of gemcitabine, and 11 months after the last dose of cisplatin, whichever is longer
* Lactating females are not eligible unless they have agreed not to breastfeed their infants starting with the first dose of study therapy through 5 months after the last dose of nivolumab
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
A Dose Escalation and Dose Expansion Study of Intratumoral ONM-501 Alone and in Combination With Cemiplimab in Patients With Advanced Solid Tumors and Lymphomas. (ON-5001)
A phase 1, multicenter, open label, non-randomized dose escalation and dose expansion study to examine the maximum tolerated dose, (MTD), minimum effective dose (MED) and/or recommended dose for expansion (RDE) of intratumoral ONM-501 as monotherapy and in combination with a PD-1 checkpoint inhibitor in patients with advanced solid tumors and lymphomas.
• Ability to understand and willingness to sign written informed consent before performance of any study procedures
• Age ≥ 18 years
• Participants with solid tumors or lymphomas, confirmed by available histopathology records or current biopsy, that are advanced, nonresectable, or recurrent and progressing since last antitumor therapy, and for which no alternative standard therapy exists.
• Participants must have a minimum of one injectable and measurable lesion.
• Participants with prior Hepatitis B or C are eligible if they have adequate liver function
• Participants with human immunodeficiency virus (HIV) are eligible if on established HAART for a minimum of 4 weeks prior to enrollment, have an HIV viral load \<400 copies/mL, and have CD4+ T-cell (CD4+) counts ≥ 350 cells/uL
• Adequate bone marrow function:
• Adequate liver function
Exclusion Criteria:
Patients will be excluded from this study if they meet any of the following criteria (Part 1a and Part 1b).
• Other malignancy active within the previous 2 years except for basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast that has completed curative therapy.
• Major surgery within 4 weeks before the first dose of study drug.
• Brain metastases that are untreated or in the posterior fossa or involve the meninges. Participants with stable or previously treated progressing brain metastases (except in the posterior fossa or involving the meninges) may be permitted in a case-by-case basis at the Sponsor's discretion.
• Prolongation of corrected QT (QTc) interval to \>470 millisecond (ms) for males and females when electrolytes balance is normal.
• Females who are breastfeeding or pregnant at screening or baseline
• Females of childbearing potential that refuse to use a highly effective method of contraception.
• Has uncontrolled or poorly controlled hypertension as defined by a sustained BP \> 9. Has received prior investigational therapy within 5 half-lives of the agent or 4 weeks before the first administration of study drug, whichever is shorter.
• Has had any major cardiovascular event within 6 months prior to study drug 10. Has known hypersensitivity to any component in the formulation of ONM-501
• Has an active infection requiring systemic treatment
• Is participating in another therapeutic clinical trial
Additional Exclusion Criteria for ONM-501 in Combination with cemiplimab (Part 1b)
• Has known hypersensitivity to any component in the formulation of cemiplimab
• Has any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (\>10 mg daily prednisone equivalent)
• Has a condition requiring systemic treatment with corticosteroids
DRUG: ONM-501, DRUG: Cemiplimab
Bladder Cancer, Metastatic Cancer, Lymphoma, Non-Hodgkin, Skin Cancer, Head and Neck Squamous Cell Carcinoma, Triple Negative Breast Cancer, Follicular Lymphoma, Mantle Cell Lymphoma, Diffuse Large B Cell Lymphoma, Carcinoma In Situ, Tumor, Solid, Uveal Melanoma, Recurrent, Cervix Cancer, Tumor Recurrence
A Study of Disitamab Vedotin in Previously Treated Solid Tumors That Express HER2
This clinical trial is studying advanced or metastatic solid tumors. Once a solid tumor has grown very large in one spot or has spread to other places in the body, it is called advanced or metastatic cancer. Participants in this study must have head and neck squamous cell cancer, non-small cell lung cancer, endometrial cancer, or ovarian cancer. Participants must have tumors that have a marker called HER2.
This clinical trial uses an experimental drug called disitamab vedotin (DV). DV is a type of antibody-drug conjugate or ADC. ADCs are designed to stick to cancer cells and kill them. In this study, all participants will get DV once every 2 weeks.
This study is being done to see if DV works to treat different types of solid tumors that express HER2. It will also test how safe the drug is for participants. This trial will also study what side effects happen when participants get the drug. A side effect is anything a drug does to your body besides treating the disease.
* Cohort 1: Head and neck squamous cell carcinoma (HNSCC)
* Pathologically-documented squamous cell carcinoma of the head and neck with primary tumor site arising from the oral cavity, oropharynx, hypopharynx, and larynx
* Unresectable locally recurrent or metastatic stage disease
* Prior therapies:
* Participants must have disease progression after treatment with a platinum-based therapy
* No more than 1 line of cytotoxic chemotherapy for advanced disease
* Cohort 2: Non-small cell lung cancer (NSCLC)
* Pathologically documented NSCLC
* Unresectable locally-advanced or metastatic stage disease
* Prior therapies
* Must have progressed during or after a platinum-based therapy or, within 6 months of platinum-based adjuvant, neoadjuvant, or concomitant chemoradiotherapy for early or locally-advanced stage disease
* Must have received prior anti-PD(L)1 therapy, unless contraindicated
* No more than 2 prior lines of cytotoxic chemotherapy for advanced disease
* Cohort 3: Ovarian Cancer
* Pathologically documented epithelial cancers of ovarian, fallopian tube, or peritoneal origin
* Unresectable locally-advanced or metastatic stage disease
* Prior therapies
* Must have platinum resistant disease (6 months or less between the completion of platinum-based treatment and identification of recurrence)
* Must not have received more than 4 lines of prior cytotoxic chemotherapies for advanced disease
* May have received prior anti-PD(L)1 therapy
* Cohort 4: Endometrial Cancer
* Must have pathologically documented adenocarcinoma of the endometrium
* Must have unresectable locally-advanced or metastatic stage disease.
* Prior therapies
* Must have relapsed/progressed after at least one prior platinum-based chemotherapy for recurrent, metastatic or primary unresectable disease
* Must not have received more than 3 lines of prior cytotoxic chemotherapies for advanced disease
* May have received prior anti-PD(L)1 therapy
* HER2 expression of 1+, 2+, or 3+, as determined by local IHC testing on a fresh or archival tumor tissue. Note: Participants with HER2 mutations are eligible.
* Measurable disease per RECIST v1.1 criteria as assessed by the investigator
* Able to provide formalin-fixed, paraffin-embedded (FFPE) tumor tissue blocks (or freshly sectioned slides)
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
Exclusion Criteria:
* Prior treatment with an MMAE-containing agent.
* Known hypersensitivity to any excipient contained in the drug formulation of disitamab vedotin.
* History of another invasive malignancy within 2 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy.
* Active untreated CNS or leptomeningeal metastasis
DRUG: disitamab vedotin
Carcinoma, Squamous Cell of Head and Neck, Carcinoma, Non-Small-Cell Lung, Ovarian Neoplasms, Endometrial Neoplasms
A Safety and Efficacy Study of HCB101, Fc-fusion Protein Targeting SIRPα-CD47 Pathway, in Solid or Hematological Tumors
The purpose of this study is to find out whether IV injection of HCB101 is an effective
treatment for different types of advanced solid tumors or relapsed and refractory non-Hodgkin
lymphoma and what side effects (unwanted effects) may occur in subjects aged 18 years old and
above.
• Able to understand and willing to sign the ICF.
• Male and female subjects of ≥18 years of age.
• Histologically/cytologically confirmed, locally advanced solid tumor: subjects with
histologically or cytologically confirmed advanced solid tumors refractory to standard
therapy, or for which no standard treatment exists or non-Hodgkin lymphoma, relapsed
or refractory to at least 2 prior lines of therapy.
• For subjects with advanced solid tumor - must have at least 1 measurable lesion as
defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at baseline.
• For subjects with non-Hodgkin lymphoma - must have non-Hodgkin lymphoma that is
measurable or assessable for response per Lugano Classification (with 2016
refinement).
• Must have ECOG performance status of 0 to 2 at Screening.
• Able to provide tumor tissue samples.
• Have life expectancy of ≥12 weeks.
Exclusion Criteria:
• With known history of hypersensitivity to any components of HCB101.
• Known active or untreated CNS metastases and/or carcinomatous meningitis.
• Have undergone a major surgery or radical radiotherapy or palliative radiotherapy or
have used a radioactive drug that is not completed at least 2 weeks prior to the first
dose of HCB101.
• Clinically significant cardiovascular condition.
• Any previous treatment-related toxicities which have not recovered to ≤ Grade 1 as
evaluated by National Cancer Institute, Common Terminology Criteria for Adverse Events
(NCI CTCAE) version 5.0 or baseline, except alopecia and anemia.
• With known inherited or acquired bleeding disorder or bleeding diathesis. .
• Have RBC transfusion within 4 weeks prior to Screening.
• With a previously documented diagnosis of hemolytic anemia or Evans Syndrome in the
last 3 months.
• Any investigational or approved systemic cancer therapy.
• Active use of vitamin K antagonist anticoagulant like warfarin. Use of low molecular
weight heparin and factor Xa inhibitors will be permitted on case by case basis. There
will be no restriction for daily aspirin ≤ 81 mg/QD.
• Have used herbal medication within 14 days prior to the first dose of HCB101.
• Have received any treatment targeting the CD47 or SIRPα pathway.
• Have other malignancies requiring treatment within 2 years prior to the first dose of
HCB101.
• Participation in another clinical study with an investigational product administered
in the last 14 days prior to receiving the first dose of HCB101.
• An investigational device used within 28 days prior to the first dose of HCB101.
• Positive for hepatitis B, active hepatitis C infections, positive for HIV, or known
active or latent tuberculosis.
• Known to have a history of alcoholism or drug abuse.
Drug: HCB101
Multiple Myeloma, Advanced Solid Tumor, Refractory Non-Hodgkin Lymphoma, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Esophagus, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Ovary, Pancreas, Prostate, Rectum, Stomach, Thyroid, Urinary Bladder, Hodgkins Lymphoma, Kaposis sarcoma, Non-Hodgkins Lymphoma, Small Intestine
Immunotherapy, CD47, SIRPα, Solid Tumor, Lymphoma
UT Southwestern; Parkland Health & Hospital System
A Study of Revumenib in Combination With Chemotherapy for Patients Diagnosed With Relapsed or Refractory Leukemia
This phase II trial tests the safety and best dose of revumenib in combination with chemotherapy, and evaluates whether this treatment improves the outcome in infants and young children who have leukemia that has come back (relapsed) or does not respond to treatment (refractory) and is associated with a KMT2A (MLL) gene rearrangement (KMT2A-R). Leukemia is a cancer of the white blood cells, where too many underdeveloped (abnormal) white blood cells, called "blasts", are found in the bone marrow, which is the soft, spongy center of the bones that produces the three major blood cells: white blood cells to fight infection; red blood cells that carry oxygen; and platelets that help blood clot and stop bleeding. The blasts crowd out the normal blood cells in the bone marrow and spread to the blood. They can also spread to the brain, spinal cord, and/or other organs of the body. The leukemia cells of some children have a genetic change in which a gene (KMT2A) is broken and combined with other genes that typically do not interact with one another; this is called "rearranged". This genetic rearrangement alters how other genes are turned on or off in the cell, turning on genes that drive the development of leukemia. Patients with KMT2A rearrangement have higher risk for cancer coming back after treatment. Revumenib is an oral medicine that directly targets the changes that occur in a cell with a KMT2A rearrangement and has been shown to specifically kill these leukemia cells in preclinical laboratory settings and in animals. Drugs used in chemotherapy, such as vincristine, prednisone, asparaginase, fludarabine and cytarabine work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This trial is being done to find out if the combination of revumenib and chemotherapy would be safe and/or effective in treating infants and young children with relapsed or refractory KMT2A-R leukemia.
* Patients must be 1 month to \< 6 years old at the time of study enrollment and must have had initial diagnosis of leukemia at \< 2 years old.
* Patients must have KMT2A-rearranged acute lymphoblastic leukemia (ALL), acute leukemia of ambiguous lineage (ALAL), or mixed phenotype acute leukemia (MPAL), which is determined to be refractory or in first marrow relapse. All patients must undergo cytogenetics and fluorescence in situ hybridization (FISH) testing of a relapsed/refractory blast sample at a Children's Oncology Group (COG)-approved laboratory for KMT2A-R status determination and the presence of a KMT2A- rearrangement must be confirmed by central review. Cytogenetics results must be submitted for central review by Day 10 of protocol therapy, for confirmation of KMT2A-R status. Patients enrolled with refractory disease may utilize initial diagnostic cytogenetics for eligibility and submission for central review if testing was performed at a COG approved laboratory. Patients will be eligible to remain on protocol therapy if KMT2A-R is confirmed by central review. Additional methods of assessing for KMT2A-R may be considered if FISH does not detect the rearrangement.
* Disease status at time of enrollment must be one of the following:
* First relapse (untreated): Any recurrence of marrow disease, with or without other extramedullary sites(s), at any point after achieving remission ("remission-1", per definition below) and meeting one of the below criteria. Patients must not have received any disease-directed therapy for the marrow relapse prior to enrollment, other than permitted cytoreduction.
* Relapse M1: M1 morphology (\< 5% blasts) + at least 2 confirmatory tests showing \>= 1% blasts (testing includes flow, cytogenetics, polymerase chain reaction \[PCR\]/next-generation sequencing \[NGS\] of immunoglobulin \[Ig\]/T-cell receptor \[TCR\] rearrangement, and/or PCR or NGS of fusion gene identical to diagnosis), OR
* Relapse M2: M2 morphology (5-25% blasts) + 1 confirmatory test showing \> 1% blasts, OR
* Relapse M3: M3 morphology (\> 25% blasts)
* Primary refractory, or failure to achieve remission-1: remission-1 is defined as \< 1% marrow blasts by flow MRD and resolution of extramedullary disease following at least 2 courses of frontline chemotherapy. Patients who receive 2 courses of chemotherapy and 1 course of blinatumomab are also eligible, but no further treatment attempts beyond that are permitted
* Central nervous system (CNS) disease: Patients must have CNS1 or CNS2 status and no clinical signs or neurologic symptoms suggestive of CNS leukemia, such as cranial palsy.
* Patients with CNS3 disease may receive antecedent intrathecal chemotherapy to achieve CNS1 or CNS2 status prior to enrollment.
* Patients with a history of CNS chloromatous disease are required to have no radiographic evidence of CNS disease prior to enrollment.
* White blood cell (WBC) must be \< 50,000/uL at the time of study enrollment. Patients can receive cytoreduction with hydroxyurea and/or corticosteroids for up to 7 days prior to enrollment.
* Patients \>= 12 months of age must have a performance status by Lansky Scale of \>= 50%.
* Patients must be able to take enteral medications. Acceptable routes of administration for revumenib (SNDX-5613) include: oral (PO), nasogastric (NG) tube, nasojejunal (NJ) tube, nasoduodenal (ND), and gastrostomy tube (G-tube).
* Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
* Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive:
* \>= 14 days must have elapsed after the completion of other cytotoxic therapy, including patients who relapse during pre-Maintenance upfront therapy, with these specific exceptions: cytoreduction with hydroxyurea and/or corticosteroids, and intrathecal chemotherapy, which have no required washout periods. For patients who relapse during upfront Maintenance therapy, \>= 7 days must have elapsed after the last dose of chemotherapy. Additionally, patients must have fully recovered from all acute toxic effects of prior therapy.
* NOTE: Cytoreduction with hydroxyurea and/or corticosteroids is permitted prior to enrollment for patients with WBC \>= 50,000/uL, and by provider discretion regardless of WBC, to reduce potential risk of differentiation syndrome with revumenib initiation. Hydroxyurea and/or corticosteroids may be given for up to 7 days, with no wash-out required.
* NOTE: No waiting period is required for patients having received intrathecal cytarabine, methotrexate, and/or hydrocortisone. Intrathecal chemotherapy that is given up to 7 days prior to the initiation of protocol therapy counts as protocol therapy and not prior anti-cancer therapy. Intrathecal chemotherapy given \> 7 days prior does not count as protocol therapy.
* NOTE: Prior exposure to fludarabine and cytarabine (FLA) is permitted.
* Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or absolute neutrophil count \[ANC\] counts): \>= 7 days after the last dose of agent.
* Antibodies: \>= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =\< 1. There is an exception for blinatumomab infusions, for which patients must have been off for at least 3 days and all drug related toxicity must have resolved to grade 2 or lower as outlined in the inclusion/exclusion criteria.
* Hematopoietic growth factors: \>= 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or \>= 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator.
* Interleukins, interferons and cytokines (other than hematopoietic growth factors): \>= 21 days after the completion of interleukins, interferon, or cytokines
* Stem cell infusions (with or without total body irradiation (TBI):
* Allogeneic (non-autologous) bone marrow or stem cell transplant, or stem cell boost: \>= 84 days after infusion
* Donor leukocyte infusion: \>= 28 days
* Cellular therapy: \>= 28 days after the completion of any type of cellular therapy (e.g., modified T cells, natural killer \[NK\] cells, dendritic cells, etc.)
* Radiation therapy (XRT)/external beam irradiation including protons: \>= 14 days after local XRT; \>= 84 days after TBI, craniospinal XRT or if radiation to \>= 50% of the pelvis; \>= 42 days if other substantial bone marrow radiation.
* A creatinine based on age as follows:
* Age 1 month to \< 6 months: maximum creatinine 0.4 mg/dL
* Age 6 months to \< 1 year: maximum creatinine 0.5 mg/dL
* Age 1 to \< 2 years: maximum creatinine 0.6 mg/dL
* Age 2 to \< 6 years: maximum creatinine 0.8 mg/dL OR
* a 24-hour urine creatinine clearance \>= 70 mL/min/1.73 m\^2 OR
* a glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard).
* NOTE: Estimated GFR (eGFR) from creatinine, cystatin C or other estimates are not acceptable for determining eligibility.
* A direct bilirubin =\< 1.5 x upper limit of normal (ULN) for age, unless disease related
* Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 135 U/L (3 x ULN) unless disease related.
* Note: For the purpose of eligibility, the ULN for SGPT (ALT) has been set to the value of 45 U/L
* Shortening fraction of \>= 27% by echocardiogram, or ejection fraction of \>= 50% by radionuclide angiogram.
* Corrected QT interval using Fridericia formula (QTcF) of \< 450 msec (using the average of triplicate measurements)
* NOTE: There are no specific electrolyte parameters for eligibility. However, it should be noted that, to limit QTc prolongation risk, patients must maintain adequate potassium and magnesium levels to initiate and continue revumenib (SNDX-5613) on protocol therapy.
* Patients must be able to comply with the safety monitoring requirements of the study, in the opinion of the treating investigator.
Exclusion Criteria:
* Patients with isolated extramedullary leukemia.
* Patients diagnosed with Down syndrome.
* Patients known to have one of the following syndromes:
* Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome.
* Patients with a secondary KMT2A-R leukemia that developed after treatment of prior malignancy with cytotoxic chemotherapy.
* Patients with a history of congenital prolonged QT syndrome, congestive heart failure or uncontrolled arrhythmia in the past 6 months prior to study enrollment.
* Patients with an active, uncontrolled infection, further defined below:
* Positive bacterial blood culture within 48 hours of study enrollment
* Fever above 38.2 degrees Celsius (C) within 48 hours of study enrollment with clinical signs of infection. Fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability
* A positive fungal culture within 30 days of study enrollment or active therapy for presumed invasive fungal infection
* Patients may be receiving IV or oral antibiotics to complete a course of therapy for a prior documented infection as long as cultures have been negative for at least 48 hours and signs or symptoms of active infection have resolved. For patients with Clostridium (C.) difficile diarrhea, at least 72 hours of antibacterial therapy must have elapsed and stools must have normalized to baseline
* Active viral or protozoal infection requiring IV treatment
* Human immunodeficiency virus (HIV)-infected patients are eligible if on effective anti-retroviral therapy that does not interact with planned study agents and with undetectable viral load within 6 months of enrollment.
* Patients with active acute graft-versus-host disease (GVHD) \> grade 0 (unless skin only), or chronic GVHD \> mild (unless skin only) are not eligible. Patients with acute or chronic skin GVHD that is =\< grade 1, or chronic skin GVHD that is graded as mild are eligible.
* Patients who have received a prior solid organ transplantation.
* Patients with known Charcot-Marie-Tooth disease, if treating on Regimen A (with vincristine).
* CYP3A4 Inhibitors or Inducers: Patients who require concomitant therapy with strong CYP3A4 inhibitors or moderate or strong CYP3A4 inducers, as these are prohibited during the chemotherapy combination cycles. These agents should be discontinued at least 5 half-lives prior to starting protocol therapy. Concomitant use of strong CYP3A4 inhibitor -azole antifungals are permitted during the revumenib (SNDX-5613) monotherapy cycles, with appropriate revumenib (SNDX-5613) dose modification
* P-glycoprotein (P-gp) inhibitors or inducers: Vincristine is a substrate for P-gp. Concomitant use of P-gp inhibitors or inducers with vincristine (patients receiving Regimen A Cycle 1) should be avoided.
* Investigational drugs: Patients who are currently receiving another investigational drug.
* Anti-cancer agents: Patients who are currently receiving other anti-cancer agents (exceptions: hydroxyurea and corticosteroids, which may be used as cytoreduction prior to enrollment).
* Anti-GVHD agents: Patients who are receiving cyclosporine, tacrolimus, or other systemic agents to treat graft-versus-host disease post bone marrow transplant. Patients should discontinue anti-GVHD agents \> 7 days prior to enrollment and have no evidence of worsening GVHD. Topical steroids are permitted.
* Patients who have previously been treated with revumenib (SNDX-5613). Prior exposure to other menin inhibitors is permitted.
* All patients and/or their parents or legal guardians must sign a written informed consent.
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.
Leukemia, Other, Leukemia, Not Otherwise Specified, Recurrent Acute Lymphoblastic Leukemia, Recurrent Mixed Phenotype Acute Leukemia, Refractory Mixed Phenotype Acute Leukemia, Refractory Acute Leukemia of Ambiguous Lineage, Recurrent Acute Leukemia of Ambiguous Lineage, Recurrent Acute Myeloid Leukemia Due to Lineage Switch From Acute Leukemia of Ambiguous Lineage, Recurrent Acute Myeloid Leukemia Due to Lineage Switch From B Acute Lymphoblastic Leukemia, KMT2A-Rearranged, Recurrent Acute Myeloid Leukemia Due to Lineage Switch From Mixed Phenotype Acute Leukemia, Refractory Acute Lymphoblastic Leukemia, Refractory Acute Myeloid Leukemia Due to Lineage Switch From Acute Leukemia of Ambiguous Lineage, Refractory Acute Myeloid Leukemia Due to Lineage Switch From B Acute Lymphoblastic Leukemia, KMT2A-Rearranged, Refractory Acute Myeloid Leukemia Due to Lineage Switch From Mixed Phenotype Acute Leukemia
Evaluating Safety and Biomarkers Using DK210 (EGFR) for Locally Advanced or Metastatic EGFR+ Tumors
This study will evaluate safety, pharmacodynamics and biomarkers of subcutaneous (SC)
DK210(EGFR) given as monotherapy and in combination with immunotherapy, chemotherapy or
radiation.
• ECOG performance status of 0-1
• Life expectancy of >3 months according to the investigator's judgment
• Solid tumors known for response on Il-2 or Il-10 and/or high expression of EGFR like
all Non-small cell Lung, Skin, Head and Neck, Colon, Kidney, Bladder, Pancreatic
cancers and all squamous cell carcinoma of other organs can be included with a
classical histology report, specific EGFR expression or amplification reports are
needed for other solid tumor types like gynecologic, prostate or triple negative
breast cancer
• Measurable disease, defined as at least one (non-irradiated) lesion measurable on
CT/MRI or bone scan as defined by RECIST 1.1.
• Progressive disease (PD) at study entry defined as one or more of the following
criteria:
• Clinical PD with performance decline, clinical symptoms and/or observed tumor growth
• PD documented with imaging showing at least 20% growth (largest diameter) and/or new
lesions
• Adequate cardiovascular, hematological, liver, and renal function.
• Subjects have failed one or more lines of systemic therapy and have not been operated
on or receiving anti-cancer medication for at least 4 weeks.
• Males and females of childbearing potential must agree to use effective contraception
starting prior to the first day of treatment and continuing during treatment
• Additional criteria may apply
Exclusion Criteria:
• Subjects with documented diffuse peritoneal disease or persistent abundant ascites
• Subjects with known prolonged QtC interval
• Concomitant or recent (<4 weeks or 5 half-lives of the last treatment, whichever is
shorter) treatment with agents with anti-tumor activity, including immunotherapies, or
experimental therapies. Bone treatments and supportive care can be continued
• Major surgery within 4 weeks, Radiation therapy for the treatment of metastases within
less than 3 weeks (if single fraction of radiotherapy, then within 2 weeks) and
radionuclide therapy for the treatment of metastases within 4 weeks prior to screening
• Uncontrolled intercurrent illness including, but not limited to, ongoing and
uncontrolled infection (TBC, COVID or HIV patients treated with at least two
anti-retroviral drugs and control of their infection with at least 500 /mm3 CD4+
T-cells in their blood and patients cured from Hepatitis B or C (i.e negativity of
PCR) and liver function compatible with eligibility criteria are allowed to
participate), multiple myeloma, multiple sclerosis, myasthenia gravis, or psychiatric
illness/social situations that, in the opinion of the investigator, would limit
compliance with study requirement
• Any other conditions that, in the investigator's opinion, might indicate the subject
to be unsuitable for the study
• Additional criteria may apply
Kidney Cancer, Cancer, Colorectal Cancer, Head and Neck Cancer, Non Small Cell Lung Cancer, Gynecologic Cancer, Skin Cancer, Solid Tumor, Breast - Female, Breast - Male, Cervix, Colon, Kidney, Lung/Thoracic, Melanoma, skin, Other Urinary, Pancreas, Urinary Bladder, Pancreas Cancer
A Study of LOXO-435 in Participants With Cancer With a Change in a Gene Called FGFR3
The main purpose of this study is to learn more about the safety, side effects, and effectiveness of LOXO-435. LOXO-435 may be used to treat cancer of the cells that line the urinary system and other solid tumor cancers that have a change in a particular gene (known as the FGFR3 gene). Participation could last up to 30 months (2.5 years) and possibly longer if the disease does not get worse.
* Have solid tumor cancer with an FGFR3 pathway alteration on molecular testing in tumor or blood sample that is deemed as actionable.
* Cohort A1 (Dose Escalation): Presence of an alteration in FGFR3 or its ligands.
* Cohort A2 (Dose Optimization): Histological diagnosis of urothelial cancer (UC) that is locally advanced or metastatic with a qualifying FGFR3 alteration.
* Cohorts B1, B2 and B3 (Dose Expansion): Histological diagnosis of urothelial cancer that is locally advanced or metastatic with a prespecified activating FGFR3 alteration.
* Cohort C (Dose Expansion): Must have histological diagnosis of a non-urothelial solid tumor malignancy that is locally advanced or metastatic with a prespecified activating FGFR3 alteration.
* Measurability of disease:
* Cohort A1: Measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v 1.1 (RECIST v1.1)
* Cohorts A2, B1, B2, B3, and C1: Measurable disease required as defined by RECIST v1.1
* Have adequate archival tumor tissue sample available or undergo a screening biopsy if allowed per country-specific regulations.
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Prior Systemic Therapy Criteria:
* Cohort A1/C1: Participant has received all standard therapies for which the participant was deemed to be an appropriate candidate by the treating Investigator; OR the participant is refusing the remaining most appropriate standard of care treatment; OR there is no standard therapy available for the disease. There is no restriction on number of prior therapies.
* Cohort A2/B1/B2/B3: Participants must have received at least one prior regimen in the advanced or metastatic setting. There is no restriction on number of prior therapies.
* FGFR inhibitor specific requirements:
* Cohort A1/A2: Prior FGFR inhibitor treatment is permitted, but not required.
* Cohort B1: Participants must have been previously treated with a FGFR inhibitor.
* Cohort B2, B3, C1: Participants must be FGFR inhibitor naïve.
Exclusion Criteria:
* Participants with primary central nervous system (CNS) malignancy.
* Known or suspected history of uncontrolled CNS metastases.
* Current evidence of corneal keratopathy or retinal disorder.
* Have a history and/or current evidence of extensive tissue calcification.
* Any serious unresolved toxicities from prior therapy.
* Significant cardiovascular disease.
* Prolongation of the QT interval corrected for heart rate using Fridericia's formula (QTcF).
* Active uncontrolled systemic infection or other clinically significant medical conditions.
* Participants who are pregnant, lactating, or plan to breastfeed during the study or within 6 months of the last dose of study treatment. Participants who have stopped breastfeeding may be enrolled.
DRUG: LOXO-435, DRUG: Pembrolizumab
Neoplasm Metastasis, Urinary Bladder Neoplasms, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Esophagus, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Thyroid, Urinary Bladder, Kaposis sarcoma, Small Intestine, Soft Tissue, Unknown Sites, Ureteral Neoplasms
Molecular and Clinical Risk-Directed Therapy for Infants and Young Children With Newly Diagnosed Medulloblastoma
This is a multi-center, multinational phase 2 trial that aims to explore the use of molecular and clinical risk-directed therapy in treatment of children 0-4.99 years of age with newly diagnosed medulloblastoma.
Inclusion Criteria - Screening Phase (All Patients)
* Participants with presumptive/suspected newly diagnosed medulloblastoma.
* Participant meets one of the following criteria at the time of screening:
* Age \< 36 months OR Age ≥ 36 months and \< 60 months with presumptive/suspected non-metastatic disease
* Participant must have adequate tumor tissue from primary tumor for central review of pathology and molecular classification by methylation and IHC
* Participant must be able to begin treatment as outlined in the protocol within 36 days of definitive surgery (day of surgery is Day 0). In case a second surgery is clinically indicated to remove the residual tumor prior to starting treatment, the second surgery will be considered as the definitive surgery (Day 0).
* Parent or legal guardian can understand and is willing to sign a written informed consent document according to institutional guidelines.
Exclusion Criteria - Screening Phase
* Participants with other clinically significant medical disorders (i.e., serious infections or significant cardiac, pulmonary, hepatic, psychiatric, or other organ dysfunction) that could compromise their ability to tolerate protocol therapy or would interfere with the study procedure.
Inclusion Criteria - Study Enrollment (All Patients)
* Participant must be \< 60 months of age at time of enrollment.
* Note: Each treatment stratum has additional specific age requirements
* Participant must have confirmation of newly diagnosed medulloblastoma per Central Review:
* Central review includes histopathology, IHC and St. Jude Clinical Genomic Methylation Profiling conducted on MLPNet. If tissue or the extracted DNA does not meet quality control criteria for methylation analysis or if methylation classifier is unable assign molecular group/subgroup within the assigned classifier (MLPNet) parameters, then IHC will be used to define molecular group of these cases. IHC cannot be used to determine molecular subgroup. Therefore, IHC defined SHH patients will be enrolled on Stratum S-1 under "SHH-NOS", and all NWNS and indeterminate molecular group will be enrolled on stratum N.
* Note: Diagnosis of medulloblastoma, as well as group and subgroup assignment, will be done by central pathology review at St. Jude only. No outside testing is allowed for trial enrollment.
* Participant must have disease staged by MRI of the brain and spine and by cytologic examination of CSF\* and be placed into the following categories:
* M0: no evidence of metastatic disease.
* must include a negative CSF cytology result
* M1: Tumor cells found in the CSF but no other evidence of metastasis
* M2: Intracranial tumor beyond the primary tumor site
* M3: Metastatic disease in the spine
* M4: Extraneural metastatic disease
* \*All participants are to undergo CSF cytologic examination regardless of presence or absence of gross metastatic disease unless procedure is medically contraindicated. CSF is to be obtained by lumbar puncture (LP) performed at least 10 days after surgery. If LP is medically contraindicated, ventricular CSF from a shunt or Ommaya reservoir may be used for staging but this is not the preferred option due to lower sensitivity. If LP is medically contraindicated and the patient doesn't have a shunt or reservoir for CSF sampling, the treating physician should reach out to PI or Co-PI regarding decision on enrollment to SJiMB21. The decision to enroll without CSF cytology will be made on case-by-case basis.
* Note: Participants who have M2 disease and positive CSF will be assigned to M3.
* Note: Participants will be assigned to the highest stage number for which they meet eligibility.
* Note: Treatment stratums may have additional stage requirements.
* Patient must have received no previous radiotherapy, chemotherapy, or other brain tumor-directed therapy other than corticosteroid therapy and surgery.
* Participant must have a Lansky performance score of \> 30 (except for patients with posterior fossa syndrome.
* Participant must have adequate organ function prior to study entry, as defined by:
* Absolute neutrophil counts (ANC) \>750/mm\^3
* Platelet count ≥ 50,000/mm\^3 without support of a platelet transfusion within 7 days
* Hemoglobin ≥8.0 g/dL (with or without support of a blood transfusion).
* Normal liver function as defined by Alanine aminotransferase (ALT) concentration ≤ 3 x 45 U/L and total bilirubin ≤ 3 x 1.0.
* Adequate renal function as defined by a serum creatinine concentration:
* Age - 0 to \<1year; Maximum Serum Creatinine (mg/dl) - Male 0.5; Female 0.5
* Age - 1 to \< 2years; Maximum Serum Creatinine (mg/dl) - Male 0.6; Female 0.6
* Age - 1 to \< 2yearsr; Maximum Serum Creatinine (mg/dl) - Male 0.8; Female 0.8
* Participant's parent or legal guardian has the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines.
Inclusion Criteria - Stratum S-2
* Participant must have confirmed diagnosis of the following medulloblastoma molecular group and subgroup per Central Review.
* Medulloblastoma SHH-2
* Participant must meet one of the following criteria at time of enrollment:
* Age \<36 months OR Age ≥ 36 months and \< 60 months with non-metastatic disease (M0) Inclusion Criteria - Stratum S-1
* Participant must have confirmed diagnosis of one of the following medulloblastoma molecular subgroups per Central Review.
* Medulloblastoma SHH-1
* Medulloblastoma SHH-3
* Medulloblastoma SHH-4
* Medulloblastoma SHH-NOS
* Includes medulloblastoma cases that could not be assigned to a molecular subgroup using the DNA methylation classifier, but which are in the SHH group and/or cases defined as SHH by IHC.
* Participant must be \< 36 months of age at time of enrollment
* Note: Patients who are \< 36 months of age, regardless of metastatic status (M0/M+), are eligible for enrollment on stratum S-1.
Inclusion Criteria - Stratum N
* Participant must have confirmed diagnosis of one of the following medulloblastoma molecular subgroups per Central Review.
* Medulloblastoma G3
* Medulloblastoma G4
* Medulloblastoma - Not classified into SHH (i.e., NWNS or indeterminate)
* Includes medulloblastoma cases that could not be assigned to a molecular group using the DNA methylation classifier but which are in the NWNS class and/or defined as NWNS by IHC.
* Participant must be \<36 months of age at time of enrollment
* All NWNS patients (M+ and M0) are eligible for enrollment in stratum N
Exclusion Criteria - All Patients
* CNS embryonal tumor other than medulloblastoma, for example, patients with diagnosis of Atypical Teratoid/Rhabdoid Tumor (ATRT), PNET, Pineoblastoma, Ependymoma, and ETMR are excluded.
* Participant with prior treatment for medulloblastoma, including:
* Radiotherapy
* Chemotherapy
* Cancer directed immunotherapy
* Targeted agents
* NOTE: Corticosteroid therapy is acceptable; prior treatment with chemotherapy, immunotherapy or targeted agents for non-cancer directed indications are acceptable as long as these have been stopped at least 14 days prior to start of therapy or 2 half-lives from last dose. (i.e., methotrexate for juvenile rheumatoid arthritis, JAK inhibitor therapy for eczema, etc.)
* Participant who is actively receiving any other investigational agents.
* Participant with other clinically significant medical disorders (i.e., serious infections or significant cardiac, pulmonary, hepatic, psychiatric, or other organ dysfunction) that could compromise their ability to tolerate protocol therapy or would interfere with the study procedures or results.
PROCEDURE: Surgical resection, PROCEDURE: Ommaya/VPS, DRUG: Methotrexate, DRUG: Cisplatin, DRUG: Vincristine, DRUG: Cyclophosphamide, DRUG: Carboplatin, DRUG: Topotecan, DRUG: Etoposide, DRUG: Pegfilgrastim, DRUG: Filgrastim, RADIATION: Irradiation, OTHER: Educational and Media Intervention, OTHER: SOC, Educational and Media Intervention
Medulloblastoma, Brain and Nervous System
SJiMB21, Brain Cancer, Brain Tumors in Children, Medulloblastoma Sonic Hedgehog subgroup 1, Medulloblastoma Sonic Hedgehog subgroup 2, Medulloblastoma Sonic Hedgehog subgroup 3, Medulloblastoma Sonic Hedgehog subgroup 4, Medulloblastoma Sonic Hedgehog-not otherwise specified, Medulloblastoma G3, Medulloblastoma G4, Medulloblastoma indeterminate, MLPNet, Neural Net Classification Pipeline, Non-WNT non-SHH medulloblastoma, Posterior fossa syndrome, St. Jude Brain Tumor Studies, Treatment for Brain Tumors in Infants and Young Children, Untreated Childhood Medulloblastoma
Blood-BrainBarrier Disruption (BBBD) for Liquid Biopsy in Subjects With GlioBlastomaBrainTumors
The purpose of this study is to evaluate the safety and efficacy of targeted blood brain
barrier disruption with Exablate Model 4000 Type 2.0/2.1 for liquid biopsy in subjects with
suspected Glioblastoma brain tumors
• Male or Female between >18-80 years of age who are able and willing to give informed
consent
• Subjects with stereotactically-targetable suspected glioblastoma tumor on
pre-operative brain imaging scans
• Subjects that are scheduled, or will be scheduled within 4 weeks, for surgical
resection or biopsy per standard clinical tumor care
• Karnofsky Performance Score >70
• Able to communicate sensations during the Exablate BBBD procedure
Exclusion Criteria:
• Tumor originating from the deep midline, thalamus, midbrain, cerebellum or brainstem.
• Multifocal tumors
• Tumor morphology or other imaging findings that precludes the ability to sonicate the
planned tumor volume (including significant tumor volume outside the treatment
envelope or tumor volume that exceeds the maximum sonication volume allowed, i.e.
currently 110 ccs at the treatment volume level). Concern for adequate tumor coverage
by sonication based on tumor morphology should be discussed with the Sponsor.
• MRI or clinical findings of:
• Active or chronic infection(s) or inflammatory processes
• Acute or chronic hemorrhages, specifically any lobar microbleeds, and no
siderosis, amyloid angiopathy, or macro-hemorrhages
• Intracranial thrombosis, vascular malformation, cerebral aneurysm or vasculitis
• MR non-compatible metallic implants in the skull or the brain or the presence of
unknown MR unsafe devices
• Significant cardiac disease or unstable hemodynamic status
• Documented myocardial infarction within six months of enrollment
• Unstable angina on medication
• Unstable or worsening congestive heart failure
• Left ventricular ejection fraction below the lower limit of normal
• History of a hemodynamically unstable cardiac arrhythmia
• Cardiac pacemaker
• History of hypersensitivity to Perflutren lipid microsphere or its components,
e.g., polyethylene glycol
• Uncontrolled hypertension (systolic > 180 and diastolic BP > 120 on medication)
• Unable to discontinue use of anti-coagulant/antiplatelet therapy as per local
standard.
• History of a liver disease, bleeding disorder, coagulopathy or a history of
spontaneous hemorrhage or evidence of increased risk of bleeding
• Abnormal coagulation profile (Platelets < 80,000), PT (>14) or PTT (>36), and INR >
• 3
• Known cerebral or systemic vasculopathy
• Significant depression and at potential risk of suicide
• Known sensitivity/allergy to gadolinium or DEFINITY,
• Active seizures despite medication treatment (defined as >1 seizure per week) which
could be worsened by disruption of the blood brain barrier
• Active drug or alcohol disorder which have a higher risk for seizures, infection
and/or poor executive functioning
• Positive HIV status, which can lead to increased entry of HIV into the brain
parenchyma leading to HIV encephalitis
• Potential blood-borne infections which can lead to increased entry to brain parenchyma
leading to meningitis or brain abscess
• Any contraindications to MRI scanning, including:
• Large subjects not fitting comfortably into the scanner
• Difficulty lying supine and still for up to 3 hours in the MRI unit or
claustrophobia
• Impaired renal function with estimated glomerular filtration rate <30 mL/min/1.73m2
• Severe Respiratory Illness: chronic pulmonary disorders e.g. severe emphysema,
pulmonary vasculitis, or other causes of reduced pulmonary vascular cross-sectional
area, subjects with a history of severe drug allergies, asthma or hay fever, and
multiple allergies where the benefit/risk of administering Definity® is considered
unfavorable by the study physicians in relation to the product labeling for Definity
• Currently in a clinical trial involving an investigational product or non-approved use
of a drug or device
• Pregnancy or Lactation
Device: Focused Ultrasound (Exablate Model 4000)
Glioma, Glioblastoma, Brain and Nervous System, Liquid Biopsy
This pilot trial compares drug exposure levels using a new method for dosing vincristine in infants and young children compared to the standard dosing method based on body surface area (BSA) in older children. Vincristine is an anticancer drug used to a variety of childhood cancers. The doses anticancer drugs in children must be adjusted based on the size of the child because children vary significantly in size (height, weight, and BSA) and ability to metabolize drugs from infancy to adolescence. The dose of most anticancer drugs is adjusted to BSA, which is calculated from a patient's weight and height. However, infants and young children have more severe side effects if the BSA is used to calculate their dose, so new dosing models have to be made to safely give anticancer drugs to the youngest patients. This new method uses a BSA-banded approach to determine the dose. Collecting blood samples before and after a dose of the drug will help researchers determine whether this new vincristine dosing method results in equivalent drug levels in the blood over time in infants and young children compared to older children.
* Patients must be =\< 12 years of age at the time of study enrollment. Patients will be stratified into 4 age groups:
* 0 to 6 months
* 6 months and 1 day to 12 months
* 12 months and 1 day to 36 months
* 36 months and 1 day to 12 years with a BSA ≥ 0.6 m\^2
* Newly diagnosed and relapsed cancer diagnosis that is being treated with vinCRIStine at the 1.5 mg/m\^2 dose level
* Any disease status
* Patients must have a Lansky performance status of 50 or higher
* Patients must be receiving a treatment regimen that includes 1.5 mg/m\^2 vinCRIStine (maximum dose 2 mg)
* Patients with a BSA \< 0.6 m\^2 must be dosed according to the Children's Oncology Group (COG) BSA-banded infant dosing table for the 1.5mg/m2 dose level for vinCRIStine
* Note: Patients can be studied after any dose of vinCRIStine
* Patients who are NOT enrolled on a COG clinical trial and who have a BSA \< 0.6 m\^2 and who are being dosed according to another infant dosing method (e.g., the 30-Rule) can receive a dose of vinCRIStine from the infant dosing table for the pharmacokinetic study. These patients will NOT be part of the Dose Modification Assessment
* Patients with a seizure disorder may be enrolled if on allowable anticonvulsants and well controlled as evidenced by no increase in seizure frequency in the prior 7 days
* Nervous system toxicities (Common Terminology Criteria for Adverse Events \[CTCAE\]) version (v)5 resulting from prior therapy must be grade =\< 2
* Central venous access device in place (e.g., percutaneous indwelling central catheter \[PICC\], port, Broviac) or scheduled to be placed prior to the dose of vinCRIStine and that can be used for pharmacokinetic (PK) sampling
* VinCRIStine may be given as an outpatient, as long as all sample time points can be collected, which will require return for hour 24 sampling
Exclusion Criteria:
* Azoles antifungals and macrolide antibiotics: Patients who are currently receiving an azole or macrolide (e.g., fluconazole, isavuconazole, itraconazole, posaconazole, voriconazole, ketoconazole, eryromycin, clarithromycin, azithromycin, roxithromycin, or telithromycin) are not eligible
* CYP3A4/5 inducers/inhibitors: Patients receiving any medications or substances that are considered moderate or strong inhibitors or inducers of CYP3A4/5 are not eligible. Moderate or strong inducers or inhibitors of CYP3A4/5 should be avoided from 14 days prior to enrollment to the end of the study.
* Note the following are allowed:
* Dexamethasone for CNS tumors or metastases, on a stable dose
* Aprepitant for management of nausea and vomiting
* Anticonvulsants: Patients receiving moderate or strong CYP3A4/5 enzyme inducing anticonvulsants are not eligible.
* Patients with Charcot-Marie-Tooth disease
* A baseline neurological disorder with manifestations that overlap with vinCRIStine-associated neurotoxicities
* Patients being treated on a Children Oncology Group (COG) clinical trial, that does not use the infant dosing tables for vinCRIStine are not eligible for this study.
* Patients receiving a modified dose (\< 1.5 mg/m\^2) of vinCRIStine due to prior toxicity
* Patients who in the opinion of the investigator may not be able to comply with the sampling requirements of the study
Study of XL092 in Combination With Immuno-Oncology Agents in Subjects With Solid Tumors (STELLAR-002)
This is a multicenter Phase 1b, open label, dose-escalation and cohort-expansion study,
evaluating the safety, tolerability, PK, preliminary antitumor activity, and effect of
biomarkers of XL092 administered alone, and in combination with nivolumab (doublet),
nivolumab + ipilimumab (triplet) and nivolumab + relatlimab (triplet) in subjects with
advanced solid tumors.
In the Expansion Stage, the safety and efficacy of XL092 as monotherapy and in combination
therapy will be further evaluated in tumor-specific Expansion Cohorts.
• Cytologically or histologically confirmed solid tumor that is unresectable, locally
advanced or metastatic.
• Dose-Escalation Cohorts: Subjects with a solid tumor that is unresectable or
metastatic and for which life-prolonging therapies do not exist or available therapies
are intolerable or no longer effective.
• Expansion Cohort 1 (ccRCC): Subjects with unresectable advanced or metastatic RCC with
a clear cell component who have not received prior systemic therapy.
• Note: Prior non-VEGF targeted adjuvant or neoadjuvant is allowed if disease
recurrence occurred 6 months after the last dose.
• Expansion Cohort 2 (ccRCC): Subjects with unresectable advanced or metastatic RCC with
a clear cell component.
• Must have radiographically progressed after a combination therapy consisting of a
PD-1/PD-L1 targeting mAb with a VEGFR-TKI or a PD-1 targeting mAb with a CTLA-4
mAb as the preceding line of therapy.
• Must have received no more than one prior systemic anticancer therapy for
unresectable advanced or metastatic renal cell carcinoma.
• Expansion Cohort 3 (mCRPC): Men with metastatic adenocarcinoma of the prostate.
• Must have progressed during or after one NHT given for castration-sensitive
locally advanced (T3 or T4) or metastatic castration-sensitive prostate cancer
(CSPC), M0 CRPC, or mCRPC.
• Expansion Cohort 4 (UC, ICI-naive): Subjects with histologically confirmed
unresectable, locally advanced or metastatic transitional cell carcinoma of the
urothelium (including the renal pelvis, ureter, urinary bladder, or urethra).
• Must have progressed during or after prior first-line platinum-based combination
therapy, including subjects who received prior neoadjuvant or adjuvant
platinum-containing therapy with disease recurrence < 12 months from the end of
last therapy.
• Must have received no more than 1 prior line of systemic anticancer therapy for
unresectable, locally advanced or metastatic disease.
• Expansion Cohort 5 (UC, ICI-experienced): Subjects with histologically confirmed
unresectable, locally advanced or metastatic transitional cell carcinoma of the
urothelium (including the renal pelvis, ureter, urinary bladder, or urethra).
• Must have progressed during or after prior PD-1/PD-L1 targeting ICI therapy given
as monotherapy, combination therapy, maintenance therapy or adjuvant therapy.
• Must have received no more than 2 prior lines of systemic anticancer therapy for
unresectable advanced or metastatic disease.
• Expansion Cohort 6 (nccRCC): Subjects with unresectable advanced or metastatic nccRCC
of the following subtypes: Papillary RCC (any type), unclassified RCC, and
translocation-associated. Among the eligible histologic subtypes, sarcomatoid features
are allowed.
• No prior systemic anticancer therapy is allowed except adjuvant or neoadjuvant
therapy if disease recurrence occurred at least 6 months after the last dose.
• Expansion Cohort 7 (HCC): Subjects with inoperable locally advanced, recurrent, or
metastatic HCC that is not amenable to curative treatment or locoregional therapy.
• Expansion Cohort 8 (NSCLC): Subjects with Stage IV non-squamous NSCLC with positive
PD-L1 expression (tumor proportion score [TPS] 1-49%) and without prior systemic
anticancer therapy for metastatic disease.
• Expansion Cohort 9 (NSCLC): Subjects with Stage IV non-squamous NSCLC who have
radiologically progressed following treatment with one prior immune checkpoint
inhibitor (anti-PD-1 or anti-PD-L1) for metastatic disease.
• Expansion Cohort 10 (CRC): Subjects with histologically confirmed unresectable,
locally advanced, or metastatic adenocarcinoma of the colon or rectum.
• Expansion Cohort 11 (HNSCC): Subject with inoperable, refractory, recurrent or
metastatic HNSCC of the oral cavity, oropharynx, hypopharynx, and larynx. PD-L1
combined positive score (CPS) ≥1.
• For all Expansion Cohorts except Cohort 3: Measurable disease per RECIST 1.1 as
determined by the Investigator.
• For expansion cohorts only: Archival tumor tissue material, if available, or fresh
tumor tissue if it can be safely obtained.
• Recovery to baseline or ≤ Grade 1 CTCAE v5 from AE(s) related to any prior treatments
unless AE(s) are deemed clinically nonsignificant by the Investigator and/or stable on
supportive therapy.
• Karnofsky Performance Status (KPS) ≥ 70%.
• Adequate organ and marrow function.
• Sexually active fertile subjects and their partners must agree to use highly effective
methods of contraception.
• Female subjects of childbearing potential must not be pregnant at screening.
Exclusion Criteria:
• For all Dose-Escalation cohorts: Prior treatment with XL092. For all Expansion
Cohorts: Prior treatment with XL092, nivolumab, ipilimumab or relatlimab with the
following exceptions: Prior PD-1/PD-L1, LAG-3 and CTLA-4 targeting therapy for locally
advanced or metastatic disease is allowed for Cohort 2 (ccRCC), Cohort 5 (UC), Cohort
9 (NSCLC).
• For all Dose-Escalation Cohorts and Expansion Cohort 2 (ccRCC), 3 (mCRPC), Cohort 5
(UC), Cohort 9 (NSCLC) and Cohort 10 (CRC): Receipt of any type of small molecule
kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before
first dose of study treatment.
• For Cohort 3 (mCRPC): Receipt of abiraterone within 1 week; cyproterone within 10
days; or receipt of flutamide, nilutamide, bicalutamide, enzalutamide, or other
androgen receptor inhibitors within 2 weeks before first dose of study treatment.
• For all Dose-Escalation Cohorts and Expansion Cohort 2 (ccRCC), Cohort 3 (mCRPC),
Cohort 5 (UC), Cohort 9 (NSCLC) and Cohort 10 (CRC): Receipt of any type of anticancer
antibody or systemic chemotherapy within 4 weeks before first dose of study treatment.
• Any complementary medications (eg, herbal supplements or traditional Chinese
medicines) to treat the disease under study within 2 weeks before first dose of study
treatment.
• Prior external radiation therapy for bone metastasis within 2 weeks, for other tumor
sites within 4 weeks, and prior radium-223 therapy within 6 weeks before first dose of
study treatment, unless otherwise specified.
• Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy (including radiosurgery) or surgically removed and stable for at least 4
weeks before first dose of study treatment.
• Concomitant anticoagulation with oral anticoagulants and platelet inhibitors.
• Administration of a live, attenuated vaccine within 30 days prior to enrollment.
• Uncontrolled, significant intercurrent or recent illness.
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per
electrocardiogram (ECG) within 14 days before first dose of study treatment.
• Subjects with inadequately treated adrenal insufficiency.
• Pregnant or lactating females.
• Any other active malignancy within two years before first dose of study treatment,
except for locally curable cancers that have been apparently cured such as basal or
squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the
prostate, cervix, or breast.
• For Cohort 2 (ccRCC, 2L): Receipt of a prior triplet therapy including a VEGFR-TKI, a
PD1 targeting mAb, and a CTLA-4 mAb.
• For Cohort 3 (mCRPC): Receipt of a taxane-based chemotherapy for mCRPC.
• For Cohort 4 (UC, ICI-naïve): Subjects who have had recurrence within the 6 months of
completing adjuvant anti-PD-(L)1 treatment.
• For Cohort 6 (nccRCC, 1L): Subjects with chromophobe, renal medullary carcinoma, or
pure collecting duct nccRCC.
• For Cohort 7 (HCC):
• Documented hepatic encephalopathy (HE) within 6 months before randomization (see
Section 6.5.2 for a case definition of HE).
• Clinically meaningful ascites (ie, ascites requiring paracentesis or escalation
in diuretics) within 6 months before randomization.
• Subjects who have received any local anticancer therapy including surgery, PEI,
RFA, MWA, transarterial chemoembolization (TACE), or transarterial
radioembolization (TARE) within 28 days prior to randomization.
• Subjects with known fibrolamellar carcinoma, sarcomatoid HCC, or mixed
hepatocellular cholangiocarcinoma
• For Cohort 10 (CRC, 2L+): Receipt of prior therapy with regorafenib and/or TAS-102.
• For Cohort 11 (HNSCC): Primary tumor site of the nasopharyngeal area.
• For Cohorts 1 (ccRCC, 1L), 2 (ccRCC, 2L), 4, 5 (UC), 7 (HCC), 8 (NSCLC 1L PD-L1 low),
9 (NSCLC, 2L+), 10 (CRC, MSS, 2L+), and 11 (HNSCC):
• Troponin T (TnT) or I (TnI) > 2 × institutional ULN.
Note: Additional Inclusion and Exclusion criteria may apply.
A Study of the Drug Selinexor With Radiation Therapy in Patients With Newly-Diagnosed Diffuse Intrinsic Pontine (DIPG) Glioma and High-Grade Glioma (HGG)
This phase I/II trial tests the safety, side effects, and best dose of selinexor given in combination with standard radiation therapy in treating children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG) with a genetic change called H3 K27M mutation. It also tests whether combination of selinexor and standard radiation therapy works to shrink tumors in this patient population. Glioma is a type of cancer that occurs in the brain or spine. Glioma is considered high risk (or high-grade) when it is growing and spreading quickly. The term, risk, refers to the chance of the cancer coming back after treatment. DIPG is a subtype of HGG that grows in the pons (a part of the brainstem that controls functions like breathing, swallowing, speaking, and eye movements). This trial has two parts. The only difference in treatment between the two parts is that some subjects treated in Part 1 may receive a different dose of selinexor than the subjects treated in Part 2. In Part 1 (also called the Dose-Finding Phase), investigators want to determine the dose of selinexor that can be given without causing side effects that are too severe. This dose is called the maximum tolerated dose (MTD). In Part 2 (also called the Efficacy Phase), investigators want to find out how effective the MTD of selinexor is against HGG or DIPG. Selinexor blocks a protein called CRM1, which may help keep cancer cells from growing and may kill them. It is a type of small molecule inhibitor called selective inhibitors of nuclear export (SINE). Radiation therapy uses high energy to kill tumor cells and shrink tumors. The combination of selinexor and radiation therapy may be effective in treating patients with newly-diagnosed DIPG and H3 K27M-Mutant HGG.
* PRE ENROLLMENT: Patients must be =\< 25 years of age at the time of enrollment on APEC14B1 part A cnetral nervous system (CNS)/high grade glioma (HGG) pre-enrollment eligibility screening
* Please note:
* This required age range applies to pre-enrollment eligibility for all HGG patients. Individual treatment protocols may have different age criteria.
* Non-DIPG patients with tumors that do not harbor an H3K27M-mutation and are \>= 18 years of age will not be eligible to enroll on ACNS1821 (Step 1).
* PRE ENROLLMENT: Patient is suspected of having localized, newly diagnosed HGG, excluding metastatic disease, OR patient has an institutional diagnosis of DIPG
* Please note: there are specific radiographic criteria for DIPG patient enrollment on ACNS1821 (Step 1)
* PRE ENROLLMENT:
* For patients with non-pontine tumors: Patients and/or their parents or legal guardians must have signed informed consent for eligibility screening on APEC14B1 Part A.
* For patients with DIPG: Patients and/or their parents or legal guardians must have signed informed consent for ACNS1821.
* PRE ENROLLMENT:
* For patients with non-pontine tumors only, the specimens obtained at the time of diagnostic biopsy or surgery must be submitted through APEC14B1 ASAP, preferably within 5 calendar days of definitive surgery
* STEP 1: Patients must be \>= 12 months and =\< 21 years of age at the time of enrollment
* STEP 1: Patients must have newly-diagnosed DIPG or HGG (including DMG).
* STEP 1: Stratum DIPG
* Patients with newly-diagnosed typical DIPG, defined as tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons on at least 1 axial T2 weighted image, are eligible. No histologic confirmation is required.
* Patients with pontine tumors that do not meet radiographic criteria for typical DIPG (e.g., focal tumors or those involving less than 2/3 of the pontine cross-sectional area with or without extrapontine extension) are eligible if the tumors are biopsied and proven to be high-grade gliomas (such as anaplastic astrocytoma, glioblastoma, high-grade glioma not otherwise specified \[NOS\], and/or H3 K27M-mutant) by institutional diagnosis.
* STEP 1: Stratum DMG (with H3 K27M mutation)
* Patients must have newly-diagnosed non-pontine H3 K27M-mutant HGG without BRAF V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1
* Note: Patients need not have either measurable or evaluable disease, i.e., DMG patients may have complete resection of their tumor prior to enrollment. Primary spinal tumors are eligible for enrollment. For rare H3 K27M-mutant HGG in non-midline structures (e.g., cerebral hemispheres), these patients will be considered part of Stratum DMG.
* STEP 1: Stratum HGG (without H3 K27M mutation)
* Patients must have newly-diagnosed non-pontine H3 K27M-wild type HGG without BRAF V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1
* Please note:
* Patients who fall in this category and who are \>= 18 years of age are not eligible due to another standard-of-care regimen (radiation/temozolomide) that is available
* Patients need not have either measurable or evaluable disease, i.e., HGG patients may have complete resection of their tumor prior to enrollment. Primary spinal tumors are eligible for enrollment
* STEP 1: Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients \> 16 years of age and Lansky for patients =\<16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
* STEP 1: Peripheral absolute neutrophil count (ANC) \>= 1000/uL (within 7 days prior to step 1 enrollment)
* STEP 1: Platelet count \>= 100,000/uL (transfusion independent) (within 7 days prior to step 1 enrollment)
* STEP 1: Hemoglobin \>= 8.0 g/dL (may receive red blood cell \[RBC\] transfusions) (within 7 days prior to step 1 enrollment)
* STEP 1: Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 (within 7 days prior to step 1 enrollment) or
A serum creatinine based on age/gender as follows (within 7 days prior to step 1 enrollment):
* Age / Maximum Serum Creatinine (mg/dL)
* 1 to \< 2 years / male: 0.6; female: 0.6
* 2 to \< 6 years / male: 0.8; female: 0.8
* 6 to \< 10 years / male: 1; female: 1
* 10 to \< 13 years / male: 1.2; female: 1.2
* 13 to \< 16 years / male: 1.5; female: 1.4
* \>= 16 years / male: 1.7; female: 1.4
* STEP 1: Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age
* STEP 1: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.
* STEP 1: Serum amylase =\< 1.5 x ULN
* STEP 1: Serum lipase =\< 1.5 x ULN
* STEP 1: No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry \> 94% if there is clinical indication for determination.
* STEP 1: Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
* STEP 1: Patients must be enrolled and protocol therapy must begin no later than 31 days after the date of radiographic diagnosis (in the case of non-biopsied DIPG patients only) or definitive surgery, whichever is the later date (Day 0).
For patients who have a biopsy followed by resection, the date of resection will be considered the date of definitive diagnostic surgery. If a biopsy only was performed, the biopsy date will be considered the date of definitive diagnostic surgery.
Exclusion Criteria:
* STEP 1: Patients must not have received any prior therapy for their central nervous system (CNS) malignancy except for surgery and steroid medications.
* STEP 1: Patients who are currently receiving another investigational drug are not eligible.
* STEP 1: Patients who are currently receiving other anti-cancer agents are not eligible.
* STEP 1: Patients \>=18 years of age who have H3 K27M-wild type HGG.
* STEP 1: Patients who have an uncontrolled infection.
* STEP 1: Patients who have received a prior solid organ transplantation.
* STEP 1: Patients with grade \> 1 extrapyramidal movement disorder.
* STEP 1: Patients with known macular degeneration, uncontrolled glaucoma, or cataracts.
* STEP 1: Patients with metastatic disease are not eligible; MRI of spine with and without contrast must be performed if metastatic disease is suspected by the treating physician.
* STEP 1: Patients with gliomatosis cerebri type 1 or 2 are not eligible, with the exception of H3 K27M-mutant bithalamic tumors.
* STEP 1: Patients who are not able to receive protocol specified radiation therapy.
* STEP 1:
* Female patients who are pregnant are ineligible since there is yet no available information regarding human fetal or teratogenic toxicities.
* Lactating females are not eligible unless they have agreed not to breastfeed their infants. It is not known whether selinexor is excreted in human milk.
* Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
* Sexually active patients of reproductive potential are not eligible unless they have agreed to use two effective methods of birth control (including a medically accepted barrier method of contraception, e.g., male or female condom) for the duration of their study participation and for 90 days after the last dose of selinexor. Abstinence is an acceptable method of birth control.
Pediatric Radiation Oncology With Movie Induced Sedation Effect (PROMISE)
PROMISE (Pediatric Radiation Oncology with Movie Induced Sedation Effect) is an interactive incentive-based movie system that integrates with a video surveillance gating module (VisionRT) as an alternative sedation solution for pediatric patients undergoing radiation treatment (RT). This single-arm, open label, single-center phase II clinical trial is to implement PROMISE for all children ages 3-11 who are planned to undergo RT at the institution. The primary goal is to decrease the total number of pediatric patients who require general anesthesia through the use of PROMISE, with secondary goals being to assess the impact that PROMISE has on patient/family anxiety and quality of life, treatment time and clinical efficiency, and overall cost. The investigators hypothesize that PROMISE will lead to a reduction in the percentage of patients ages 3-7 who require general anesthesia use from 70% (historical control) to 30%.
• Planned to undergo radiation treatment
• Age 3-11 years
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening
• Parents or guardians with the ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria:
• Subjects with documented medical behavior conditions or other conditions necessitating anesthesia use
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements.
• Subjects whose parents opt to not include them (the subject) in the clinical trial.
OTHER: PROMISE (Pediatric Radiation Oncology with Movie Induced Sedation Effect)
Multiple Myeloma, Pediatric Cancer, Brain and Nervous System, Eye and Orbit, Bones and Joints, Kidney, Lip, Oral Cavity and Pharynx, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Rectum, Thyroid, Leukemia, Other, Leukemia, Not Otherwise Specified, Lymphoid Leukemia, Myeloid and Monocytic Leukemia, Non-Hodgkins Lymphoma, Other Hematopoietic, Soft Tissue
Testing the Addition of the Chemotherapy Drug Lomustine (Gleostine®) to the Usual Treatment (Temozolomide and Radiation Therapy) for Newly Diagnosed MGMT Methylated Glioblastoma
This phase III trial compares the effect of adding lomustine to temozolomide and radiation
therapy versus temozolomide and radiation therapy alone in shrinking or stabilizing newly
diagnosed MGMT methylated glioblastoma. Chemotherapy drugs, such as lomustine and
temozolomide, work in different ways to stop the growth of tumor cells, either by killing the
cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy
uses high energy photons to kill tumor cells and shrink tumors. Adding lomustine to usual
treatment of temozolomide and radiation therapy may help shrink and stabilize glioblastoma.
• STEP 1 REGISTRATION: No known IDH mutation. (If tested before step 1 registration,
patients known to have IDH mutation in the tumor on local or other testing are
ineligible and should not be registered)
• STEP 1 REGISTRATION: Availability of formalin-fixed paraffin-embedded (FFPE) tumor
tissue block and hematoxylin and eosin (H&E) stained slide to be sent for central
pathology review for confirmation of histology and MGMT promoter methylation status.
Note that tissue for central pathology review and central MGMT assessment must be
received by the NYU Center for Biospecimen Research and Development (CBRD) on or
before postoperative calendar day 30. If tissue cannot be received by postoperative
calendar day 30, then patients may NOT enroll on this trial as central pathology
review will not be complete in time for the patient to start treatment no later than 8
weeks following surgery. Results of central pathology review and central MGMT analysis
will generally be conveyed to NRG Oncology within 10 business days of receipt of
tissue. Note: In the event of an additional tumor resection(s), tissue must be
received within 30 days of the most recent resection and the latest resection must
have been performed within 30 days after the initial resection. Surgical resection is
required; stereotactic biopsy alone is not allowed because it will not provide
sufficient tissue for MGMT analysis
• STEP 1 REGISTRATION: Contrast-enhanced brain MRI after surgery
• STEP 1 REGISTRATION: Willing to use highly effective method of contraception for
participants of childbearing potential (participants who may become pregnant or who
may impregnate a partner) during therapy and for 6 months after completing treatment;
this inclusion is necessary because the treatment in this study may be significantly
teratogenic
• STEP 1 REGISTRATION: The patient or a legally authorized representative must provide
study-specific informed consent prior to study entry and, for patients treated in the
United States (U.S.), authorization permitting release of personal health information
• STEP 2 REGISTRATION: Histopathologically proven diagnosis of glioblastoma (or
gliosarcoma as a subtype of glioblastoma) confirmed by central pathology review
• STEP 2 REGISTRATION: MGMT promoter with methylation confirmed by central pathology
review (See Section 10 for details). Note: Patients with tissue that is insufficient
or inadequate for analysis, fails MGMT testing, or has indeterminate or unmethylated
MGMT promoter are excluded.
• STEP 2 REGISTRATION: IDH mutation testing by at least one method (such as
immunohistochemistry for IDH1 R132H) must be performed as part of standard of care and
no mutation must be found (i.e IDH wildtype). (If a mutation is identified then the
patient will be ineligible and must be registered as ineligible at Step 2.)
• STEP 2 REGISTRATION: History/physical examination within 28 days prior to Step 2
registration
• STEP 2 REGISTRATION: Karnofsky performance status (KPS) >= 70 within 28 days prior to
Step 2 registration
• STEP 2 REGISTRATION: Neurologic function assessment within 28 days prior to Step 2
registration
• STEP 2 REGISTRATION: Age 18-70 years
Adequate hematologic, renal, and hepatic function within 14 days prior to STEP 2
REGISTRATION defined as follows:
• STEP 2 REGISTRATION: Hemoglobin >= 10 g/dl (Note: the use of transfusion or other
intervention to achieve hemoglobin (Hgb) >= 10.0 g/dl is acceptable)
• STEP 2 REGISTRATION: Leukocytes >= 2,000/mm^3
• STEP 2 REGISTRATION: Absolute neutrophil count >= 1,500/mm^3
• STEP 2 REGISTRATION: Platelets >= 100,000/mm^3
• STEP 2 REGISTRATION: Total bilirubin =< 1.5 x institutional/lab upper limit of normal
(ULN)
• STEP 2 REGISTRATION: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic
transaminase [SGOT]) =< 2.5 x ULN
• STEP 2 REGISTRATION: Alanine aminotransferase (ALT) (serum glutamate pyruvate
transaminase [SGPT]) =< 2.5 x ULN
• STEP 2 REGISTRATION: Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >=
50 mL/min (if using the Cockcroft-Gault formula
• STEP 2 REGISTRATION: For patients with evidence of chronic hepatitis B virus (HBV)
infection, the HBV viral load must be undetectable on suppressive therapy, if
indicated
• Note: Known positive test for hepatitis B virus surface antigen (HBV sAg)
indicating acute or chronic infection would make the patient ineligible unless
the viral load becomes undetectable on suppressive therapy. Patients who are
immune to hepatitis B (anti-hepatitis B surface antibody positive) are eligible
(e.g. patients immunized against hepatitis B)
• STEP 2 REGISTRATION: For patients with a history of hepatitis C virus (HCV) infection
must have been treated and cured. For patients with HCV infection who are currently on
treatment, they are eligible if they have an undetectable HCV viral load
• Note: Known positive test for hepatitis C virus ribonucleic acid (HCV ribonucleic
acid [RNA]) indicating acute or chronic infection would make the patient
ineligible unless the viral load becomes undetectable on suppressive therapy
• STEP 2 REGISTRATION: Known human immunodeficiency virus (HIV) infected patients on
effective anti-retroviral therapy with undetectable viral load within 6 months prior
to step 2 registration are eligible for this trial. Testing is not required for entry
into protocol
• STEP 2 REGISTRATION: Negative serum or urine pregnancy test (in persons of
childbearing potential) within 14 days prior to Step 2 registration
• Childbearing potential is defined as any person who has experienced menarche and
who has not undergone surgical sterilization (hysterectomy or bilateral
oophorectomy) or who is not postmenopausal
Exclusion Criteria:
• STEP 2 REGISTRATION: Prior therapy for tumor, except for resection or prior laser
interstitial thermal therapy (LITT). For example, prior chemotherapy, immunotherapy,
or targeted therapy for GBM or lower grade glioma is disallowed (including but not
limited to temozolomide, lomustine, bevacizumab, any viral therapy, ipilimumab or
other CTLA-4 antibody, PD-1 antibody, CD-137 agonist, CD40 antibody, PDL-1 or 2
antibody, vaccine therapy, polio or similar viral injection as treatment for the
tumor, and/or any other antibody or drug specifically targeting T-cell co-stimulation
or immune checkpoint pathways) as is Gliadel wafer, radiotherapy, radiosurgery,
vaccine or other immunotherapy, brachytherapy, or convection enhanced delivery
• Note: 5-aminolevulinic acid (ALA)-mediated fluorescent guided resection (FGR)
photodynamic therapy (PDT) or fluorescein administered prior to/during surgery to
aid resection is not exclusionary and is not considered a chemotherapy or
intracerebral agent. Prior laser interstitial thermal therapy (LITT) is allowed.
• STEP 2 REGISTRATION: Current or planned treatment with any other investigational
agents for the study cancer
• STEP 2 REGISTRATION: Definitive clinical or radiologic evidence of metastatic disease
outside the brain
• STEP 2 REGISTRATION: Prior invasive malignancy (except non-melanomatous skin cancer,
cervical cancer in situ and melanoma in situ) unless disease free for a minimum of 2
years
• STEP 2 REGISTRATION: Prior radiotherapy to the head or neck that would result in
overlap of radiation therapy fields
• STEP 2 REGISTRATION: Pregnancy and individuals unwilling to discontinue nursing due to
the potential teratogenic effects and potential risk for adverse events in nursing
infants
• STEP 2 REGISTRATION: History of allergic reactions attributed to compounds of similar
chemical or biologic composition to temozolomide or lomustine
• STEP 2 REGISTRATION: History of pulmonary fibrosis
• STEP 2 REGISTRATION: Uncontrolled intercurrent illness including, but not limited to:
• Ongoing or active infection requiring IV antibiotics, IV antiviral, or IV
antifungal treatment
• Symptomatic congestive heart failure, defined as New York Heart Association
Functional Classification III/IV (Note: Patients with known history or current
symptoms of cardiac disease, or history of treatment with cardiotoxic agents,
should have a clinical risk assessment of cardiac function using the New York
Heart Association Functional Classification)
• Unstable angina pectoris within 6 months prior to Step 2 registration
• Uncontrolled cardiac arrhythmia
• Psychiatric illness/social situations that would limit compliance with study
requirements
• STEP 2 REGISTRATION: No evidence of diffuse leptomeningeal disease that requires whole
brain irradiation.
Olanzapine Versus Megestrol Acetate for the Treatment of Loss of Appetite Among Advanced Cancer Patients
This phase III trial compares the effects of olanzapine versus megestrol acetate in treating loss of appetite in patients with cancer that has spread to other places in the body (advanced). Olanzapine may stimulate and increase appetite. This study aims to find out if olanzapine is better than the usual approach (megestrol acetate) for stimulating appetite and preventing weight loss.
* Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom)
* Diagnosis of advanced cancer
* Patient-reported 2-month weight loss of at least 5 pounds (2.3 kilograms) and/or physician-estimated caloric intake of less than 20 calories/kilogram of body weight per day
* The patient must perceive loss of appetite and/or weight as a problem; and have an appetite score of 4 or worse on the "Please rate your appetite...." question that requires a patient response on a 0-10 numeric rating scale
* Not receiving ongoing tube feedings or parenteral nutrition at the time of registration
* Not currently using systemic adrenal steroids (with the exception of short-term dexamethasone within 3 days of chemotherapy for control of chemotherapy side effects)
* No use of androgens, progesterone analogs, or other appetite stimulants within the past month
* Patient should not have poorly controlled hypertension or congestive heart failure at registration
* Patient should not have an obstruction of the alimentary canal, malabsorption, or intractable vomiting (defined as vomiting more than 3 times per day over the preceding week)
* Not currently using olanzapine for another medical condition or had previously used olanzapine for chronic nausea or for any pre-existing psychotic disorder
* Patient should not have had a previous blood clot at any time in the past
* No history of poorly controlled diabetes
* No symptomatic leptomeningeal disease or known brain metastases as these patients may have difficulty taking oral medications
* No history of hypersensitivity to olanzapine or megestrol acetate
* No COVID-19 infection in the past that, in the opinion of the treating physician, had left patients with compromised taste, which has not resolved at the time of registration
* Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done =\< 14 days prior to registration is required
* Age \>= 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
* Estimated life expectancy of 3 months or longer
* Serum creatinine =\< 2.0 mg/dL
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =\< 3 x upper limit of normal (ULN)
* Fasting glucose \< 140 mg/dL
* Granulocytes \> 1000/hpf
* No treatment with another antipsychotic agent, such as risperidone, quetiapine, clozapine, butyrophenone within 30 days of enrollment
* In order to complete the mandatory patient-completed measures, participants must be able to speak and/or read English or Spanish. Sites seeking to enroll Spanish-speaking patients should have access to Spanish speaking staff on site or through the use of a translation service to be able to conduct the informed consent discussion in Spanish, and to conduct the weekly phone calls
Exclusion Criteria:
* Psychiatric illness which would prevent the patient from giving informed consent
* Medical condition such as uncontrolled infection (including human immunodeficiency virus \[HIV\]), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient
* Patients who cannot swallow oral formulations of the agents
* Patients with impaired decision-making capacity (such as with a diagnosis of dementia or memory loss) are not eligible for this study
* No presence of a hormone-sensitive tumor, such as breast, endometrial, or prostate cancer (this exclusion criterion is intended to circumvent any confounding antineoplastic effects of megestrol acetate)
A Study of Avapritinib in Pediatric Patients With Solid Tumors Dependent on KIT or PDGFRA Signaling
This is a Phase 1/2, multicenter, open-label trial of avapritinib in participants 2 to < 18
years of age with advanced relapsed/refractory (R/R) solid tumors, including central nervous
system (CNS) tumors, that harbor a PDGFRA and/or KIT mutation (including non-synonymous point
mutations, insertions, and deletions) or amplification, or DMG-H3K27a who have no available
curative treatment options. This is a single-arm trial in which all participants will receive
avapritinib. The study consists of 2 parts: dose confirmation, safety, and PK (Part 1) and
initial efficacy, safety, and PK at the Part 2 recommended dose (Part 2).
Inclusion Criteria
• Participant must be 2 to < 18 years of age at the time of signing the informed
consent.
• Diagnosis
• Participant has confirmed diagnosis of R/R solid tumor, including CNS tumors,
with a mutation (including non-synonymous point mutations, insertions, and
deletions) in PDGFRA and/or KIT (confirmed by local mutational testing of tumor
sample) that has progressed despite standard therapy and no alternative treatment
option is available. Participant with R/R solid tumors with only PDGFRA and/or
KIT amplifications may be included with approval from the Sponsor.
OR
• Participant has confirmed diagnosis of DMG-H3K27a (confirmed by local testing of
tumor sample) that has failed standard therapy or for which no standard therapy
that may convey clinical benefit exists, as judged by the investigator.
• Participants with CNS disease should be on a stable (≤ 10% change) or decreasing dose
of corticosteroids for at least 7 days prior to first dose of avapritinib, with no
plans for dose escalation.
• Disease extent: a. Part 1: All participants must have at least 1 measurable lesion as
defined by RECIST v1.1 or Response Assessment in Neuro-Oncology (RANO) (for CNS
tumors). If radiation therapy has been administered, at least 1 measurable lesion must
not have been irradiated, or must have clearly progressed since being irradiated as
per RANO and must be ≥ 12 weeks from radiation to any target lesion.
b. Part 2: All participants must have at least 1 measurable lesion as defined by
RECIST v1.1 or RANO (for CNS tumors). For Participants with DMG-H3K27a or PDGFRA
and/or KIT mutant/amplified solid tumors, including CNS tumors that have progressed
despite prior therapy, who have received radiation therapy, at least 1 measurable
lesion must not have been irradiated, or must have clearly progressed since being
irradiated as per RANO and must be ≥ 12 weeks from radiation to any target lesion. For
up to 5 Participants with newly diagnosed DMG-H3K27a where there is no standard
therapy that may convey clinical benefit exists as judged by the investigator,
progression of disease of a measurable lesion after irradiation is not required.
• A Lansky (< 16 years of age) or Karnofsky (≥ 16 years of age) score of at least 50. If
the Participant is unable to walk due to paralysis, but is mobile in a wheelchair, the
participant is considered ambulatory for the purpose of assessing their performance
status.
• Participant agrees to utilize contraception consistent with local regulations.
• Male participants: Are vasectomized, or agree to use condoms, as defined in
Section 5.4.2, from the start of Screening until 6 weeks after the last dose of
study treatment, or practice true abstinence (when this is in line with the
preferred and usual lifestyle of the Participant, see Section 5.4.2), or have a
female partner who is NOT of childbearing potential.
• Female participants: Agree to use effective contraception, as defined in Section
• 4.2, from the start of Screening until 6 weeks after the last dose of study
treatment and have a male partner who uses a condom, or practice true abstinence
(when this is in line with the preferred and usual lifestyle of the Participant),
or have a male partner who is vasectomized with confirmed azoospermia.
• Participant can give written informed consent/assent before any study-specific
Screening procedures (if feasible). Parental/legal guardian consent will be determined
by local, regional, and/or national guidelines.
Exclusion Criteria
• Participant has any of the following within 14 days before the first dose of study
treatment:
• Platelet count < 75 × 10^9/L (< 100 × 10^9/L if a CNS tumor) with no platelet
transfusion within 14 days prior to the measurement.
• Absolute neutrophil count (ANC) < 1.0 × 10^9/L.
• Hemoglobin < 8.0 g/dL with no RBC transfusion ≤ 7 days prior to the measurement.
• AST or ALT > 3 × the ULN for age; except in Participants with tumor involvement
of the liver who must not have AST and ALT > 5 × ULN for age.
• Total bilirubin > 1.5 × ULN for age; and in presence of Gilbert's syndrome, total
bilirubin > 3 × ULN or direct bilirubin > 1.5 × ULN.
• Serum creatinine > 1.5 × ULN for age.
• International normalized ratio or prothrombin time (PT) > ULN (> 1.5 × ULN if on
prophylactic reversible anticoagulants).
• Participant has a QTcF > 470 msec. Participant has a familial or personal history of
prolonged QT syndrome or Torsades de pointes.
• Participant has clinically significant, uncontrolled cardiovascular disease including
congestive heart failure Grade III or IV according to the New York Heart Association
classification; myocardial infarction or unstable angina within the previous 6 months,
uncontrolled hypertension (> 95th percentile for age), or clinically significant,
uncontrolled arrhythmias, including bradyarrhythmias that may cause QT prolongation
(eg, Type II second-degree heart block or third-degree heart block).
• Participant received the following systemic antineoplastic therapies:
• Temozolomide within 4 weeks prior to the first dose of study drug
• Nitrosurea within 6 weeks prior to the first dose of study drug
• Any other systemic antineoplastic therapy (including experimental therapy) within
5 half-lives or 28 days prior to the first dose of study drug, whichever is
shorter.
• Focal external beam radiotherapy, including stereotactic radiosurgery, within 6
weeks prior to the first dose of avapritinib to either target or nontarget
lesions. Systemic radiopharmaceuticals, including nonstereotactic radiosurgery,
within 2 weeks of the first dose of avapritinib (within 6 weeks for Participants
with CNS tumors). Craniospinal irradiation within 6 weeks prior to the first dose
of avapritinib.
• All AEs related to other antineoplastic therapies (eg, systemic antineoplastics,
radiotherapy) must have resolved to Grade ≤ 1 (Grade ≤ 2 for peripheral
neuropathy and/or ototoxicity) prior to the first dose of avapritinib.
• Participant has previously received treatment with avapritinib.
• Participant received autologous stem cell transplant following myeloablative therapy
or chimeric antigen receptor T cell therapy within 3 months prior to the first dose of
avapritinib or prior allogeneic stem cell transplant within 1 year and no evidence of
Grade 1 or greater graft-versus-host disease and no immunosuppressants for
graft-versus-host disease (steroids for primary malignancy being permitted).
Participants who received stem cell reinfusion following nonmyeloablative therapy are
eligible once they meet the peripheral blood count criteria in Exclusion Criterion #1.
• Participant requires ongoing treatment or has received treatment within 28 days before
the start of avapritinib administration with drugs or foods that are strong CYP3A
inhibitors or inducers.
• Participant has had a major surgical procedure within 14 days of the first dose of
study treatment (procedures such as central venous catheter placement, tumor needle
biopsy, and feeding tube placement are not considered major surgical procedures).
• Participant has a history of another primary malignancy that has been diagnosed or
required therapy within 3 years before the first dose of avapritinib. The following
prior malignancies are not exclusionary: completely resected basal cell and squamous
cell skin cancer, curatively treated localized prostate cancer, and completely
resected carcinoma in situ of any site.
• Female subjects of childbearing potential who are unwilling, if not postmenopausal or
surgically sterile, to abstain from sexual intercourse or employ highly effective
contraception from the time of informed consent and for at least 6 weeks after the
last dose of study treatment. Male subjects who are unwilling, if not surgically
sterile, to abstain from sexual intercourse or employ highly effective contraception
from the time of informed consent and for at least 6 weeks after the last dose of
study treatment.
• Participant is pregnant, as documented by a serum β-hCG pregnancy test consistent with
pregnancy obtained at Screening and within 72 hours before the first dose of study
treatment. Participants with β-hCG values that are within the range for pregnancy but
are not pregnant (false-positives) may be enrolled with written consent of the Sponsor
after pregnancy has been ruled out. Female subjects of nonchildbearing potential
(premenarchal, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) do
not require a serum β-hCG test.
• Participant is breastfeeding.
• Participant has prior or ongoing clinically significant illness, medical condition,
surgical history, physical finding, or laboratory abnormality that, in the
Investigator's opinion, could affect the safety of the Participant; alter the
absorption, distribution, metabolism, or excretion of the study drug; or impair the
assessment of study results.
• History of thrombosis requiring treatment within the past 6 months. This exclusion
does not apply to catheter-related thrombosis if the catheter has been removed and did
not require any other treatment in the previous 3 months.
• Participants who require anticoagulants, with the exception of stable doses of
prophylactic reversible anticoagulants.
• Participants who are unable to swallow tablets (in Part 1) or minitablets (in Part 2)
within the sprinkle capsules.
• Participants with a known risk of intracranial bleeding, such as a brain aneurysm that
has not been removed or repaired, or a history of intracranial bleeding within the
past year, or radiographic evidence of hemorrhage on Screening MRI. Exceptions are:
Participants with primary CNS tumors (provided they have not had CNS bleeding within 2
weeks of the first dose of avapritinib) or Participants with punctate hemorrhages < 3
mm.
• History of a seizure disorder that is not well controlled on current antiepileptic
medications.
• Participant is unwilling or unable to comply with scheduled visits, treatment
administration plan, laboratory tests, or other study procedures and study
restrictions.
A Phase 1 Study With ABBV-CLS-484 in Subjects With Locally Advanced or Metastatic Tumors
The study will assess the safety, PK, PD, and preliminary efficacy of ABBV-CLS-484 as monotherapy and in combination with a PD-1 targeting agent or with a or a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI).
The trial aims to establish a safe, tolerable, and efficacious dose of ABBV-CLS-484 as monotherapy and in combination. The study will be conducted in three parts. Part 1 Monotherapy Dose Escalation, Part 2 Combination Dose Escalation and Part 3 Dose Expansion (Monotherapy and Combination therapy).
Part 1, ABBV-CLS-484 will be administered alone in escalating dose levels to eligible subjects who have advanced solid tumors.
Part 2, ABBV-CLS-484 will be administered at escalating dose levels in combination with a PD-1 targeting agent or with a VEGFR TKI to eligible subjects who have advanced solid tumors.
Part 3, ABBV-CLS-484 will be administered alone as a monotherapy at the determined recommended dose in subjects with locally advanced or metastatic, relapsed or refractory head and neck squamous cell carcinoma (HNSCC), relapsed or refractory non-small cell lung cancer (NSCLC), and advanced clear cell renal cell carcinoma (ccRCC). ABBV-CLS-484 will also be administered at the determined recommended dose in combination with a PD-1 targeting or with a VEGFR TKI agent in subjects with locally advanced or metastatic, HNSCC, NSCLC, MSI-H tumors refractory to PD-1/PD-L1, and advanced ccRCC.
* Must weigh at least 35 kilograms (kg).
* An Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
* Life expectancy of ≥ 12 weeks.
* Laboratory values meeting protocol criteria.
* QT interval corrected for heart rate \< 470 msec (using Fridericia's correction), and no clinically significant electrocardiographic findings.
* Measurable disease defined by RECIST 1.1 criteria.
For Monotherapy and Combination Dose Escalation:
• Subjects with histologically or cytologically proven metastatic or locally advanced tumors, for which no effective standard therapy exists, or where standard therapy has failed. Subjects must have received at least 1 prior systemic anticancer therapy for the indication being considered.
For Monotherapy Dose Expansion only:
* Subjects must have received at least 1 prior line containing PD-1/PD-L1 targeted therapy with a best response by RECIST v1.1 of CR/PR/stable (any duration) or stable disease (for greater than 6 months); AND
* Must have been previously treated with 1 or more prior lines of therapy in the locally advanced or metastatic setting with the following tumor types:
* Relapsed/refractory HNSCC
* Relapsed/refractory NSCLC
* Advanced ccRCC
For PD-1 Targeting Agent Combination Dose Expansion only:
* For the following tumor types, subject must have received at least 1 prior line containing PD-1/PD-L1 targeted therapy with response by RECIST v1.1 of CR/PR (any duration) or stable disease (for greater than 6 months):
* Relapsed HNSCC
* Relapsed NSCLC
* Relapsed Advanced ccRCC
* For the following tumor types, subject must have received at least 1 prior line containing PD-1/PD-L1 targeted therapy and have had disease progression with PD-1/PD-L1 targeted therapy:
* Locally Advanced or metastatic MSI-H tumors
For VEGFR TKI Combination Dose Expansion only:
* Relapsed advance ccRCC with no more than 1 prior VEGFR TKI
* Subjects no recent history of hemorrhage, including hemoptysis, hematemesis, or melena
* Subjects with poorly controlled hypertension are excluded
Exclusion Criteria:
* Untreated brain or meningeal metastases (i.e., subjects with history of metastases are eligible provided they do not require ongoing steroid treatment and have shown clinical and radiographic stability for at least 28 days after definitive therapy)
* Unresolved Grade 2 or higher toxicities related to previous anticancer therapy except alopecia.
* Unresolved Grade 2 or higher peripheral neuropathy.
* History of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.
* Recent history (within 6 months) of congestive heart failure (defined as New York Heart Association, Class 2 or higher), ischemic cardiovascular event, pericarditis, or clinically significant pericardial effusion or arrythmia.
* Recent history (within 6 months) of Childs-Pugh B or C classification of liver disease.
* History of clinically significant medical and/or psychiatric conditions or any other reason that, in the opinion of the investigator, would interfere with the subject's participation in this study or would make the subject an unsuitable candidate to receive study drug.
* History of uncontrolled, clinically significant endocrinopathy.
* Known gastrointestinal disorders making absorption of oral medications problematic; subject must be able to swallow capsules.
* If treated with a PD-1/aPD-L1 targeting or other immune-oncology agents in the past, excluded if had prior pneumonitis, prior Grade 3 or higher immune mediated toxicity, hypersensitivity to administered drug or drug related toxicity requiring discontinuation.
* Active autoimmune disease requiring systemic treatment in past 2-years (exceptions for endocrinopathies, vitiligo or atopic conditions).
* History of solid organ transplant or allogeneic stem cell transplant.
* History of other malignancy, with the following exceptions:
* No known active disease present within ≥ 3 years before first dose of study treatment and felt to be at low recurrence by investigator.
* Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
* Adequately treated carcinoma in situ without evidence of disease.
* History of interstitial lung disease or pneumonitis.
* Major surgery ≤ 28 days prior to first dose of study drug
* Known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection per local testing practices.
The ACCEL® Absorbable Hemostat Powder Clinical IDE Trial is designed as a prospective, multi-center, randomized, non-inferiority, controlled pivotal clinical trial to evaluate the safety and efficacy of the ACCEL® Absorbable Hemostat Powder as compared to gelatin sponge, for achieving hemostasis in subjects undergoing cardiovascular, liver, or soft tissue surgery, when control of oozing to moderate bleeding by standard surgical techniques is ineffective and/or impractical.
Pre-Surgery:
• Subject is greater than or equal to 22 years old
• Subject is undergoing a cardiovascular surgery, liver surgery or soft tissue surgical procedure
• Subject is willing and able to provide appropriate (Institutional Review Board (IRB) approved) informed consent.
• The subject is willing and able to comply with the requirements of the protocol, including follow-up evaluations and schedule.
• The subject is willing to be treated with ACCEL® Absorbable Hemostat Powder
• The subject is willing to be treated with a commercially available absorbable gelatin sponge
During Surgery:
• Subject has not received blood transfusions between screening and application of investigational product or commercially available absorbable gelatin sponge
• There is an estimated TBS surface area of ≤ 60 cm2
• Visual observation of oozing (0.01 g/10s ˂ Flow ˂ 0.04 g/10s), mild (0.04 g/10s ≤ Flow ˂ 0.32 g/10s), or moderate (0.32 g/10s ≤ Flow ˂ 1.01 g/10s) bleeding as validated and when control by conventional surgical techniques, including but not limited to suture, ligature and cautery, is ineffective and/or impractical
• There is an absence of intra-operative complications other than bleeding, which, in the opinion of the Investigator, may interfere with the assessment of efficacy or safety
• There has been no intra-operative use of adjunct hemostat(s) on the target bleeding site identified for application of the study treatment
Exclusion Criteria:
Pre-Surgery:
• The subject is pregnant (verified in a manner consistent with institution's standard of care)
• Subject is lactating
• Subject is currently participating in another investigational device or drug trial or has participated in one in the past 4 weeks (prior to surgery) or is planning to participate in another research study involving any investigational product within 4 weeks after surgery
• Subject is a prisoner, a minor or unable to adequately give informed consent due to mental or physical condition
• Subject has medical, social, or psychosocial issues that the Investigator believes could impact the subject's safety or compliance with study procedures
• Subject has a known allergy to potatoes
• Subject has a known allergy to porcine collagen/gelatin
• Subject has a religious or other objection to porcine products
• Subject is unwilling to receive blood products
• Subject has history of heparin-induced thrombocytopenia (only for cardiovascular subjects where heparin use is required)
• Subject with a baseline abnormality of INR \> 2.5 or an aPTT\> 100 seconds during screening that is not explained by current drug treatment (e.g. heparin, warfarin, etc.).
• Subjects with platelets \< 100 X 109 PLT/L during screening
• Subject with Aspartate Aminotransferase (AST) or Alanine aminotransferase (ALT) \> 3 X upper limit normal range during screening, except for subjects undergoing liver resection surgery or with a diagnosis of liver metastases where there is no upper limit normal for these analytes due to the nature of their disease
• Subject is unwilling or unable to return for the required follow-up after surgery
During Surgery:
• Subject has an operative bleeding site which the surgeon is unable or unwilling to control with a hemostatic agent
• Extracorporeal cardiopulmonary bypass circuits or blood salvage circuits are to be used during or after identification of the TBS.
• There has been intra-operative use of thrombin on the patient.
DEVICE: ACCEL® Absorbable Hemostat Powder, DEVICE: Gelfoam® (Absorbable Gelatin Sponge, Pfizer Manufacturer Part Number 0342-01)
Other, Cardiovascular, Head and Neck, Liver, Hemostasis
A Study of a New Way to Treat Children and Young Adults With a BrainTumorCalled NGGCT
This phase II trial studies the best approach to combine chemotherapy and radiation therapy (RT) based on the patient's response to induction chemotherapy in patients with non-germinomatous germ cell tumors (NGGCT) that have not spread to other parts of the brain or body (localized). This study has 2 goals: 1) optimizing radiation for patients who respond well to induction chemotherapy to diminish spinal cord relapses, 2) utilizing higher dose chemotherapy followed by conventional RT in patients who did not respond to induction chemotherapy. Chemotherapy drugs, such as carboplatin, etoposide, ifosfamide, and thiotepa, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays or high-energy protons to kill tumor cells and shrink tumors. Studies have shown that patients with newly-diagnosed localized NGGCT, whose disease responds well to chemotherapy before receiving radiation therapy, are more likely to be free of the disease for a longer time than are patients for whom the chemotherapy does not efficiently eliminate or reduce the size of the tumor. The purpose of this study is to see how well the tumors respond to induction chemotherapy to decide what treatment to give next. Some patients will be given RT to the spine and a portion of the brain. Others will be given high dose chemotherapy and a stem cell transplant before RT to the whole brain and spine. Giving treatment based on the response to induction chemotherapy may lower the side effects of radiation in some patients and adjust the therapy to a more efficient one for other patients with localized NGGCT.
* Patients must be \>= 3 years and \< 30 years at the time of study enrollment
* Patients must be newly diagnosed with localized primary CNS NGGCT of the suprasellar and/or pineal region by pathology and/or serum or cerebrospinal fluid (CSF) elevation of AFP above institutional normal or \> 10 ng/mL or human chorionic gonadotropin (hCG) beta \> 100 mIU/mL as confirmed by Rapid Central Marker Screening Review on APEC14B1-CNS. Suprasellar, pineal and bifocal tumors are included. (CSF tumor markers and cytology must be within 31 days prior to enrollment and start of protocol therapy \[repeat if necessary\]. Serum tumor markers, AFP and hCGbeta must be within 7 days prior to enrollment and start of protocol therapy \[repeat if necessary\]). Basal ganglia or other primary sites are excluded
* Patients with any of the following pathological elements are eligible: endodermal sinus (yolk sac), embryonal carcinoma, choriocarcinoma, malignant/immature teratoma and mixed germ cell tumor (GCT) (i.e., may include some pure germinoma) if malignant elements listed above are present. Patients with only mature teratoma are excluded. Patients with pure germinoma admixed with mature teratoma are excluded (would be eligible for pure germinoma protocols)
* Patients must have a cranial MRI with and without gadolinium at diagnosis/prior to enrollment. If surgical resection is performed, patients must have pre-operative and post operative brain MRI with and without gadolinium. The post operative brain MRI should be obtained within 72 hours of surgery. If patient has a biopsy only, post-operative brain MRI is recommended but not required (within 31 days prior to study enrollment and start of protocol therapy )
* Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to enrollment. Spine MRI with and without gadolinium is recommended (within 31 days prior to study enrollment and start of protocol therapy)
* Lumbar CSF must be obtained prior to study enrollment unless medically contraindicated. If a patient undergoes surgery and lumbar CSF cytology cannot be obtained at the time of surgery, then it should be performed at least 10 days following surgery and prior to study enrollment. False positive cytology can occur within 10 days of surgery
* Patients must have RAPID CENTRAL TUMOR MARKER REVIEW CSF tumor markers obtained prior to enrollment unless medically contraindicated. Ventricular CSF obtained at the time of CSF diversion procedure (if performed) is acceptable for tumor markers but lumbar CSF is preferred. In case CSF diversion and biopsy/surgery are combined, CSF tumor markers should be collected first
* Peripheral absolute neutrophil count (ANC) \>= 1000/uL (within 7 days prior to enrollment)
* Platelet count \>= 100,000/uL (transfusion independent) (within 7 days prior to enrollment)
* Hemoglobin \>= 8.0 g/dL (may receive red blood cell \[RBC\] transfusions) (within 7 days prior to enrollment)
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 or a serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
* Age: Maximum serum creatinine (mg/dL)
* 3 to \< 6 years: 0.8 (male), 0.8 (female)
* 6 to \< 10 years: 1 (male), 1 (female)
* 10 to \< 13 years: 1.2 (male), 1.2 (female)
* 13 to \< 16 years: 1.5 (male), 1.4 (female)
* \>= 16 years: male (1.7), 1.4 (female)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
* Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 135 U/L (within 7 days prior to enrollment)
* Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
* Central nervous system function defined as:
* Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
* Patients must not be in status epilepticus, coma or assisted ventilation prior to study enrollment
* Protocol therapy must begin within 31 calendar days of definitive surgery or clinical diagnosis, whichever is later. If a biopsy only was performed, the biopsy date will be considered the date of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery.
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
* NEUROCOGNITIVE FUNCTION AND QUALITY OF LIFE ASSESSMENT:
* English-, Spanish-, or French- speaking
* Note: Patients who speak a language other than English, Spanish, or French will be allowed to participate in ACNS2021 but will not complete the neurocognitive and quality of life assessments
* No known history of neurodevelopmental disorder prior to diagnosis of NGGCT (e.g., Down syndrome, fragile X, William syndrome, intellectual disability). Patients with NF1 will be allowed to participate
* Additional eligibility criteria for the COG Standardized Neuropsychological Battery only: must be at a site that has a psychologist to administer the battery
* Note: If not eligible for the COG Standardized Battery, patients should still complete the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2), Pediatric Quality of Life Inventory (PedsQL), Adaptive Behavior Assessment System Third Edition (ABAS-3), and Behavior Assessment System for Children, Third Edition (BASC-3) questionnaires
Exclusion Criteria:
* Patients with tumors located outside the ventricles (i.e., basal ganglia, thalamus)
* Patients with only mature teratoma and non-elevated markers upon tumor sampling at diagnosis
* Patients who have received any prior tumor-directed therapy for their diagnosis of NGGCT other than surgical intervention and corticosteroids
* Patients with metastatic disease (i.e., MRI evaluation, lumbar CSF cytology or intraoperative evidence of dissemination)
* Female patients who are pregnant, since fetal toxicities and teratogenic effects have been noted for several of the study drugs
* Note: Serum and urine pregnancy tests may be falsely positive due to HCGbeta-secreting germ cell tumors. Ensure the patient is not pregnant by institutional standards
* Lactating females who plan to breastfeed their infants
* Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
A Study to Compare Treatment With the Drug Selumetinib Alone Versus Selumetinib and Vinblastine in Patients With Recurrent or Progressive Low-Grade Glioma
This phase III trial investigates the best dose of vinblastine in combination with selumetinib and the benefit of adding vinblastine to selumetinib compared to selumetinib alone in treating children and young adults with low-grade glioma (a common type of brain cancer) that has come back after prior treatment (recurrent) or does not respond to therapy (progressive). Selumetinib is a drug that works by blocking a protein that lets tumor cells grow without stopping. Vinblastine blocks cell growth by stopping cell division and may kill cancer cells. Giving selumetinib in combination with vinblastine may work better than selumetinib alone in treating recurrent or progressive low-grade glioma.
* Feasibility phase: patients must be \>= 2 years and =\< 21 years of age at the time of enrollment
* Efficacy phase: patients must be \>= 2 years and =\< 25 years of age at the time of enrollment
* All patients \> 21 years of age at the time of enrollment must have had initial diagnosis of low-grade glioma by 21 years of age
* Patients must have a body surface area (BSA) of \>= 0.5 m\^2 at enrollment
* Patients must have eligibility confirmed by rapid central pathology and central molecular screening reviews performed on APEC14B1
* Non-neurofibromatosis type 1 (non-NF1), non-tuberous sclerosis complex (non-TSC) low-grade glioma (LGG) without a BRAFV600E or IDH1 mutation
* Patients must have progressive or recurrent LGG. Note: Biopsy may be at either initial diagnosis or recurrence
* Patients must have measurable disease, defined as having a two-dimensional measurable tumor volume of \>= 1 cm\^2
* Tumor size will be measured to include both solid and cystic components of the tumor (whether or not tumor is enhancing) + fluid attenuated inversion recovery (FLAIR) signal
* Eligible histologies will include all tumors considered low-grade glioma or low-grade astrocytoma (World Health Organization \[WHO\] grade 1 and II) by the WHO Classification of Tumors of the Central Nervous System - 4th Edition Revised, with the exception of subependymal giant cell astrocytoma
* Patients with metastatic disease or multiple independent primary LGGs are eligible
* Patients must be progressive or recurrent after having been treated with at least one prior tumor-directed therapy before enrollment
* Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
* Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry onto this study (4 weeks if prior nitrosourea);
* Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent;
* Radiation therapy (RT): \>= 2 weeks (wks) for local palliative RT (small port); \>= 6 months must have elapsed if prior craniospinal RT or if \>= 50% radiation of pelvis; \>= 6 wks must have elapsed if other substantial bone marrow (BM) radiation;
* Antibodies: \>= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to =\< grade 1;
* MEK inhibitor or vinblastine: Must not have received treatment with a MEK inhibitor or vinblastine within 6 months of study enrollment
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^ 2 or a serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
* 2 to \< 6 years: 0.8 mg/dL (male) 0.8 mg/dL (female)
* 6 to \< 10 years: 1 mg/dL (male) 1 mg/dL (female)
* 10 to \< 13 years: 1.2 mg/dL (male) 1.2 mg/dL (female)
* 13 to \< 16 years: 1.5 mg/dL (male) 1.4 mg/dL (female)
* \>= 16 years: 1.7 mg/dL (male) 1.4 mg/dL (female)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment) (children with a diagnosis of Gilbert's syndrome will be allowed on study regardless of their total and indirect \[unconjugated\] bilirubin levels as long as their direct \[conjugated\] bilirubin is \< 3.1 mg/dL)
* Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 135 U/L (within 7 days prior to enrollment)
* Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
* Albumin \>= 2 g/L (within 7 days prior to enrollment)
* Left ventricular ejection fraction (LVEF) \>= 53% (or institutional normal; if the LVEF result is given as a range of values, then the upper value of the range will be used) by echocardiogram (within 4 weeks prior to enrollment)
* Corrected QT interval (QTc interval) =\< 450 msec by electrocardiogram (EKG) (within 4 weeks prior to enrollment)
* Absolute neutrophil count \>= 1,000/uL (unsupported) (within 7 days prior to enrollment)
* Platelets \>= 100,000/uL (unsupported) (within 7 days prior to enrollment)
* Hemoglobin \>= 8 g/dL (may be supported) (within 7 days prior to enrollment)
* Patients with a known seizure disorder should be stable and should not have experienced a significant increase in seizure frequency within 2 weeks prior to enrollment
* Stable neurological examination for \>= 1 week
* HYPERTENSION:
* Patients 2-17 years of age must have a blood pressure that is =\< 95th percentile for age, height, and gender at the time of enrollment (with or without the use of anti-hypertensive medications);
* Patients \>= 18 years of age must have a blood pressure =\< 130/80 mmHg at the time of enrollment (with or without the use of anti-hypertensive medications)
* Note for patients of all ages: Adequate blood pressure can be achieved using medication for the treatment of hypertension
* All patients must have ophthalmology toxicity assessments performed within 4 weeks prior to enrollment
* For all patients, an MRI of the brain (with orbital cuts for optic pathway tumors) and/or spine (depending on the site\[s\] of primary disease) with and without contrast must be performed within 4 weeks prior to enrollment
* Note: If surgical resection or biopsy is performed at the time of progression or recurrence, a post-operative MRI is required
* Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients \> 16 years of age and Lansky for patients =\< 16 years of age
* Patients must have the ability to swallow whole capsules
Exclusion Criteria:
* Prior therapy with vinblastine and/or a MEK inhibitor is permitted, with the following exceptions:
* Patients must not have had progressive disease while on therapy with vinblastine or a MEK inhibitor;
* Patients must not have discontinued vinblastine or selumetinib due to toxicity
* Patients with a concurrent malignancy or history of treatment (other than surgery) for another tumor within the last year are ineligible
* Patients with diffuse intrinsic pontine tumors as seen on MRI (\> 2/3 of pons involvement on imaging) are not eligible even if biopsy reveals grade I/II histology
* Patients may not be receiving any other investigational agents
* Patients must not have known hypersensitivity to selumetinib, vinblastine, or similar compounds
* CYP3A4 agents: Patients must not have received fluconazole or drugs that are strong inducers or inhibitors of CYP3A4 within 7 days prior to study enrollment
* Patients with any serious medical or psychiatric illness/condition, including substance use disorders or ophthalmological conditions, likely in the judgment of the investigator to interfere or limit compliance with study requirements/treatment
* Patients who, in the opinion of the investigator, are not able to comply with the study procedures are not eligible
* PRE-EXISTING CONDITIONS (CARDIAC):
* Known genetic disorder that increases risk for coronary artery disease. Note: The presence of dyslipidemia in a family with a history of myocardial infarction is not in itself an exclusion unless there is a known genetic disorder documented;
* Symptomatic heart failure
* New York Heart Association (NYHA) class II-IV prior or current cardiomyopathy
* Severe valvular heart disease
* History of atrial fibrillation
* PRE-EXISTING CONDITIONS (OPHTHALMOLOGIC CONDITIONS):
* Current or past history of central serous retinopathy
* Current or past history of retinal vein occlusion or retinal detachment
* Patients with uncontrolled glaucoma
* If checking pressure is clinically indicated, patients with intraocular pressure (IOP) \> 22 mmHg or upper limit of normal (ULN) adjusted by age are not eligible
* Any multivitamin containing vitamin E must be stopped prior to study enrollment even if it contains less than 100% of the daily recommended dosing for vitamin E
* Surgery within 2 weeks prior to enrollment, with the exception of a surgical biopsy, placement of a vascular access device or cerebrospinal fluid (CSF) diverting procedure such as endoscopic third ventriculostomy (ETV) and ventriculoperitoneal (VP) shunt
* Note: Patients must have healed from any prior surgery
* Patients who have an uncontrolled infection are not eligible
* Female patients who are pregnant are not eligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
* Lactating females who plan to breastfeed their infants
* Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 12 weeks after stopping study therapy are not eligible
* Note: Women of child-bearing potential and males with sexual partners who are pregnant or who could become pregnant (i.e., women of child-bearing potential) should use effective methods of contraception for the duration of the study and for 12 weeks after stopping study therapy to avoid pregnancy and/or potential adverse effects on the developing embryo
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
A Study to See if Memantine Protects the BrainDuring Radiation Therapy Treatment for Primary Central Nervous System Tumors
This phase III trial compares memantine to placebo in treating patients with primary central nervous system tumors. Memantine may block receptors (parts of nerve cells) in the brain known to contribute to a decline in cognitive function. Giving memantine may make a difference in cognitive function (attention, memory, or other thought processes) in children and adolescents receiving brain radiation therapy to treat a primary central nervous system tumors.
* \>= 4 and \< 18 years at time of study entry
* Patients must weigh 15 kg or greater at time of study entry
* Primary central nervous system tumors that have not received prior cranial radiotherapy
* Planned focal, cranial or craniospinal radiation treatment for a primary central nervous system tumor
* The patient must have receptive and expressive language skills in English, French or Spanish since the neurocognitive function and quality of life (QOL) assessment instruments are available in these languages only
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 or a serum creatinine based on age/gender as follows:
* Age: 4 to \< 6 years; Maximum serum creatinine (mg/dL): 0.8 male; 0.8 female
* Age: 6 to \< 10 years; Maximum serum creatinine (mg/dL): 1 male; 1 female
* Age: 10 to \< 13 years; Maximum serum creatinine (mg/dL): 1.2 male; 1.2 female
* Age: 13 to \< 16 years; Maximum serum creatinine (mg/dL): 1.5 male; 1.4 female
* Age: \>= 16 years; Maximum serum creatinine (mg/dL): 1.7 male; 1.4 female
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age
* Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 135 U/L
* Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
* The patient must be able to undergo magnetic resonance imaging
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Exclusion Criteria:
* Life expectancy of less than 18 months
* Pre-existing conditions:
* Any contraindication or allergy to study drug (memantine or placebo)
* Intractable seizures while on adequate anticonvulsant therapy, defined as more than one seizure per month for the past 2 months or since initiating anticonvulsant therapy
* History of neurodevelopmental disorder such as Down syndrome, Fragile X, William's Syndrome, intellectual disability (presumed intelligence quotient \[IQ\] \< 70), etc
* Co-morbid systemic illnesses, psychiatric conditions, social situations, or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens or would limit compliance with the study requirements
* Patients with a motor, visual, or auditory condition that precludes participation in computerized neurocognitive assessments
* Patients with any medical condition or taking medications that lead to alterations of urine pH towards the alkaline condition (e.g., renal tubular acidosis, carbonic anhydrase inhibitors, sodium bicarbonate)
* Personal history of prior cranial or craniospinal radiotherapy is not allowed
* Note: Prior anti-cancer therapy including surgery, chemotherapy, targeted agents are allowed as per standard of care clinical treatment guidelines
* Female patients who are pregnant are excluded since fetal toxicities and teratogenic effects have been noted for the study drug. A pregnancy test is required for female patients of childbearing potential
* Lactating females who plan to breastfeed their infants
* Sexually active patients of reproductive potential who do not agree to use an effective contraceptive method for the duration of their study participation
* Diagnosis of EBV+ disorder
* Eastern Cooperative Oncology Group performance status \<= 3 for participants aged \>= 16 years; Lansky score \>= 20 for participants from \>=1 year to \< 16 years
* Adequate organ function test results, unless organ dysfunction is considered to be due to the underlying EBV-associated disease by the investigator
Cohort-specific
Inclusion Criteria:
* For participants with PID LPD:
* R/R or newly diagnosed PID LPD for whom the standard first-line therapy is inappropriate, as determined by investigator. The LPD is confirmed by at least biopsy-proven EBV+ LPD or positive cerebrospinal fluid (CSF) cytology with or without radiographically measurable intracranial disease with EBV detected in CSF.
* Participants with R/R disease must have had at least one prior line of systemic therapy and one of the following: radiographic disease progression per Lugano Classification (Cheson BD, et al. J Clin Oncol. 2014;27:3059) during or after treatment or failure to achieve a CR or partial response (PR) (defined by Lugano radiographic criteria) after standard first-line therapy
* Participant may have systemic disease only, systemic and CNS disease, or CNS disease only
* For participants with AID LPD:
* R/R or newly diagnosed AID LPD for whom the standard first line therapy is inappropriate, as determined by the investigator. The LPD is confirmed by at least biopsy-proven EBV+ LPD or positive CSF cytology, with or without radiographically measurable intracranial disease, with EBV detected in CSF.
* Participants with R/R disease must have had at least one prior line of systemic therapy and one of the following: radiographic disease progression per Lugano Classification during or after treatment or failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy
* Participant may have systemic disease only, systemic and CNS disease, or CNS disease only
* For participants with AID etiology or AID attributable to immunosenescence, objective laboratory evidence of immunodeficiency
* For participants with CNS PTLD:
* R/R or newly diagnosed EBV+ CNS PTLD for whom the standard first-line therapy is inappropriate, as determined by the investigator. The CNS PTLD is histologically confirmed by at least biopsy-proven EBV+ CNS PTLD or positive CSF cytology with or without radiographically measurable intracranial disease with EBV detected in CSF.
* Participants with R/R disease must have had at least one prior line of systemic therapy and one of the following: radiographic disease progression per Lugano Classification during or after treatment or failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy
* Participant may have systemic and CNS disease or CNS disease only
* For participants with EBV+ PTLD, including CD20-negative disease:
* Biopsy-proven EBV+ PTLD for whom standard first-line therapy (rituximab and/or chemotherapy) is inappropriate, as determined by the investigator
* Participants must have systemic disease measurable per Lugano Classification criteria, except when contraindicated or mandated by local practice, then MRI may be used
* For participants with sarcoma, including LMS, or smooth muscle tumors:
* EBV+ sarcoma or smooth muscle tumor with rapidly progressive disease defined as progressive disease per RECIST 1.1 criteria as documented radiographically within a 6-month interval prior to enrollment
* Participants with newly diagnosed EBV+ sarcoma for whom the standard first-line therapy is inappropriate, as determined by the investigator
* Biopsy-proven EBV+ sarcoma meeting one of the criteria's of pathologically confirmed EBV+ Leiomyosarcoma or EBV+ sarcoma or smooth muscle tumor
* Measurable disease using diagnostic CT and/or MRI following RECIST 1.1 criteria (Eisenhauer et al. 2009. Eur J Cancer 45\[2\]:228-247)
Exclusion Criteria:
* Currently active Burkitt, T-cell, natural killer/T-cell lymphoma/LPD, Hodgkin, plasmablastic, transformed lymphoma, active hemophagocytic lymphohistiocytosis, or other malignancies requiring systemic therapy
* Serious known active infections, defined as ongoing uncontrolled adenovirus infection or infections requiring systemic therapy at the time of enrollment, or known history of human immunodeficiency virus (HIV) infection
* Suspected or confirmed Grade \>= 2 acute graft-versus-host disease (GvHD) per the Center for International Blood and Marrow Transplant Research (CIBMTR) consensus grading system or extensive chronic GvHD per National Institutes of Health (NIH) consensus criteria at the time of the enrollment
* Need for vasopressor or ventilatory support at the time of enrollment
* Prior therapy (in order of increasing washout period) prior to enrollment as follows:
* Within 4 weeks or 5 half-lives (whichever is shorter) for any investigational product and/ or any chemotherapy (systemic or intrathecal), targeted small molecule therapy, or antibody/biologic therapy. Note: prior anti-CD20 antibody use is permitted within the washout period if a subsequent disease response assessment indicates disease progression
* Within 8 weeks: prior tabelecleucel (\>8 weeks prior to enrollment) is permitted if response was obtained or if usual protocol-directed therapeutic options were not exhausted, for cellular therapies (chimeric antigen receptor therapies directed at T-cells or T-cell subsets, donor lymphocyte infusion, other CTLs or virus-specific T-cells); and/or therapies which could impact tabelecleucel function (anti-thymocyte globulin, alemtuzumab)
* Any prior treatment with EBV-CTLs with the exception of tabelecleucel as above
* Women who are breastfeeding or pregnant
* Unwilling to comply with protocol specified contraceptive/reproductive restrictions from enrollment through 90 days after the last treatment
* Ongoing need for daily steroids of \> 0.5 mg/kg prednisone or glucocorticoid equivalent, ongoing methotrexate, or extracorporeal photopheresis (for participants with CNS disease, protocol-specified dexamethasone is permitted and concludes by the time of enrollment)
* Any conditions that may put the study outcomes at undue risk (life expectancy \< 60 days or any life-threatening illness, medical condition, or organ system dysfunction)
* For participants with PID LPD or AID LPD: history of prior allogeneic HCT or solid organ transplant
* For participants with EBV+ PTLD: prior systemic therapy for PTLD
BIOLOGICAL: Tabelecleucel
Sarcoma, Leiomyosarcoma, Stem Cell Transplant Complications, Lymphoproliferative Disorders, Solid Organ Transplant Complications, Allogeneic Hematopoietic Cell Transplant, Brain and Nervous System, Epstein-Barr Virus (EBV)-Associated Diseases, EBV+ Post-transplant Lymphoproliferative Disease (EBV+ PTLD), EBV+ Sarcomas, EBV+ Lymphoproliferative Disease With Primary Immunodeficiency (EBV+ PID LPD), EBV+ Lymphoproliferative Disease With Acquired (Non-congenital) Immunodeficiency (EBV+ AID LPD), EBV+ Posttransplant Lymphoproliferative Disease in Central Nervous System (EBV+ CNS PTLD)
A Phase II Trial of Poly-ICLC for Low-Grade Gliomas (NF111)
This is a phase II, prospective, longitudinal, multi-center trial of poly-ICLC (Hiltonol ®)
treatment for progressive low-grade gliomas in pediatric patients with NF1. The primary
objective is to evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive
low-grade glioma (LGG) as measured by objective tumor response rate (CR+PR) within the first
48 weeks (12 cycles) of therapy. There will also be secondary and exploratory objectives
listed in the detailed description below.
• Age: Patients must be less than 22 years at the time of enrollment; there is no lower
age limit.
• All participants must have an identified pathogenetic constitutional NF1 mutation OR
the clinical diagnosis of NF1 using the NIH Consensus Conference criteria.
• Diagnosis: LGG (WHO Grade 1 and 2) of the brain and spinal cord are eligible.
Histologic confirmation of tumor is not necessary in the presence of consistent
clinical and radiographic findings. Biopsy for histologic diagnosis is required if
there is clinical suspicion for a high-grade tumor; special attention is recommended
in older adolescents or young adults to the potential for malignant transformation.
Patients with metastatic disease are eligible.
• Patients must meet at least one of the following criteria for progression or
recurrence of a previously treated target tumor:
• Progression or recurrence on MRI.
• New or worsening neurologic symptoms attributable to the target tumor.
• For patients with OPG: visual worsening, defined as worsening of visual acuity
(VA) or visual fields (VF) documented within the past year by examination or
history, attributable to tumor.
• Measurable Disease: Patients must have two-dimensional measurable tumor >1cm2.
• Prior Therapy: Patients must have had at least one prior medical treatment for the
target LGG.
• Performance Level: Patients must have a performance status of equal or > than 50 using
Karnofsky for patients equal or ≥ 16 years of age and Lansky for patients < 16 years
of age.
• Patients must have recovered to grade ≤1 from any acute toxicities from all prior
treatments. to enroll on this study and meet time restrictions from end of prior
therapy as defined below:
• Myelosuppressive chemotherapy: must have received the last dose of
myelosuppressive therapy at least 4 weeks prior to study registration, or at
least 6 weeks if nitrosourea.
• Investigational/biological agent: Patient must have received the last dose of
other investigational, immunotherapy, or biological agent > 14 days prior to
study registration or at least 5 half-lives, whichever is greater. Bevacizumab
last dose > 36 days prior to enrollment.
• Radiation therapy: Patients SHOULD NOT have received prior irradiation.
• Study specific limitations on prior therapy: There is no limit on the number of
prior treatment regimens.
• Growth factor(s): Must not have received any hematopoietic growth factors within
7 days of study entry or > 14 days if pegylated GCSF is used.
• Prior surgery: At the time of enrollment, must be ≥ 3 weeks from prior major
surgery such as craniotomy, orthopedic surgery, abdominal surgery or ≥1 week from
minor surgery and completely recovered. Port or central line placement is not
considered a major surgery.
• Organ Function Requirements:
All patients must have adequate organ function defined as:
• 1 Hematologic Function:
• Hemoglobin: > 8.0 gm/dl (may transfuse PRBCs)
• ANC: > 750/mm3. Must be at least 7 days after last dose of growth factor or > 14
days since last dose of pegylated GCSF
• Platelet Count: > 75,000/mm3 (transfusion independent; ≥ 7 days from last
transfusion)
• 2 Renal Function: Serum creatinine which is less than 1.5 times ULN for age (as per
the table below) or GFR > 70 ml/min/1.73m2
Renal Function Normal for Age
Age Maximum Serum Creatinine (mg/dL) Male Female 1 month to < 6 months 0.4 0.4 6
months to < 1 year 0.5 0.5 1 to < 2 years 0.6 0.6 2 to < 6 years 0.8 0.8 6 to < 10
years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4
≥ 16 years 1.7 1.4
Liver Function:
• Total bilirubin < 1.5 x ULN (Children with diagnosis of Gilbert's Syndrome will
be allowed on the study regardless of their total and indirect bilirubin levels
as long as the direct bilirubin is less than 3.1 mg/dL.)
• SGPT (ALT) ≤ 5 x ULN
• SGOT (AST) ≤ 5 x ULN
Pulmonary Function:
No evidence of dyspnea at rest, and a pulse oximetry ≥ 92%.
Reproductive Function:
Female patients of childbearing potential must have negative serum or urine pregnancy
test within 7 days prior to the first dose of poly-ICLC. Patient must not be pregnant
or breast-feeding. Patients of childbearing or child-fathering potential must be
willing to use a medically acceptable form of birth control, including abstinence,
while being treated on this study and for 90 days following cessation of treatment.
• Patient is able to start treatment within 7 days after enrollment.
• Patients with neurological deficits must be stable for a minimum of 1 week prior to
enrollment.
• Patients are only eligible if complete resection of the LGG with acceptable morbidity
is not feasible, or if a patient with a surgical option refuses surgery.
• Parents/legal guardians must provide written informed consent and agree that they will
comply with the study.
Exclusion Criteria:
• Prior radiation treatment for the low-grade glioma.
• Prior exposure to poly-ICLC.
• Patients currently receiving other anti-tumor therapy or experimental therapy
(targeted agents, chemotherapy radiation).
• Patients with a current or prior diagnosis of malignant glioma (WHO grade III or IV).
• Patients with a prior diagnosis of malignant peripheral nerve sheath tumor or other
malignancy requiring treatment in the last 48 months.
• Patients may not have fever (≥38.50 C) within 3 days of enrollment.
• Patients who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study.
• Active auto-immune illness.
• Pregnant or lactating females.
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation and for
90 days after stopping study therapy are not eligible.
• Severe unresolved infection that requires systemic IV antibiotics.
• Patients with any significant medical illnesses that in the investigator's opinion
cannot be adequately controlled with appropriate therapy or would compromise the
patient's ability to tolerate this therapy.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, impaired gastrointestinal function, or psychiatric illness/social
situations that would limit compliance with study requirements.
• Patients requiring high doses of steroids. Patients may not be on immunosuppressive
therapy, including corticosteroids (with the exception of physiologic replacement,
defined as ≤ 0.75 mg/m2/day dexamethasone or equivalent) at time of enrollment.
However, patients who require intermittent use of bronchodilators or local steroid
injections will not be excluded from the study.
Post-Surgical Stereotactic Radiotherapy (SRT) Versus GammaTile-ROADS (Radiation One and Done Study)
This trial will be a randomized controlled study comparing the efficacy and safety of intraoperative radiation therapy using GammaTilesTM (GT) versus SRT 3-4 weeks following metastatic tumor resection which is the current standard of care.
• Patients aged 18 years old and above. Eligibility is restricted to this age group given that the battery of neurocognitive tests utilized in this protocol are not developed or validated for use in a younger population.
• One to four newly diagnosed brain metastases, identified on the screening MRI, from an extracranial primary tumor.
• One lesion, designated the index lesion, is planned for surgical resection and is to be between 2.5 cm and 5.0 cm on the screening MRI. Index lesions ≥2.0 cm but \<2.5 cm are also eligible if surgery is deemed clinically necessary and appropriate for an attempted gross total resection by the neurosurgeon.
• Non-index lesions must measure \< 4.0 cm in maximal extent on the screening MRI brain scan. The unresected lesions will be treated with SRT as outlined in the treatment section of the concept.
• All metastases must be located \> 5 mm from the optic chiasm and outside the brainstem. Dural based metastasis are eligible.
• Previous and/or concurrent treatment with investigational or FDA approved systemic therapies (e.g., chemotherapy, targeted therapeutics, immunotherapy) is permitted and must follow protocol guidelines as follows: Systemic therapy is allowed a minimum of one week from last systemic therapy cycle to surgical resection, and one week after surgical resection to allow a minimum of one week before starting/resuming systemic therapy, depending on the specific systemic agent(s), as recommended by medical/neuro-oncology. Systemic therapy is not allowed 1 day before SRT, the same day as the SRT, or 1 day after the completion of the SRT or longer, depending on the specific systemic agent(s), as recommended by medical/neuro-oncology. Agents that are delivered by implant or depot injections (such as hormonal therapies) are excluded from these restrictions.
• KPS score of ≥70.
• Stable systemic disease or reasonable systemic treatment options predicting a life expectancy of ≥6 months.
• Ability to complete an MRI of the head with contrast
• Adequate renal and hepatic function to undergo surgery, in investigators opinion.
• For women of childbearing potential only, a negative urine or serum pregnancy test done \<7 days prior to randomization is required. Women must be willing to notify investigator immediately if they become pregnant at any time during the trial period.
• Men and women of childbearing potential must be willing to employ adequate contraception throughout the study and for men for up to 3 months after completing treatment.
• Subjects must be fluent in English or Spanish language. English speaking subjects will complete Neurocognitive assessments. Non-English speaking subjects will not complete the Neurocognitive assessments as the psychometric properties for translated tests are either not known or not as robust.
• Willingness and ability to provide written informed consent and HIPAA authorization prior to performance of any study-related procedures. A legally authorized representative may provide consent if the potential subject lacks the capacity to provide consent themselves.
Exclusion Criteria
• Age \<18 years.
• KPS\<70
• Past radiation or surgical therapy to the index lesion or the newly diagnosed non-index lesion(s) is exclusionary. However, up to a total of 2 prior courses of SRT treatment to previously diagnosed lesions are allowed as long as any treated lesions are were \>15mm from the index lesion.
• Patients with \>4 newly diagnosed metastases on screening MRI
• Pregnant patients.
• Primary germ cell tumor, small cell carcinoma, or lymphoma.
• Leptomeningeal metastasis (LMD). Note: For the purposes of exclusion, LMD is a clinical diagnosis, defined as radiologic or clinical evidence of leptomeningeal involvement with or without positive cerebrospinal fluid (CSF) cytology.
• Prior WBRT for brain metastases.
• Concomitant therapy that, in the investigator's opinion, would interfere with the evaluation of the safety or efficacy of the study device.
• Comorbid psychiatric or neurologic disease or injury impacting cognition, in the opinion of the treating physician, that might impair patient's ability to understand or comply with the requirements of the study or to provide consent
• Subjects who, in the investigator's opinion, are unable to understand the protocol or to give informed consent, have a history of poor cooperation, noncompliance with medical treatment, or difficulty in returning for follow up care.
A Study of the Drugs Selumetinib vs. Carboplatin and Vincristine in Patients With Low-Grade Glioma
This phase III trial compares the effect of selumetinib versus the standard of care treatment with carboplatin and vincristine (CV) in treating patients with newly diagnosed or previously untreated low-grade glioma (LGG) that does not have a genetic abnormality called BRAFV600E mutation and is not associated with systemic neurofibromatosis type 1. Selumetinib works by blocking some of the enzymes needed for cell growth and may kill tumor cells. Carboplatin and vincristine are chemotherapy drugs that work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. The overall goal of this study is to see if selumetinib works just as well as the standard treatment of CV for patients with LGG. Another goal of this study is to compare the effects of selumetinib versus CV in subjects with LGG to find out which is better. Additionally, this trial will also examine if treatment with selumetinib improves the quality of life for subjects who take it.
* Patients must be \>= 2 years and =\< 21 years at the time of enrollment
* Patients must have a body surface area (BSA) of \>= 0.5 m\^2 at enrollment
* Patients must have non-neurofibromatosis type 1 (non-NF1) low-grade glioma (LGG) without a BRAFV600E mutation as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1 (NCT02402244) and that has not been treated with any modality besides surgery. Note: Patients may be newly-diagnosed OR previously diagnosed, and there is no required time frame between biopsy/surgery and treatment initiation.
* Patients with residual tumor after resection or progressive tumor after initial diagnosis (with or without surgery) who have not received treatment (chemotherapy and/or radiation) are eligible
* Patients must have two-dimensional measurable tumor \>= 1 cm\^2 to be eligible
* Eligible histologies will include all tumors considered low-grade glioma or low-grade astrocytoma (World Health Organization \[WHO\] grade I and II) by 5th edition WHO classification of central nervous system (CNS) tumors with the exception of subependymal giant cell astrocytoma
* Patients with metastatic disease or multiple independent primary LGG are eligible
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 OR a serum creatinine based on age/gender as follows (performed within 7 days prior to enrollment):
* Age: Maximum Serum Creatinine (mg/dL)
* 2 to \< 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female)
* 6 to \< 10 years: 1 mg/dL (male); 1 mg/dL (female)
* 10 to \< 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female)
* 13 to \< 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)
* \>= 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age (performed within 7 days prior to enrollment) (children with a diagnosis of Gilbert's syndrome will be allowed on study regardless of their total and indirect \[unconjugated\] bilirubin levels as long as their direct \[conjugated\] bilirubin is \< 3.1 mg/dL)
* Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 135 U/L (performed within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L
* Albumin \>= 2 g/dL (performed within 7 days prior to enrollment)
* Left ventricular ejection fraction (LVEF) \>= 53% (or institutional normal; if the LVEF result is given as a range of values, then the upper value of the range will be used) by echocardiogram (performed within 4 weeks prior to enrollment)
* Corrected QT (QTc) interval =\< 450 msec by electrocardiography (EKG) (performed within 4 weeks prior to enrollment)
* Absolute neutrophil count \>= 1,000/uL (unsupported) (performed within 7 days prior to enrollment)
* Platelets \>= 100,000/uL (unsupported) (performed within 7 days prior to enrollment)
* Hemoglobin \>= 8 g/dL (may be supported) (performed within 7 days prior to enrollment)
* Patients with a known seizure disorder should be stable and should not have experienced a significant increase in seizure frequency within 2 weeks prior to enrollment
* Patients 2-17 years of age must have a blood pressure that is =\< 95th percentile for age, height, and gender at the time of enrollment (with or without the use of anti-hypertensive medications)
* Patients \>= 18 years of age must have a blood pressure =\< 130/80 mmHg at the time of enrollment (with or without the use of anti-hypertensive medications)
* Note for patients of all ages: Adequate blood pressure can be achieved using medication for the treatment of hypertension
* All patients must have ophthalmology toxicity assessments performed within 4 weeks prior to enrollment
* For all patients, a magnetic resonance imaging (MRI) of the brain (with orbital cuts for optic pathway tumors) and/or spine (depending on the site(s) of primary disease) with and without contrast must be performed within 4 weeks prior to enrollment
* Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients \> 16 years of age and Lansky for patients =\< 16 years of age
* Patients must have the ability to swallow whole capsules
* All patients have signed an appropriate consent form and Health Insurance Portability and Accountability Act (HIPAA) authorization form (if applicable)
* All patients and/or their parents or legal guardians must sign a written informed consent
* All patients have been consented and enrolled on APEC14B1 (NCT02402244) followed by enrollment on the ACNS1833 Pre-Enrollment Eligibility Screening (Step 0) on the same day to complete the Rapid Central Review
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Exclusion Criteria:
* Patients must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Prior surgical intervention is permitted
* Patients with a concurrent malignancy or history of treatment (other than surgery) for another tumor within the last year are ineligible
* Patients with diffuse intrinsic pontine tumors as seen on MRI (\> 2/3 of pons involvement on imaging) are not eligible even if biopsy reveals grade I/II histology
* Patients may not be receiving any other investigational agents
* Patients with any serious medical or psychiatric illness/condition, including substance use disorders or ophthalmological conditions, likely in the judgment of the investigator to interfere or limit compliance with study requirements/treatment
* Patients who, in the opinion of the investigator, are not able to comply with the study procedures are not eligible
* Female patients who are pregnant are not eligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
* Lactating females who plan to breastfeed their infants are not eligible
* Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 12 weeks after stopping study therapy are not eligible.
* Note: Women of child-bearing potential and males with sexual partners who are pregnant or who could become pregnant (i.e., women of child-bearing potential) should use effective methods of contraception for the duration of the study and for 12 weeks after stopping study therapy to avoid pregnancy and/or potential adverse effects on the developing embryo
* Known genetic disorder that increases risk for coronary artery disease. Note: The presence of dyslipidemia in a family with a history of myocardial infarction is not in itself an exclusion unless there is a known genetic disorder documented
* Symptomatic heart failure
* New York Health Association (NYHA) class II-IV prior or current cardiomyopathy
* Severe valvular heart disease
* History of atrial fibrillation
* Current or past history of central serous retinopathy
* Current or past history of retinal vein occlusion or retinal detachment
* Patients with uncontrolled glaucoma
* If checking pressure is clinically indicated, patients with intraocular pressure (IOP) \> 22 mmHg or ULN adjusted by age are not eligible
* Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to study enrollment even if less than 100% of the daily recommended dosing for vitamin E
* Surgery within 2 weeks prior to enrollment, with the exception of surgical biopsy, placement of a vascular access device or cerebral spinal fluid (CSF) diverting procedure such as endoscopic third ventriculostomy (ETV) and ventriculoperitoneal (VP) shunt.
* Note: Patients must have healed from any prior surgery
* Patients who have an uncontrolled infection are not eligible
A Study of Repotrectinib in Pediatric and Young Adult Subjects Harboring ALK, ROS1, OR NTRK1-3 Alterations
Phase 1 will evaluate the safety and tolerability at different dose levels of repotrectinib in pediatric and young adult subjects with advanced or metastatic malignancies harboring anaplastic lymphoma kinase (ALK), receptor tyrosine kinase encoded by the gene ROS1 (ROS1), or neurotrophic receptor kinase genes encoding TRK kinase family (NTRK1-3) alterations to estimate the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) and select the Pediatric Recommended Phase 2 Dose (RP2D).
Phase 2 will determine the anti-tumor activity of repotrectinib in pediatric and young adult subjects with advanced or metastatic malignancies harboring ROS1 or NTRK1-3 alterations.
• Documented genetic ROS1 point mutation, fusion, or amplification or NTRK1-3 fusion as identified by local testing in a Clinical Laboratory Improvement Amendments (CLIA) laboratory in the US or equivalently accredited diagnostic lab outside the United States (US) is required.
• Phase 1: Age \<12 years; Phase 2: Age 12- 25 years
• Prior cytotoxic chemotherapy is allowed.
• Prior immunotherapy is allowed.
• Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer therapy to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 Grade less than or equal to 1.
• All subjects must have measurable disease by RECIST v1.1 or Response Assessment in Neuro-Oncology (RANO) criteria at time of enrollment.
• Subjects with a primary CNS tumor or CNS metastases must be neurologically stable on a stable or decreasing dose of steroids for at least 7 days prior to enrollment.
• Subjects must have a Lansky (\< 16 years) or Karnofsky (≥ 16 years) score of at least 50.
• Life expectancy greater than or equal to 12 weeks, in the investigator's opinion.
• Adequate hematologic, renal and hepatic function.
Phase 2
Inclusion Criteria:
• Cohort Specific
Inclusion Criteria:
* Cohort 1: Subjects with NTRK fusion gene positive (NTRK+) advanced solid tumors (including primary CNS tumors), that are tropomyosin receptor kinase (TRK) TKI naïve;
* Cohort 2: subjects with NTRK+ advanced solid tumors (including primary CNS tumors), that are TRK TKI pre-treated;
* Cohort 3: subjects with advanced solid tumors with ROS1 gene fusions or other ROS1 aberrations (including amplifications and point mutations) with measurable disease.
• Subjects in Cohorts 1 and 2 must have prospectively confirmed measurable disease by BICR prior to enrollment.
Key Exclusion Criteria (Phase 1 and Phase 2):
• Subjects with neuroblastoma with only bone marrow disease evaluable by bone marrow aspiration only.
• Major surgery within 14 days (2 weeks) of start of repotrectinib treatment. Central venous access (Broviac, Mediport, etc.) placement does not meet criteria for major surgery.
• Known active infections requiring ongoing treatment (bacterial, fungal, viral including HIV positivity).
• Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption.
• Any of the following cardiac criteria:
* Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTc) \> 480 msec obtained from three ECGs, using the screening clinic ECG machine-derived QTc value
* Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval \> 250 msec)
* Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval
• Peripheral neuropathy of CTCAE ≥grade 2.
• Subjects being treated with or anticipating the need for treatment with strong CYP3A4 inhibitors or inducers.
• Any potential allergies to repotrectinib and/or its excipients.
Cobimetinib in Refractory Langerhans Cell Histiocytosis (LCH), and Other Histiocytic Disorders (NACHO-COBI)
This is a research study of a drug called cobimetinib in children and adults diagnosed with
Langerhans cell histiocytosis (LCH), and other histiocytic disorders that has returned or
does not respond to treatment. Cobimetinib blocks activation of a protein called
Mitogen-activated protein kinase (MEK) that is part of incorrect growth signals in
histiocytosis cells. Four different groups of patients will be enrolled.
INCLUSION CRITERIA:
Age at study entry
• For Group 1: Participant must be at least 6 months of age and less than 21 years of
age at the time of enrollment
• For Group 2: Participant may be at least 6 months of age at the time of enrollment
• For Group 3: Participant must be at least 6 months of age and less than 21 years of
age at the time of enrollment
• For Group 4: Participant must be 21 years of age or older at the time of enrollment
• Participant must be able to take an enteral dose and formulation of medication. Study
medication is only available as an oral suspension or tablet which may be taken by
mouth or other enteral route such as nasogastric or gastric tube.
• Biopsy proven LCH -AND
• Failure of at least front-line therapy for LCH with evaluable disease. -OR
• Diagnosis of LCH-associated neurodegenerative disease with radiologic or clinical
progression within the past 3 months. -OR
• Biopsy proven JXG, ECD, RDD, histiocytic sarcoma, or other histiocytic lesion (newly
diagnosed or relapsed/refractory disease) with evaluable active disease.
Performance Level:
-Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50% for patients ≤ 16 years of
age.
Adequate Hematologic Function Defined as:
• ANC ≥ 0.75 x 10^9/L (unsupported/without growth factor stimulant)
• Platelet count ≥ 75 x 10^9/L (unsupported/without transfusion within the past 7 days).
• Patients with marrow disease must have platelet count of >/= 75 x 10^9/L (transfusion
support allowed) and must not be refractory to platelet transfusions.
• Hemoglobin ≥ 8 g/dL (unsupported/without transfusion within the past 7 days)
• Patients with marrow disease must have hemoglobin ≥ 8 g/dL (transfusion support
allowed).
Adequate Renal Function Defined as:
• Calculated creatinine clearance (or radioisotope GFR) ≥ 70 mL/min/1.73m^2 or serum
creatinine based on age/gender as follows:
Maximum Serum Creatinine (mg/dL) Age 2 to < 6 years: Male 0.8 mg/d, Female 0.8; 6 to < 10
years: Male 1 mg/dL,Female 1; 10 to < 13 years: Male 1.2 mg/dL; Female 1.2; 13 to < 16
years: Male 1.5 mg/dL ; Female 1.4; ≥ 16 years: Male 1.7 mg/dL; Female 1.4;
Adequate Liver Function Defined as:
• Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for
age
• AST and ALT ≤ 3x ULN (≤ 5 x ULN for participants with liver involvement)
• Serum albumin ≥ 2 g/dL.
For patients with liver disease caused by histiocytic disorder:
• Patients may be enrolled with abnormal bilirubin, AST, ALT and albumin with documentation
of histiocytic liver disease.
Adequate Cardiac Function Defined as:
• Fractional shortening (FS) of ≥ 30% or ejection fraction of ≥ 50% by echocardiogram at
baseline, as determined by echocardiography or multigated acquisition scan (MUGA) within 28
days prior to enrollment. Depending on institutional standard, either FS or LVEF is
adequate for enrollment if only one value is measured; if both values are measured, then
both values must meet criteria above
Pregnancy/Birth Control
• Female patients of childbearing potential require a negative urine or serum pregnancy
test for eligibility and again at database registration, if more than 2 weeks has
elapsed.
• Female patients of childbearing potential must agree to follow the contraceptive
requirements using two forms of effective contraceptive methods for the duration of
the study treatment. Male patients with sexual partners who are pregnant or who could
become pregnant (i.e., women of child-bearing potential) must agree to use two forms
of effective methods of contraception (one of which must be a barrier method) during
the treatment period and for at least 3 months after the last dose of the study drug
to avoid pregnancy and/or potential adverse effects on a developing embryo. Agreement
to true abstinence (not periodic abstinence or withdrawal method) is an acceptable
method of birth control.
EXCLUSION CRITERIA:
• Prior and Concomitant Use of Drugs with CYP3A4 inducing/inhibiting activity: Patient
taking strong inducers or inhibitors of CYP3A4 within 14 days prior to study enrollment,
including but not limited to the following: erythromycin, clarithromycin, ketoconazole,
azithromycin, itraconazole, grapefruit juice or St. John's wort.
• Prior Therapy Restrictions Completion of previous chemotherapy, immunotherapy,
radiotherapy, or targeted therapy for LCH (or other histiocytic disorder) at least 28
days (except where specified below) prior to study enrollment, with resolution of all
associated toxicity to ≤ Grade 1 prior to study enrollment (exception for alopecia and
ototoxicity which do not need to be resolved ≤ Grade 1). Patients must have fully
recovered from the acute toxic effects of all prior anti-cancer therapy and must meet
the following minimum duration from prior anti-cancer directed therapy prior to
enrollment. If after the required timeframe, the laboratory eligibility criteria are
met, the patient is considered to have recovered adequately.
• Radiation therapy within the 28 days prior to enrollment.
• Any prior treatment with Cobimetinib.
• Treatment with a long-acting hematopoietic growth factor within 14 days prior to
initiation of study drug or a short-acting hematopoietic growth factor within 7
days prior to enrollment.
• Treatment with hormonal therapy (except hormone replacement therapy or oral
contraceptives), immunotherapy, biologic therapy, investigational therapy, or
herbal cancer therapy within 28 days or < 5 half-lives, whichever is longer,
prior to study enrollment.
• Treatment with high-dose chemotherapy and stem-cell rescue (autologous stem cell
transplant) or allogeneic stem cell transplant within 90 days prior to
enrollment. Anti-GVHD agents post-transplant: Patients who are receiving
cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease
post bone marrow transplant are not eligible for this trial.
• For patients with brain tumors (intracranial masses), use of anticoagulants
within 7 days prior to enrollment.
• Corticosteroid therapy <0.5 mg/kg/day averaged during the month prior to study
enrollment is permissible but must be discontinued fourteen (14) days prior to
enrollment. Patients with documented brain lesions receiving corticosteroids for
management of cerebral edema must be on a stable dose for fourteen (14) days
prior to enrollment.
• Patient has received treatment with investigational therapy within 4 weeks prior
to initiation of study drug.
• Patients taking anticoagulants or have a pre-existing bleeding disorder unrelated
to histiocytic disease.
• Exclusions for other illness
• Other active malignancy or history of secondary malignancy.
• Refractory nausea and vomiting, malabsorption, external biliary shunt
• Infection: Patients who have a known active infection (excluding documented
fungal infection of the nail beds) within 28 days prior to enrollment that has
not completely resolved.
• Major surgical procedure or significant traumatic injury within 28 days prior to
enrollment, or anticipation of need for major surgical procedure during the
course of the study. Placement of a vascular access device or minor surgery is
permitted within fourteen (14) days prior to study enrollment (provided that the
wound has healed).
• History of significant bowel resection that would preclude adequate absorption or
other significant malabsorptive disease.
• History of pneumonitis.
• Ophthalmologic considerations: Patients with known significant ophthalmologic
conditions or known risk factors for retinal vein occlusion are not eligible.
Specifically, patients with a history of retinal vein occlusion (RVO), retinal
detachment, retinal pathology on ophthalmologic exam, retinopathy of prematurity,
central serous chorioretinopathy (CSSCR), neovascular retinopathy, intraocular
pressure > 21 mmHg, and predisposing factors to RVO (e.g., uncontrolled
hypertension, diabetes, or hyperlipidemia, coagulopathy) will be excluded.
Patients with longstanding and stable ophthalmologic findings secondary to
existing conditions are eligible with appropriate written documentation and
approval from Study Chair.
• History of solid organ transplantation: Patients who have received a prior solid
organ transplantation are not eligible.
• Any other disease, metabolic or psychological dysfunction, physical examination
finding, or clinical laboratory finding giving reasonable suspicion of a disease
or condition that in the opinion of the investigator contraindicates use of an
investigational drug or places the patient at unacceptable risk from treatment
complications.
• History of clinically significant cardiac dysfunction, including the following:
• Clinically significant cardiac arrhythmias including brady-arrhythmias and/or
patients who require anti-arrhythmic therapy (with the exception of beta blockers
or digoxin). Patients with controlled atrial fibrillation are not excluded.
• Unstable arrhythmia
• Unstable angina, or new-onset angina within 3 months prior to initiation of study
treatment
• Symptomatic congestive heart failure, defined as New York Heart Association Class
II or higher
• Myocardial infarction within 3 months prior to initiation of study treatment
• Known chronic human immunodeficiency virus (HIV).
• History of Grade ≥ 2 CNS hemorrhage or history of any CNS hemorrhage within 28 days of
enrollment.
• Female patients who are pregnant or lactating. Pregnant or lactating women will not be
entered on this study because there is no available information regarding human fetal
or teratogenic toxicities.
Drug: Cobimetinib
Histiocytic Sarcoma, Juvenile Xanthogranuloma, Brain and Nervous System, Bones and Joints, Liver, Lung/Thoracic, Other Hematopoietic, Langerhan's Cell Histiocytosis, Erdheim-Chester Disease, Rosai Dorfman Disease, Neuro-Degenerative Disease, Histiocytic Disorders, Malignant
Dabrafenib Combined With Trametinib After Radiation Therapy in Treating Patients With Newly-Diagnosed High-Grade Glioma
This phase II trial studies how well the combination of dabrafenib and trametinib works after radiation therapy in children and young adults with high grade glioma who have a genetic change called BRAF V600 mutation. Radiation therapy uses high energy rays to kill tumor cells and reduce the size of tumors. Dabrafenib and trametinib may stop the growth of tumor cells by blocking BRAF and MEK, respectively, which are enzymes that tumor cells need for their growth. Giving dabrafenib with trametinib after radiation therapy may work better than treatments used in the past in patients with newly-diagnosed BRAF V600-mutant high-grade glioma.
* PRE-ENROLLMENT ELIGIBILITY SCREENING: Patients must be =\< 25 years of age at the time of enrollment on APEC14B1 Part A CNS/HGG pre-enrollment eligibility screening.
* Note: This required age range applies to the pre-enrollment eligibility screening for all HGG patients. Individual treatment protocols may have different age criteria.
* PRE-ENROLLMENT ELIGIBILITY SCREENING: Patient is suspected of having localized newly-diagnosed HGG, excluding metastatic disease.
* PRE-ENROLLMENT ELIGIBILITY SCREENING: Patient and/or their parents or legal guardians have signed informed consent for eligibility screening on APEC14B1 Part A.
* PRE-ENROLLMENT ELIGIBILITY SCREENING: The specimens obtained at the time of diagnostic biopsy or surgery must be submitted through APEC14B1 as soon as possible (ASAP), preferably within 5 calendar days of the procedure.
* Please note: See the APEC14B1 Manual of Procedures for a full list of detailed instructions for submitting required materials and for shipping details.
* Patients must be \>= 3 years and =\< 25 years of age at the time of enrollment.
* Patients must have eligibility confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1
* Newly diagnosed high-grade glioma with BRAF\^V600-mutation
* Results for H3 K27M by immunohistochemistry (IHC) or sequencing
* Histologically confirmed high-grade glioma (World Health Organization \[WHO\] grade III or IV) including but not limited to: anaplastic astrocytoma (AA), anaplastic pleomorphic xanthoastrocytoma (aPXA), anaplastic gangliogliomas (aGG), glioblastoma (GB), and high-grade astrocytoma, not otherwise specified (NOS).
* Patients must have had histologic verification of a high-grade glioma diagnosis. CSF cytology by lumbar puncture must be done if clinically indicated and determined to be safe prior to study enrollment. If cytology proves positive, the patient would be considered to have metastatic disease and would, therefore, be ineligible.
* A pre- and post-operative brain MRI with and without contrast and a baseline spine MRI with contrast must be obtained prior to enrollment. The requirement for a post-operative MRI is waived for patients who undergo biopsy only. If the spine MRI is positive, the patient would be considered to have metastatic disease and would be ineligible.
* Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients \> 16 years of age and Lansky for patients =\< 16 years of age.
* Peripheral absolute neutrophil count (ANC) \>= 1000/uL (within 7 days prior to enrollment).
* Platelet count \>= 100,000/uL (transfusion independent) (within 7 days prior to enrollment).
* Hemoglobin \>= 8.0 g/dL (may receive red blood cell \[RBC\] transfusions) (within 7 days prior to enrollment).
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 (within 7 days prior to enrollment) or
* A serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
* Age 3 to \< 6 years (Male 0.8 mg/dL, Female 0.8 mg/dL)
* Age 6 to \< 10 years (Male 1 mg/dL, Female 1 mg/dL)
* Age 10 to \< 13 years (Male 1.2 mg/dL, Female 1.2 mg/dL)
* Age 13 to \< 16 years (Male 1.5 mg/dL, Female 1.4 mg/dL)
* Age \>= 16 years (Male 1.7 mg/dL, Female 1.4 mg/dL)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment), and
* Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 135 U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L.
* Patients with a seizure disorder may be enrolled if their seizures are well controlled while on non-enzyme inducing anticonvulsants permitted on this study.
* All patients and/or their parents or legal guardians must sign a written informed consent
* Patients must be enrolled and protocol therapy must be projected to begin no later than 31 days after definitive surgery (day 0). If a biopsy only was performed, the biopsy date will be considered the date of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery.
Exclusion Criteria:
* Patients with intrinsic brainstem or primary spinal cord tumors will be excluded.
* Patients with metastatic disease (defined as neuraxis dissemination either by imaging or by cytology) will be excluded.
* Patients must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant for the treatment of HGG other than surgical intervention and/or corticosteroids.
* Previous treatment with dabrafenib or another RAF inhibitor, trametinib or another MEK inhibitor, or an ERK inhibitor.
* Patients with a history of a malignancy with confirmed activating RAS mutation.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib, trametinib, and their excipients.
* Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease, or uncontrolled infection), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol.
* Presence of active gastrointestinal (GI) disease or other condition (e.g., small bowel or large bowel resection) that will interfere significantly with the absorption of drugs.
* History of hepatitis B virus, or hepatitis C virus infection (patients with laboratory evidence of cleared hepatitis B virus and/or hepatitis C virus may be enrolled).
* History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following:
* Recent myocardial infarction (within the last 6 months);
* Uncontrolled congestive heart failure;
* Unstable angina (within last 6 months);
* Clinically significant (symptomatic) or known, uncontrolled cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree atrioventricular \[AV\] block without a pacemaker) except sinus arrhythmia within the past 24 weeks prior to the first dose of study treatment;
* Coronary angioplasty or stenting (within last 6 months);
* Intra-cardiac defibrillators;
* Abnormal cardiac valve morphology (\>= grade 2) documented by echocardiogram.
* Patients with a history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR), or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension).
* Patients with presence of interstitial lung disease or pneumonitis.
* Female patients who are pregnant are ineligible since there is yet no available information regarding human fetal or teratogenic toxicities.
* Lactating females are not eligible unless they have agreed not to breastfeed their infants for the duration of the study and for 4 months following discontinuation of study therapy.
* Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
* Sexually active patients of reproductive potential (male or female) are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 4 months following discontinuation of study therapy. Male patients (including those who have had a vasectomy) taking dabrafenib and trametinib combination therapy must use a condom during intercourse while on study and for 16 weeks after stopping treatment, and should not father a child during these periods. Women of childbearing potential should use effective non-hormonal contraception during therapy and for 4 weeks following discontinuation of dabrafenib and at least 4 months following the last dose of trametinib in patients taking combination therapy. Women should be advised that dabrafenib may decrease the efficacy of hormonal contraceptives and an alternate method of contraception, such as barrier methods, should be used.