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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
The National Liver Cancer Screening Trial is an adaptive randomized phase IV Trial comparing ultrasound-based versus biomarker-based screening in 5500 patients with cirrhosis from any etiology or patients with chronic hepatitis B infection. Eligible patients will be randomized in a 1:1 fashion to Arm A using semi-annual ultrasound and AFP-based screening or Arm B using semi-annual screening using GALAD alone. Randomization will be stratified by sex, enrolling site, Child Pugh class (A vs. B), and HCC etiology (viral vs. non-viral). Patients will be recruited from 15 sites (mix of tertiary care and large community health systems) over a 3-year period, and the primary endpoint of the phase IV trial, reduction in late-stage HCC, will be assessed after 5.5 years.
Patient must meet all of the following inclusion criteria:
• Adult patients ages 18-85 with cirrhosis from any etiology or with chronic hepatitis B with a PAGE-B score greater than 9 within 12 months of enrollment
• Patient is eligible for HCC surveillance according to treating physician or by the site investigator
• Able to provide informed consent
• Life expectancy \>6 months (after consent) as determined by the treating provider or site investigator
Exclusion Criteria:
Patient will be excluded for any of the following exclusion criteria:
• Child Pugh C cirrhosis
• History or clinical symptoms of hepatocellular carcinoma or cholangiocarcinoma
• History of solid nodule on baseline ultrasound (i.e., lesion 1cm or greater) within 9 months prior to consent without subsequent diagnostic CT/MRI demonstrating benign nature)
• AFP \>20 ng/mL within 6 months prior to consent, in the absence of a contrast-enhanced CT or MRI within 6 months of AFP (before or after) level demonstrating lack of suspicious liver lesions
• Newly diagnosed LR-3 greater than or equal to 1 cm within 6 months prior to consent
• History of LR-4, LR-5, or LR-M on multi-phase CT or contrast-enhanced MRI within 6 months prior to consent
• Presence of another active cancer besides non-melanomatous skin cancer or indolent cancer under active surveillance (e.g., prostate cancer or renal cell carcinoma) within the 2 years prior to consent
• Patient's provider is planning to use MRI- or CT- based surveillance moving forward
• History of a transjugular intrahepatic portosystemic shunt (TIPS)
• History of Fontan associated liver disease or cardiac cirrhosis
• History of solid organ transplantation
• Actively listed for liver transplantation
• Diagnosis of alcohol-associated hepatitis within 3 months prior to consent
• Documented current or continued signs and symptoms of acute Wilson disease (acute liver failure, acute neurological deficits, hemolysis)
• In patients with primary sclerosing cholangitis (PSC): Current active cholangitis within 90 days prior to consent
• Known or documented habitual non-adherence to previous research studies or medical procedures or unwillingness to adhere to protocol (e.g., unwilling to obtain consent or samples)
• In patients living with HIV: CD4+ T cell count less than 100 cells/mm3 within 60 days prior to consent
• Known pregnancy at consent
• Active warfarin use
DIAGNOSTIC_TEST: GALAD, DIAGNOSTIC_TEST: Liver Ultrasound with or without AFP
Optimization of Saturation Targets And Resuscitation Trial (OptiSTART) (OptiSTART)
This study is designed to answer one of the fundamental gaps in knowledge in the
resuscitation of preterm infants at birth: What is the optimal target oxygen saturation
(SpO2) range that increases survival without long-term morbidities? Oxygen (O2) is routinely
used for the stabilization of preterm infants in the delivery room (DR), but its use is
linked with mortality and several morbidities including bronchopulmonary dysplasia (BPD). To
balance the need to give sufficient O2 to correct hypoxia and avoid excess O2, the neonatal
resuscitation program (NRP) recommends initiating preterm resuscitation with low (≤ 30%)
inspired O2 concentration (FiO2) and subsequent titration to achieve a specified target SpO2
range. These SpO2 targets are based on approximated 50th percentile SpO2 (Sat50) observed in
healthy term infants. However, the optimal SpO2 targets remain undefined in the preterm
infants. Recent data suggest that the current SpO2 targets (Sat50) may be too low. The
investigators plan to conduct a multicenter RCT of Sat75 versus Sat50 powered for survival
without BPD. The investigators will randomize 700 infants, 23 0/7- 30 6/7 weeks' GA, to 75th
percentile SpO2 goals (Sat75, Intervention) or 50th percentile SpO2 goals (Sat50, control).
Except for the SpO2 targets, all resuscitations will follow NRP guidelines including an
initial FiO2 of 0.3. In Aim 1, the investigators will determine whether targeting Sat75
compared to Sat50 increases survival without lung disease (BPD). In addition, the
investigators will compare the rates of other major morbidities such as IVH. In Aim 2, the
investigators will determine whether targeting Sat75 compared to Sat50 increases survival
without neurodevelopmental impairment at 2 years of age. In Aim 3, the investigators will
determine whether targeting Sat75 compared to Sat50 decreases oxidative stress.
• Prenatally diagnosed cyanotic congenital heart disease
• Prenatally diagnosed congenital diaphragmatic hernia
• Parents request no resuscitation
• If preductal saturations can not be measured by 3 minutes after pulse oximeter sensor
is applied to the newborn
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
The purpose of this study is to evaluate safety and tolerability and to determine the maximum
tolerated dose (MTD) and/or recommended dose (RD) of SGR-1505.
• Subject must have a history of histologically or cytologically confirmed mature B-cell
malignancy.
• Subject must have measurable or detectable disease according to the applicable
disease-specific classification system.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
• Life expectancy ≥ 12 weeks.
Exclusion Criteria:
• For a subject with indolent NHL and CLL/SLL, the subject is in need of immediate
cytoreductive therapy (unless the patient has no remaining treatment choice with
potential benefit) and has an indication for treatment.
• Subject has previous invasive malignancy in the last 2 years.
• Subject has a known allergy to SGR-1505 or excipients of SGR-1505.
• Subject has symptomatic or active CNS involvement of disease.
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that would place the participant at increased risk to the use of an
investigational drug.
Drug: SGR-1505
Splenic Marginal Zone Lymphoma, Waldenström Macroglobulinemia, Chronic Lymphocytic Leukemia, Burkitt Lymphoma, Plasmablastic Lymphoma, Follicular Lymphoma, Nodal Marginal Zone Lymphoma, ALK-Positive Large B-Cell Lymphoma, Primary Cutaneous Diffuse Large B-Cell Lymphoma, Primary Effusion Lymphoma, Non Hodgkin Lymphoma, Mantle Cell Lymphoma, Lymphoid Leukemia, Non-Hodgkins Lymphoma, High-grade B-cell Lymphoma, Primary Mediastinal Large B Cell Lymphoma, Lymphoplasmacytic Lymphoma, DLBCL, EBV-Positive DLBCL, Nos, Mature B-Cell Neoplasm, MALT Lymphoma, Pediatric-Type Follicular Lymphoma, IRF4 Gene Rearrangement, Primary Cutaneous Follicle Center Lymphoma, DLBCL Germinal Center B-Cell Type, T-Cell/Histiocyte Rich Lymphoma, HHV8-Positive DLBCL, Nos, Duodenal-Type Follicular Lymphoma
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
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
Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1 or SMARCA4 Deficient Tumors
This phase I/II trial studies how well tiragolumab and atezolizumab works when given to children and adults with SMARCB1 or SMARCA4 deficient tumors that have either come back (relapsed) or do not respond to therapy (refractory). SMARCB1 or SMARCA4 deficiency means that tumor cells are missing the SMARCB1 and SMARCA4 genes, seen with some aggressive cancers that are typically hard to treat. Immunotherapy with monoclonal antibodies, such as tiragolumab and atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
* Patients must be \>= 12 months of age at the time of study enrollment. For part A, patients must be \< 18 years old at enrollment. For part B, there is no upper age limit
* The Part B (phase 2) cohorts will initially open concurrently with the part A but will only enroll patients at least 18 years of age. Patients \< 18 years of age will be included in the part B cohorts only after the tiragolumab monotherapy dose has been assessed to be safe in the part A portion
* Patients must have SMARCB1 (INI1) or SMARCA4 deficient tumors verified through institutional immunohistochemistry (IHC) or molecular confirmation of a pathologic SMARCB1 (INI1) or SMARCA4 loss or mutation from a Clinical Laboratory Improvement Act (CLIA) certified lab with the following disease histologies:
* Renal medullary carcinoma
* Malignant rhabdoid tumor (extra-CNS)
* Atypical teratoid rhabdoid tumor (CNS)
* Poorly differentiated chordoma
* Epithelioid sarcoma
* Other SMARCB1 or SMARCA4 deficient tumors
* Note: Molecular studies will only be used if IHC is equivocal or cannot be performed. Documentation of the institutional IHC or molecular testing must be uploaded via the RAVE system
* Part A: Patients must have either measurable or evaluable disease Part B: Patients must have either measurable disease per RECIST v1.1 for non-CNS tumors or CNS response criteria for CNS tumors
* Note: See protocol for specific exclusion for patients with CNS primary or metastatic disease
* Patients must have relapsed, refractory disease or newly diagnosed disease for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
* Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2 (Karnofsky/Lansky score of \>= 50). Use Karnofsky for patients \> 16 years of age and Lansky for patients =\< 16 years of age. Note: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment. 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
* 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 numerical eligibility criteria are met, e.g., blood count criteria, the patient is considered to have recovered adequately
* Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: See Developmental Therapeutics (DVL) homepage on the Children's Oncology Group (COG) Members site for commercial and investigational agent classifications. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator prior to enrollment
* \>= 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea). Please refer to the table of myelosuppressive/Anticancer Agents on the COG website: https://www.cogmembers.org/uploadedFiles/Site/Disc/DVL/Documents/TableOfMyelosuppressiveAnti-CancerAgents.pdf
* 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. See the DVL homepage on the COG Members site for commercial and investigational agent classifications. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator prior to enrollment
* 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
* 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
* Interleukins, interferons and cytokines (other than hematopoietic growth factors): \>= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
* Stem cell infusions (with or without total-body irradiation \[TBI\]):
* Autologous stem cell infusion including boost infusion: \>= 30 days
* Cellular therapy: \>= 30 days after the completion of any type of cellular therapy (e.g., modified T cells, natural killer \[NK\] cells, dendritic cells, etc.)
* External radiation therapy (XRT)/external beam irradiation including protons: \>= 14 days after local XRT; \>= 90 days after TBI, craniospinal XRT or if radiation to \>= 50% of the pelvis; \>= 42 days if other substantial bone marrow (BM) radiation
* Radiopharmaceutical therapy (e.g., radiolabeled antibody, iodine I 131 metaiodobenzylguanidine \[131I MIBG\]): \>= 42 days after systemically administered radiopharmaceutical therapy
* Patients must not have had prior TIGIT targeting therapy
* Patients must not have received prior therapy with an anti- PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA4 agent or with an agent directed to another stimulatory or co-inhibitory T cell receptor (i.e. OX-40, CD137)
* Patients must not have received live/attenuated vaccine within 30 days of first dose of treatment
* Patients must not be receiving concomitant systemic steroid medications and \>= 14 days must have elapsed since last dose of systemic corticosteroid with the following exceptions:
* The use of physiologic doses of corticosteroids (5 mg/m\^2/day up to 10 mg/day of prednisone equivalent) is acceptable
* The use of topical, inhaled, or ophthalmic corticosteroids are acceptable
* The use of acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are acceptable
* Treatment with systemic immunosuppressive medication (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-alpha \[TNF-alpha\] agents) must have concluded \>= 14 days prior to study enrollment
* For patients with solid tumors without known bone marrow involvement
* Peripheral absolute neutrophil count (ANC) \>= 1000/uL (must be performed within 7 days prior to enrollment)
* For patients with solid tumors without known bone marrow involvement
* Platelet count \>= 100,000/uL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) (must be performed within 7 days prior to enrollment)
* Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts above (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions). These patients will not be evaluable for hematologic toxicity
* A creatinine based on age/gender as follows (must be performed within 7 days prior to 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 OR- a 24 hour urine creatinine clearance \>= 70 mL/min/1.73 m\^2 (must be performed within 7 days prior to enrollment) 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) (must be performed within 7 days prior to enrollment)
* Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility
* Bilirubin (sum of conjugated + unconjugated or total) =\< 1.5 x upper limit of normal (ULN) for age (must be performed within 7 days prior to enrollment)
* Patients with known Gilbert disease: Total bilirubin =\< 3 x ULN
* Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 135 U/L (must be 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 (must be performed within 7 days prior to enrollment)
* Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled as evidenced by no increase in seizure frequency in the prior 7 days
* Nervous system disorders (Common Terminology Criteria for Adverse Events \[CTCAE\] v5) resulting from prior therapy must be =\< grade 2, with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible
* International normalized ratio (INR) =\< 1.5 (must be performed within 7 days prior to enrollment)
* Serum amylase =\< 1.5 x ULN (must be performed within 7 days prior to enrollment)
* Serum lipase =\< 1.5 x ULN (must be performed within 7 days prior to enrollment)
* Grade 1 or lower calcium level
* Note: can have history of hypercalcemia as long as controlled and asymptomatic
Exclusion Criteria:
* Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in female patients of childbearing potential. Female patients of childbearing potential are defined as those who are past the onset of menarche and are not surgically sterile (i.e., bilateral salpingectomy, bilateral oophorectomy, complete hysterectomy) or post-menopausal. Males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (e.g., male or female condom) for the duration of therapy and at least 90 days after final dose of tiragolumab and 150 days after final dose of atezolizumab, whichever is later. Abstinence is an acceptable method of birth control.
* It is not known if atezolizumab or tiragolumab are present in breast milk; however, IgG immunoglobulins are found in milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended during therapy and for at least 150 days after the last dose of atezolizumab and 90 days after the last dose of tiragolumab, whichever is later
* Concomitant medications:
* Corticosteroids:
* Patients must not be receiving concomitant systemic steroid medications and \>= 14 days must have elapsed since last dose of systemic corticosteroid with the following exceptions:
* The use of physiologic doses of corticosteroids (5 mg/m\^2/day up to 10 mg/day of prednisone equivalent) is acceptable
* The use of topical, inhaled, or ophthalmic corticosteroids are acceptable
* The use of acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g. 48 hours of corticosteroids for a contrast allergy) are acceptable
* Investigational drugs: Patients who are currently receiving another investigational drug are not eligible
* Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible
* Systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, and thalidomide) during study treatment because these agents could potentially alter the efficacy and safety of study treatments would not be eligible
* Patients must not have a known hypersensitivity to any component of tiragolumab or atezolizumab injection
* History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
* Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or tiragolumab formulation
* Patients who have undergone allogeneic bone marrow or allogeneic cell transplant are not eligible
* Patients with CNS metastases from non-CNS primary tumors are not eligible unless CNS metastases have been previously treated and sequential imaging shows no evidence for active disease in the CNS.
* Patients with primary CNS tumors (including ATRT) with involvement of the brainstem are not eligible. Note: Patients with ATRT with M0-M4 disease without involvement of the brain stem are allowed to participate
* Patients must not have active autoimmune disease that has required systemic treatment in the past 12 months, or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy are not excluded. Replacement therapy (e.g. thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and these patients are eligible
* Patients who have active immune deficiency are not eligible
* Patients who have known active tuberculosis are not eligible
* Hepatitis B or C infection:
* Patients \< 18 years old at enrollment, who have known hepatitis B or C
* Patients \>= 18 years old at enrollment with:
* Positive hepatitis B surface antigen (HBsAg), OR
* Positive total hepatitis B core antibody (HBcAb) who have a quantitative hepatitis B virus (HBV) deoxyribonucleic acid (DNA) \>= 500 IU/mL, OR
* Positive hepatitis C virus (HCV) antibody with a positive HCV ribonucleic acid (RNA) test
* Note: For adults (\>= 18 years old at enrollment), hepatitis B serology testing is required to determine eligibility. The HBV DNA test is required only for patients who have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb test. For adults (\>= 18 years old at enrollment), hepatitis C serology testing is required to determine eligibility. The HCV RNA test is required only for patients who have a positive HCV antibody test
* Patients who have a known, recent Epstein-Barr virus (EBV) infection or known history of chronic, active infection are not eligible
* Patients who have history of or active human immunodeficiency virus (HIV) are not eligible except patients who are stable on anti-retroviral therapy, have a CD4 count \>= 200/uL, and have an undetectable viral load
* Patients who have significant cardiovascular disease (such as New York Heart Association class III or IV congestive heart failure, myocardial infarction, or cerebrovascular accident) within 3 months prior to study enrollment, unstable arrhythmia, or unstable angina are not eligible
* Patients who have a major surgical procedure, other than for diagnosis, within 4 weeks prior to study enrollment, or the anticipation of the need for a major surgical procedure during the study are not eligible
* Patients who have a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or known active pneumonitis are not eligible. History of radiation pneumonitis in the radiation field is permitted
* Patients who have uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) are not eligible. Patients with indwelling catheters (e.g., PleurX) are allowed
* Patients who have an uncontrolled infection are not eligible
* Patients who have received a prior solid organ transplantation are not eligible
* Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
Study of the Adverse Events and Change in Disease State of Pediatric Participants (and Young Adults Between the Ages of 18-25) With Relapsed/Refractory Aggressive Mature B-cell Neoplasms Receiving Subcutaneous (SC) Injections of Epcoritamab
The most common types of mature B-cell lymphomas (MBLs) in children are Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). Initial treatment cures 90% - 95% of children with these malignancies, leaving a very small population of relapsed/refractory disease with a poor prognosis. The purpose of this study is to assess the safety and tolerability of epcoritamab in pediatric participants with relapsed/refractory aggressive mature B-cell neoplasms and young adult participants with Burkitt's or Burkitt-like lymphoma/leukemia. Adverse events and change in disease activity will be assessed.
Epcoritamab is an investigational drug being developed for the treatment of relapsed/refractory aggressive mature B-cell neoplasms. Participants will receive subcutaneous (SC) of epcoritamab. Approximately 15 pediatric participants with a diagnosis of relapsed/refractory aggressive mature B-cell neoplasms and and young adult participants, ages of 18-25, with a diagnosis of Burkitt's or Burkitt-like lymphoma/leukemia will be enrolled at 50 sites globally.
Participants will receive subcutaneous epcoritamab in 28-day cycles. Participants will be followed for a minimum of 3 years after enrollment.
There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at an approved institution (hospital or clinic). The effect of the treatment will be frequently checked by medical assessments, blood tests, questionnaires and side effects.
* Participants \>= 1 and \< 18 years old at time of primary diagnosis with Burkitt's or Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma (DLBCL), or other aggressive mature (CD20+) B-cell lymphomas. Participants up to 25 years of age with Burkitt's or Burkitt-like lymphoma/leukemia are also eligible.
* Disease pathologically confirmed (tumor tissue) by local testing.
* Relapsed or primary refractory disease meeting any of the following criteria:
* Progressive disease at any time during second-line chemoimmunotherapy (CIT).
* Best response of stable disease (SD) after a minimum of 2 cycles of second-line CIT.
* Best response of partial response (PR) after a minimum of 3 cycles of second-line CIT.
* Complete Response (CR) after a minimum of 3 cycles of second-line CIT therapy but unfit or ineligible for consolidation with cell therapy.
* Not in CR and unable to initiate or tolerate (i.e., must discontinue) second-line CIT.
* Have received cell therapy (allogeneic or autologous transplant or chimeric antigen receptor T-cell (CAR-T) therapy) as consolidation but have not obtained or maintained a CR.
* Recovery from toxic effects of prior chemoimmunotherapy.
* Performance status by Lansky (\< 16 years old at evaluation) or Karnofsky (\>= 16 years old at evaluation) score \>= 50 or Eastern Cooperative Oncology Group (ECOG) score \<= 2 .
* Adequate bone marrow, hepatic, and renal function.
Exclusion Criteria:
* Known central nervous system (CNS) involvement by lymphoma at screening as confirmed by screening magnetic resonance imaging (MRI)/computed tomography (CT)/positron emission tomography (PET) brain scans (participants with evidence of CNS disease only in the cerebrospinal fluid (CSF) will be eligible).
* Other malignancy requiring therapy.
* Currently receiving anti-cancer therapy, including chemotherapy (excluding intrathecal therapy), radiotherapy, small molecules, monoclonal antibodies, cell therapy, or other investigational agents.
Namodenoson in the Treatment of Advanced Hepatocellular Carcinoma in Patients With Child-Pugh Class B7 Cirrhosis (LIVERATION)
This is a clinical trial in patients with advanced hepatocellular carcinoma (HCC) and
Child-Pugh Class B7 (CPB7) cirrhosis whose disease has progressed on at least 1st-line
therapy. The trial will evaluate the efficacy and safety of namodenoson as compared to
placebo.
• Males and females at least 18 years of age.
• Diagnosis of HCC:
• For patients without cirrhosis at the time of diagnosis, histologic confirmation
is required (archival tissue is acceptable).
• For patients with underlying cirrhosis at the time of diagnosis, diagnosis of HCC
established according to the American Association for the Study of Liver Diseases
Practice Guideline algorithm (Marrero 2018).
• HCC is advanced (i.e., treatment-refractory or metastatic) and no standard therapies
are expected to be curative.
• HCC has progressed on at least 1, but no more than 2, prior systemic treatment
regimens; prior locoregional therapy is allowed.
• Barcelona Clinic Liver Cancer (BCLC) Stage B or C (Llovet 1999).
• Prior HCC treatment was discontinued for at least 2 weeks prior to the Baseline Visit.
• Measurable disease by RECIST v1.1 (Eisenhauer 2009).
• ECOG PS of ≤ 1.
• Cirrhosis classified as CPB7; if ascites is used as a scoring criterion, it must be
classified as Grade ≥2 by the Clinical Practice Guidelines of the European Association
for the Study of the Liver (EASL 2010).
• The following laboratory values must be documented within ten days prior to the first
dose of study drug:
• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
• Platelet count at least 75 × 10^9/L
• Creatinine clearance at least 50 mg/dL (estimated glomerular filtration rate by
the Cockcroft-Gault or the Modification of Diet in Renal Disease methods)
• AST and ALT ≤ 5 × the upper limit of normal (ULN)
• Total bilirubin ≤ 3.0 mg/dL
• Serum albumin ≥ 2.8 g/dL.
• Life expectancy of ≥ 6 weeks.
• For women of childbearing potential, negative serum pregnancy test result.
• Provide written informed consent to participate.
• Willing to comply with scheduled visits, treatment plans, laboratory assessments, and
other trial-related procedures.
Exclusion Criteria:
• Receipt of >2 prior systemic drug therapies for HCC.
• Receipt of systemic cancer therapy, immunomodulatory drug therapy, immunosuppressive
therapy, or corticosteroids > 20 mg/day prednisone or equivalent within 14 days prior
to the Baseline Visit or concurrently during the trial.
• Locoregional treatment within 4 weeks prior to the Baseline Visit.
• Major surgery or radiation therapy within 4 weeks prior to the Baseline Visit.
• Use of any investigational agent within 4 weeks prior to the Baseline Visit.
• Concomitant use of P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP)
inhibitors and/or substrates with a narrow therapeutic index unless the medication can
be taken at least 3 hours before or after taking the investigational product (see
Section 12.2).
• Child-Pugh Class A, B8/9, or C cirrhosis.
• Hepatic encephalopathy.
• Occurrence of esophageal or other gastrointestinal hemorrhage requiring transfusion
within 4 weeks prior to the Baseline Visit.
• Uncontrolled or clinically unstable thyroid disease, per judgment of the Principal
Investigator.
• Active bacterial, viral, or fungal infection requiring systemic therapy or operative
or radiological intervention.
• Known human immunodeficiency virus- or acquired immunodeficiency syndrome-related
illness.
• Liver transplant.
• Active malignancy other than HCC.
• Uncontrolled arterial hypertension or congestive heart failure (New York Heart
Association Classification 3 or 4).
• Angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery
bypass graft surgery, transient ischemic attack, or pulmonary embolism within 3 months
prior to initiation of study drug.
• History of, or ongoing, cardiac dysrhythmias requiring treatment, atrial fibrillation
of any grade, or persistent prolongation of the QTc (Fridericia) interval to > 470
msec (patients with bundle branch block will not be excluded for QTc reasons).
• Pregnant or lactating female.
• Women of childbearing potential, unless they agree to use dual contraceptive methods
which, in the opinion of the Investigator, are effective and adequate for the
patient's circumstances while on study drug.
• Men who partner with a woman of childbearing potential, unless they agree to use
effective, dual contraceptive methods (i.e., a condom, with female partner using oral,
injectable, or barrier method) while on study drug and for 3 months afterward.
• Any severe, acute, or chronic medical or psychiatric condition, or laboratory
abnormality that may increase the risk associated with trial participation or study
drug administration; may interfere with the informed consent process and/or with
compliance with the requirements of the trial; or may interfere with the
interpretation of trial results and, in the Investigator's opinion, would make the
patient inappropriate for entry into this trial.
Drug: Namodenoson, Drug: Placebo
Hepatocellular Carcinoma, Cirrhosis, Liver
Hepatocellular carcinoma, HCC, Liver cancer, Child-Pugh Class B7 cirrhosis, CPB7
UT Southwestern; Parkland Health & Hospital System
Venetoclax in Children With Relapsed Acute Myeloid Leukemia (AML)
A study to evaluate if the randomized addition of venetoclax to a chemotherapy backbone (fludarabine/cytarabine/gemtuzumab ozogamicin \[GO\]) improves survival of children/adolescents/young adults with acute myeloid leukemia (AML) in 1st relapse who are unable to receive additional anthracyclines, or in 2nd relapse.
Inclusion Criteria
* Participants must have enrolled on APAL2020SC, NCT Number: NCT04726241 prior to enrollment on ITCC-101/APAL2020D. (This is only applicable for participants in USA/Canada/Australia/New Zealand sites/LLS territory).
* Participants must be ≥ 29 days of age and ≤ 21 years of age at enrollment.
* Participants must have one of the following:
* Children, adolescents, and young adults with acute myeloid leukemia without FLT3/internal tandem duplication (ITD) mutation in:
• Second relapse, who are sufficiently fit to undergo another round of intensive chemotherapy
• First relapse who per investigator discretion cannot tolerate additional anthracycline containing chemotherapy.
* Participants must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2 (≥ 50% Lansky or Karnofsky score)
* Participants 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 start of protocol treatment:
• Cytotoxic chemotherapy: Must not have received cytotoxic chemotherapy within 14 days prior to start of protocol treatment, except for corticosteroids, low dose cytarabine or hydroxyurea that can be given up to 24 hours prior to start of protocol treatment.
• Intrathecal cytotoxic therapy: No wash-out time is required for participants having received any combination of intrathecal cytarabine, methotrexate, and/or hydrocortisone.
• Antibodies: ≥ 21 days must have elapsed from infusion of last dose of an antibody-drug conjugate before start of protocol treatment. For unmodified antibodies or T cell engaging antibodies, 2 half-lives must have elapsed before start of protocol treatment. Any toxicity related to prior antibody therapy must be recovered to Grade ≤ 1.
• Interleukins, Interferons and Cytokines (other than Hematopoietic Growth Factors): ≥ 21 days after the completion of interleukins, interferon or cytokines (other than Hematopoietic Growth Factors) before start of protocol treatment.
• 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 before start of protocol treatment.
• Radiation therapy (RT) (before start of protocol treatment):
* ≥ 14 days have elapsed for local palliative RT (small port);
* ≥ 84 days must have elapsed if prior craniospinal RT or if ≥ 50% radiation of pelvis;
* ≥ 42 days must have elapsed if other substantial bone marrow (BM) radiation.
• Stem Cell Infusions (before start of protocol treatment):
* ≥ 84 days since allogeneic (non-autologous) bone marrow or stem cell transplant (with or without total body irradiation \[TBI\]) or boost infusion (any stem cell product; not including donor lymphocyte infusion \[DLI\])
* No evidence of active graft versus host disease (GVHD).
• Participants who are receiving cyclosporine, tacrolimus or other agents to treat or prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial. Participants must be off medications to treat or prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant for at least 14 days prior to enrollment.
• Cellular Therapy: ≥ 42 days after the completion of donor lymphocyte infusion (DLI) or any type of cellular therapy (e.g., modified T cells, natural killer \[NK\] cells, dendritic cells, etc.) before start of protocol treatment.
• Participants with prior exposure to venetoclax are eligible in this trial
* Adequate organ function:
• Adequate Renal Function defined as:
* Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 60ml/min/1.73 m\^2, or
* Normal serum creatinine based on age/sex
• Adequate Liver Function defined as:
* Direct bilirubin \< 1.5 x upper limit of normal (ULN), and
* Alkaline phosphatase ≤ 2.5 x ULN, and
* Serum glutamic pyruvic transaminase (SGPT) alanine aminotransferase (ALT) ≤ 2.5 x ULN. If liver abnormality is due to radiographically identifiable leukemia infiltrate, the participant will remain eligible.
• Cardiac performance: Minimum cardiac function defined as:
* No history of congestive heart failure in need of medical treatment
* No pre-treatment diminished left ventricular function on echocardiography (shortening fraction \[SF\] \< 25% or ejection fraction \[EF\] \< 40%)
* No signs of congestive heart failure at presentation of relapse.
* Participant, parent or guardian must sign and date informed consent and pediatric assent (when required), prior to the initiation of screening or study specific procedures, according to local law and legislation.
Exclusion Criteria
* Participants who in the opinion of the investigator may not be able to comply with the study requirements of the study, are not eligible.
* Participants with Down syndrome.
* Participants with Acute promyelocytic leukemia (APL) or Juvenile myelomonocytic leukemia (JMML).
* Participants with isolated CNS3 disease or symptomatic CNS3 disease.
* Participants with malabsorption syndrome or any other condition that precludes enteral administration of venetoclax.
* Participants who are currently receiving another investigational drug (GO is not considered investigational in this study).
* Participants with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known congenital bone marrow failure syndrome.
* Participants with known prior allergy to any of the medications used in protocol therapy.
* Participants with documented active, uncontrolled infection at the time of study entry.
* No known human immunodeficiency virus (HIV) infection.
* Post menarchal female participants with positive pregnancy test.
* Concomitant Medications
* Participants who have received strong and moderate CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's wort within 7 days of the start of study treatment.
* Participants who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days of the start of study treatment.
* Participants who have hypersensitivity to the active substance or to any of the excipients listed in summary of product characteristics (SPC).
* Pregnancy or Breast-Feeding:
* Participants who are pregnant or breast-feeding.
* Participants of reproductive potential may not participate unless they have agreed to use a highly effective contraceptive method per clinical trials facilitation group (CTFG) guidelines for the duration of study therapy and for 6 months after the completion of all study therapy.
* Male participants must use a condom during intercourse and agree not to father a child or donate sperm during therapy and for the duration of study therapy and for 4 months after the completion of all study therapy.
Additional criteria to receive a gemtuzumab ozogamicin infusion:
Gemtuzumab ozogamicin should not be given:
* to participants with history of veno-occlusive disease (VOD)/Sinusoidal obstruction syndrome (SOS) grade 4
* to participants with history of VOD/SOS grade 3
* to participants with CD33 negative leukemic blasts (determined at local lab)
Note that these participants are eligible for the study but will not be treated with gemtuzumab ozogamicin.
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
Caloric Restriction and Activity to Reduce Chemoresistance in B-ALL (IDEAL2)
This study is for older children, adolescents, and young adults with B-cell Acute
Lymphoblastic Leukemia (B-ALL). Higher amounts of body fat is associated with resistance to
chemotherapy in patients with B-ALL. Chemotherapy during the first month causes large gains
in body fat in most people, even those who start chemotherapy at a healthy weight.
This study is being done to find out if caloric restriction achieved by a personalized
nutritional menu and exercise plan during routine chemotherapy can make the patient's ALL
more sensitive to chemotherapy and also reduce the amount of body fat gained during
treatment. The goals of this study are to help make chemotherapy more effective in treating
the patient's leukemia as demonstrated by fewer patients with leukemia minimal residual
disease (MRD) while also trying to reduce the amount of body fat that chemotherapy causes the
patient to gain in the first month.
• Patients must be ≥ 10.0 and <26.0 years of age.
• Patients must have a diagnosis of de novo B-ALL
• Patients must have a M3 marrow (>25% blasts by morphology) or at least 1,000/µL
circulating leukemia cells in PB confirmed by Flow Cytometry (or other convincing
evidence of a B-ALL diagnosis not meeting above criteria following central review by
the Study Hematopathologist and Study Chair or Vice-Chair).
• The treatment regimen must be the first treatment attempt for B-ALL-
• Must be a multi-agent induction regimen inclusive of vincristine, glucocorticoid,
pegaspargase/calaspargase, and daunorubicin or doxorubicin and with a planned duration
<35 days.
• Organ function must meet that required for initiation of chemotherapy
• Patients at diagnosis must meet Karnofsky > 50% for patients > 16 years of age and
Lansky > 50% for patients ≤ 16 years of age (or be expected to recover prior to Day 8)
.
• If the patient is a female of childbearing potential, a negative urine or serum
pregnancy test is required within two weeks prior to enrollment.
Exclusion Criteria:
• Patient will be excluded if they are underweight at time of enrollment (BMI% <5th
percentile for age for patients age 10-19 years, BMI <18.5 in patients 20-29 years).
• Patients with Down syndrome or a DNA fragility syndrome (such as Fanconi anemia, Bloom
syndrome) will be excluded.
• Patient receiving a SJCRH-style "Total Therapy" regimen will be excluded.
• Patients receiving anti-CD20 monoclonal antibody therapy during induction therapy.
• Patients will be excluded if they received treatment for a previous malignancy.
• Patient will be excluded if they are pregnant.
• Patient will be excluded if they have a pre-diagnosis requirement for enteral or
parenteral supplementation .
• Patient will be excluded due to inability to perform the intervention (e.g., specific
nutritional needs, severe developmental delay, paraplegia)
• Patients will be excluded if they have significant concurrent disease, illness,
psychiatric disorder or social issue that would compromise patient safety or
compliance with the protocol treatment or procedures, interfere with consent, study
participation, follow up, or interpretation of study results
Study of Selinexor and Venetoclax in Combination With Chemotherapy in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia
The purpose of this study is to test the safety and determine the best dose of venetoclax and selinexor when given with chemotherapy drugs in treating pediatric and young adult patients with acute myeloid leukemia (AML) or acute leukemia of ambiguous lineage (ALAL) that has come back (relapsed) or did not respond to treatment (refractory).
Primary Objective
* To determine the safety and tolerability of selinexor and venetoclax in combination with chemotherapy in pediatric patients with relapsed or refractory AML or ALAL.
Secondary Objectives
* Describe the rates of complete remission (CR) and complete remission with incomplete count recovery (CRi) for patients treated with selinexor and venetoclax in combination with chemotherapy at the recommended phase 2 dose (RP2D).
* Describe the overall survival of patients treated at the RP2D.
Exploratory Objectives
* Explore associations between leukemia cell genomics, BCL2 family member protein quantification, BH3 profiling, and response to therapy as assessed by minimal residual disease (MRD) and variant clearance using cell-free deoxyribonucleic acid (DNA) (cfDNA).
* Describe the quality of life of pediatric patients undergoing treatment with selinexor and venetoclax in combination with chemotherapy and explore associations of clinical factors with patient-reported quality of life outcomes.
* Describe the clinical and genetic features associated with exceptional response to the combination of venetoclax and selinexor without the addition of chemotherapy.
* Participants must have a diagnosis of AML or ALAL and meet the criteria below:
* Refractory leukemia, defined as persistent leukemia after at least two courses of induction chemotherapy, OR
* Early relapsed leukemia, defined as the re-appearance of leukemia after the achievement of remission and within one year of diagnosis, OR
* Relapsed leukemia that is refractory to at least one course of salvage therapy (i.e., therapy given after the relapse has occurred), OR
* Relapsed leukemia following HCT, OR
* Second or greater relapse
* Patients with late first relapses, defined as the re-appearance of leukemia after the achievement of remission and greater than one year of diagnosis, may be enrolled in the dose expansion portion of the study after safety data from the dose escalation portion is available.
Patients must have ≥ 5% blasts in the bone marrow as assessed by morphology or flow cytometry. However, if flow cytometry cannot be performed or if an adequate bone marrow sample cannot be obtained (e.g., in a patient with acute megakaryoblastic leukemia with marrow fibrosis), patients may be enrolled if there is unequivocal evidence of leukemia with ≥ 5% blasts in the blood.
In addition, patients in all categories must not be eligible to undergo curative therapy, such as immediate HCT, because of disease burden, time to identify a stem cell donor, or other reasons.
* Adequate organ function defined as the following:
* Direct bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
* Normal creatinine for age or a calculated creatinine clearance ≥ 30 mL/min/1.73m\^2
* Left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25%
* Patients must be ≥ 2 years of age and ≤ 30 years old. The upper age limit may be defined by each institution, but may not exceed 30 years. Patients treated at St. Jude Children's Research Hospital must be ≤ 24 years old.
* Performance status: Lansky ≥ 50 for patients who are ≤ 16 years old and Karnofsky ≥ 50% for patients who are \> 16 years old.
* At least 14 days must have elapsed since the completion of myelosuppressive therapy or hypomethylating agents and the first doses of venetoclax and selinexor.
* At least 24 hours must have elapsed since the completion of low-dose or non- myelosuppressive therapy, such as hydroxyurea or low-dose cytarabine (up to 100 mg/m\^2/day), or leukapheresis, and the first doses of venetoclax and selinexor.
* For patients who have received prior HCT, there can be no evidence of GVHD and greater than 60 days must have elapsed since the HCT.
* At least 14 days must have elapsed since the completion of any calcineurin inhibitors (e.g. tacrolimus, cyclosporine).
* Patients may not receive strong or moderate CYP3A inducers, such as rifampin, within 3 days of the first dose of venetoclax or during the administration of venetoclax. During the dose-escalation portion of the trial, we discourage the use of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) within 3 days of the first dose of venetoclax or during the administration of venetoclax. However, if an azole is required for the treatment or prevention of fungal infection during any phase of the trial, venetoclax dosing will be reduced to 60 mg/m\^2 (100 mg max) in patients who require treatment with voriconazole and reduced to 40 mg/m\^2 (70 mg max) in patients who require posaconazole.
Exclusion Criteria:
* Must not be pregnant or breastfeeding. Male or female of reproductive potential must agree to use effective contraception for the duration of study participation.
* Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocytic leukemia, or bone marrow failure syndromes are not eligible.
* Uncontrolled infection. Patients with infections that are controlled on concurrent anti-microbial agents are eligible.
* Impairment of GI function or GI disease that, in the opinion of the treating physician, may significantly alter the absorption of venetoclax or selinexor.
* History of cerebellar toxicity or cerebellar neurological findings on exam.
* Previous toxicity or hypersensitivity directly attributed to venetoclax.
Refractory Acute Myeloid Leukemia, Myeloid and Monocytic Leukemia, Acute Leukemia of Ambiguous Lineage in Relapse, Acute Myeloid Leukemia, in Relapse, Refractory Acute Leukemia of Ambiguous Lineage
Acute Myeloid Leukemia, in Relapse, Refractory Acute Myeloid Leukemia, Acute Leukemia of Ambiguous Lineage in Relapse, Refractory Acute Leukemia of Ambiguous Lineage, Pediatric, Young Adult
A Study to Evaluate DAY101 in Pediatric and Young Adult Patients With Relapsed or Progressive Low-Grade Glioma and Advance Solid Tumors (FIREFLY-1)
FIREFLY-1 is a Phase 2, multi center, open-label study to evaluate the safety and efficacy of
oral pan-RAF inhibitor DAY101 in pediatric, adolescent, and young adult patients with
recurrent or progressive low-grade glioma or an advanced solid tumor harboring a known BRAF
alteration.
• Age 6 months to 25 years with:
• Arms 1 & 2: a relapsed or progressive LGG with documented known activating BRAF
alteration
• Arm 3: locally advanced or metastatic solid tumor with documented known or
expected to be activating RAF fusion
• Confirmation of histopathologic diagnosis of LGG and molecular diagnosis of activating
BRAF alteration
• Must have received at least one line of systemic therapy and have evidence of
radiographic progression
• Must have at least 1 measurable lesion as defined by RANO (Arms 1 & 2) or RECIST v1.1
(Arm 3) criteria
Exclusion Criteria:
• Patient's tumor has additional previously-known activating molecular alterations
• Patient has symptoms of clinical progression in the absence of radiographic
progression
• Known or suspected diagnosis of neurofibromatosis type 1 (NF-1)
• Other inclusion/exclusion criteria as stipulated by protocol may apply
Drug: DAY101
Advanced Solid Tumor, Brain and Nervous System, Low-grade Glioma
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.
VITAS: Atezolizumab in Combination with Chemotherapy for Pediatric Relapsed/refractory Solid Tumors
This trial is a multi-center, non-randomized, open-label Phase I/II study evaluating the feasibility and efficacy of vincristine, irinotecan, temozolomide, and atezolizumab in children with relapsed/refractory solid tumors.
• Signed informed consent
• Relapsed or refractory solid tumor after at least one prior course of therapy.
• Hodgkin lymphoma or non-Hodgkin lymphoma are not permitted.
• Patients with CNS malignancy or asymptomatic CNS metastases may be enrolled, provided all of the following criteria are met.
* No metastatic or primary disease affecting the brainstem, midbrain, pons, or cerebellum, or within 10 mm of optic nerve
* No history of leptomeningeal disease
* No history of intracranial or spinal cord hemorrhage
* No evidence of progression of neurologic deficit, in the investigator's judgment, within 7 days prior to initiation of study medications.
• Must have histologically confirmed rhabdomyosarcoma (RMS) for RMS efficacy cohort.
• Age ≥ 6 months and ≤ 30 years
• Lansky Performance Status (patients \< 16 years old) or Karnofsky Performance Status (patients ≥ 16 years old) ≥ 50
• Ability to comply with the study protocol, in the investigator's judgment
• For RMS efficacy cohort, disease must be measurable as defined by RECIST v1.1.
• For the feasibility cohort, disease must be evaluable, but patients enrolled in the feasibility cohort will be prospectively assessed for measurable disease, RMS patients will also be included in the RMS efficacy cohort.
• Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation.
• Availability of a tumor specimen suitable for determination of PD-L1 status, either from initial diagnosis or from a recurrence.
• For PD-L1 staining to be performed at the central site, a formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least 15 slides containing unstained, freshly cut, serial sections must be available along with an associated pathology report prior to study enrollment.
• Patients for whom the required number of slides are not available may still be eligible to enroll on study with PI approval
• For the RMS efficacy cohort, it will be required that at least 8 of 17 patients have PD-L1(+) tumor. PD-L1 status will be determined at time of enrollment for all patients. When the maximum allowable number of PD-L1(-) patients has been enrolled and treated on study, PD-L1 positivity will be required for all further enrolled patients.
• Staining will be performed in the central site CAP/CLIA-certified laboratory using the 22c3 antibody for immunohistochemical analysis
• PD-L1(+) status will be defined as staining on ≥1% of tumor cells or ≥1% of stroma.
• For the feasibility cohort, PD-L1 positivity is not required but will be performed centrally in all cases for exploratory biomarker studies.
• Adequate organ and marrow function as defined by the following laboratory values obtained within 21 days prior to initiation of study medication.
• For patients without known bone marrow involvement:
* Absolute neutrophil count ≥ 1.0 x 10\^9 / L (1000/µL) without granulocyte colony-stimulating factor support (≥14 days after the last dose of a long-acting growth factor such as pegfilgrastim, or 7 days after short-acting growth factor)
* Absolute lymphocyte count ≥ 0.5 x 10\^9 / L (500/µL)
* Platelet count ≥ 75 x 10\^9 / L (75,000/µL) without transfusion in the last 7 days
• Patients with known bone marrow metastatic disease will be eligible for the study if they meet the following criteria:
* Patients with documented liver metastases: AST and ALT ≤ 5 x ULN
* Patients with documented liver or bone metastases: ALP ≤ 5 x ULN
* Absolute neutrophil count (ANC) ≥ 750/mm\^3
* Absolute lymphocyte count ≥ 0.4 x 10\^9 / L (400/µL)
* Platelet count ≥ 50,000/mm\^3 (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions)
* These patients will not be evaluable for hematologic toxicity. At least 4 of 6 patients in the feasibility cohort must be evaluable for hematologic toxicity. If dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity.
• Total bilirubin ≤1.5 x upper limit of normal (ULN) for age (Patients with known Gilbert disease: serum bilirubin ≤ 3 x ULN)
• AST (SGOT) and ALT (SPGT) ≤ 2.5 x ULN for age
• Serum albumin ≥ 25 g/L (2.5 g/dL)
• Creatinine ≤ 1.5 x ULN for age or creatinine clearance (or radioisotope glomerular filtration rate) ≥ 70 mL/min/1.73 m2
• Left ventricular ejection fraction ≥ 50% or shortening fraction ≥ 30%
• Hemoglobin ≥ 90 g/L (9 g/dL)
• Patients may be transfused to meet this criterion.
• For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN
• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
• Negative HIV and hepatitis B surface antigen (HBsAg) tests at screening
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs, as defined below:
• Women must remain abstinent or use contraceptive methods with a failure rate of \< 1% per year during the treatment period and for 5 months after the final doses of atezolizumab, vincristine, and temozolomide. Women must refrain from donating eggs during this same period.
• A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus), regardless of sexual orientation or marital status.
• Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
• The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception.
• For men who are not surgically sterile: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
• With a female partner of childbearing potential who is not pregnant, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of less 1% per year during the treatment period and for 5 months after the final doses of atezolizumab, irinotecan, and temozolomide. Men must refrain from donating sperm during this same period.
• The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception
Exclusion Criteria:
• Pregnancy or breast-feeding:
• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of study treatment
• Women of childbearing potential must have a negative serum pregnancy test result within 21 days prior to initiation of study treatment.
• Medical conditions that are excluded:
• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Guillain-Barré syndrome, multiple sclerosis, or Kawasaki syndrome with the following exceptions:
* Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.
* Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
* Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met at study initiation: (1) Rash must cover less 10% of body surface area, (2) Disease is well controlled at baseline and requires only low-potency topical corticosteroids, (3) No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
• Uncontrolled or symptomatic hypercalcemia (ionized calcium \> 1.5 mmol/L, calcium \> 12 mg/dL or corrected serum calcium \> ULN)
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
* Patients with indwelling catheters (e.g., PleurX®) are allowed.
• Uncontrolled tumor-related pain
* Patients requiring pain medication must be on a stable regimen at study entry for at least 2 weeks. Intermittent use of as-needed medication is allowed during this period.
• Clinically significant gastrointestinal disorder that may interfere with absorption of orally administered drugs (at the discretion of the treating physician)
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
* History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
• History of severe asthma or uncontrolled asthma
• Dyspnea at rest or requirement for supplemental oxygen
• Uncontrolled seizures. Patients taking a stable dose of anticonvulsants (for 2 weeks) are permitted, as long as they are not strong inducers or inhibitors of CYP3A4.
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications in the opinion of the treating investigator
• Washout periods from prior therapies:
• Myelosuppressive chemotherapy or radiotherapy within 21 days prior to starting study treatment.
* Subjects must have recovered from all acute prior treatment-related toxicities to grade 1 or baseline (excluding alopecia and clinically stable toxicities requiring ongoing medical management, such as hypothyroidism).
• Non-myelosuppressive cancer therapy, such as kinase inhibitors, within 7 days prior to study treatment.
• Treatment with monoclonal antibodies with long half-lives, within 3 half-lives prior to study treatment.
• Treatment with targeted cellular therapies within 28 days prior to starting study treatment.
• Major surgical procedure, other than for diagnosis, within 30 days prior to initiation of study treatment, or anticipation of the need for a major surgical procedure during the first four cycles of the study.
* Biopsy tissue collection or placement of a vascular access device is permitted if the site has healed prior to initiation of study medications.
* For patients with CNS disease, no neurosurgical resection, brain biopsy, or stereotactic/whole-brain radiation within 30 days prior to Cycle 1, Day 1
• Treatment with a live, attenuated vaccine within 30 days prior to initiation of study treatment, or anticipation of the need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
• Treatment with investigational therapy within 21 days prior to initiation of study treatment or concurrent participation with another investigational agent
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 \[IL-2\]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
• Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-agents) within 2 weeks prior to initiation of study treatment, or anticipation of the need for systemic immunosuppressive medication during study treatment, with the following exceptions:
* Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Principal Investigator confirmation has been obtained.
* Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
* Patients with CNS disease can be receiving concurrent treatment with corticosteroids with approval from the Principal Investigator. Patients must be receiving a stable or decreasing dose for ≥ 5 days prior to the baseline MRI scan and at the time of drug initiation. The Principal Investigator should be informed when steroid doses are increased because of declining patient status.
• Use of strong CYP3A4 inhibitors or inducers or strong UGT1A1 inhibitors within 12 days of Cycle 1, Day 1.
• Treatment with high-dose chemotherapy and hematopoietic stem-cell rescue within 3 months prior to initiation of study drug
• Treatment with herbal cancer therapy within 1 week prior to initiation of study medications.
• Treatment with a long-acting hematopoietic growth factor (such as pegfilgrastim) within 2 weeks prior to initiation of study medications, or a short-acting hematopoietic growth factor (such as G-CSF) within 1 week prior to initiation of study medications.
• Prior treatments:
• Prior allogeneic stem cell or solid organ transplantation
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies to include all anti-PD-1, and anti-PD-L1 therapeutic antibodies
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 \[IL-2\] within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
• Subjects must not have previously progressed while receiving regimens that include irinotecan or temozolomide. Patients who have received irinotecan or temozolomide and did not progress while on these medications are eligible.
• Known ongoing or untreated infection, including, but not limited to bacteremia, active tuberculosis, or severe pneumonia
• Active tuberculosis
• Current treatment with anti-viral therapy for HBV
• Active hepatitis C
• Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
• Known allergy or hypersensitivity to any component of the study medications
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
The Pediatric Acute Leukemia (PedAL) Screening Trial - A Study to Test Bone Marrow and Blood in Children With Leukemia That Has Come Back After Treatment or Is Difficult to Treat - A Leukemia & Lymphoma Society and Children's Oncology Group Study
This study aims to use clinical and biological characteristics of acute leukemias to screen for patient eligibility for available pediatric leukemia sub-trials. Testing bone marrow and blood from patients with leukemia that has come back after treatment or is difficult to treat may provide information about the patient's leukemia that is important when deciding how to best treat it, and may help doctors find better ways to diagnose and treat leukemia in children, adolescents, and young adults.
* Patients must be less than 22 years of age at the time of study enrollment
* Patient must have one of the following at the time of study enrollment:
* Patient has known or suspected relapsed/refractory (including primary refractory) AML as defined in protocol
* This includes isolated myeloid sarcoma
* Patient has known or suspected relapsed/refractory (including primary refractory) myeloid leukemia of Down syndrome (ML-DS)
* Patient has known or suspected relapsed ALL as defined in protocol that meets one of the following criteria:
* Second or greater B-ALL medullary relapse, excluding KMT2Ar
* Any first or greater B-ALL medullary relapse involving KMT2Ar
* Any first or greater T-ALL medullary relapse with or without KMT2Ar
* Patient has known or suspected relapsed/refractory (including primary refractory) mixed phenotype acute leukemia (MPAL) as defined in protocol
* Patient has known or suspected de novo or relapsed/refractory (including primary refractory) treatment-related AML (t-AML)
* Patient has known or suspected de novo or relapsed/refractory (including primary refractory) myelodysplastic syndrome (MDS) or treatment-related myelodysplastic syndrome (t-MDS)
* Note: Relapsed/refractory disease includes stable disease, progressive disease, and disease relapse.
* Patient has known or suspected de novo or relapsed/refractory (including primary refractory) juvenile myelomonocytic leukemia (JMML)
* Note: Relapsed/refractory disease includes stable disease, progressive disease, and disease relapse.
* 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
PROCEDURE: Biospecimen Collection
Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome, Juvenile Myelomonocytic Leukemia, Acute Myeloid Leukemia, Myeloid Leukemia Associated With Down Syndrome, Mixed Phenotype Acute Leukemia, Leukemia, Other, Myeloid and Monocytic Leukemia, Acute Myeloid Leukemia Post Cytotoxic Therapy, Myelodysplastic Syndrome Post Cytotoxic Therapy
A Study of a New Way to Treat Children and Young Adults With a Brain Tumor Called 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 Brain During 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
* Ages 8 to ≤ 21 years
* Participant must be able to speak and understand English
* Be willing to participate and able to comply with the study protocol
* For participants with PE: Children with acute, radiologically confirmed pulmonary embolism (PE) with our without DVT
* For control group: Cohort 1: Children who are prescribed physical activity restrictions for 2 up to 12 weeks following any minor outpatient surgery or, minor injury (surgery or injury is referred to as "diagnosis" hereafter) Cohort 2: Children who are not prescribed physical activity restrictions and are otherwise considered to be healthy.
Exclusion Criteria:
* Congenital heart disease with abnormal pulmonary circulation or with in-situ pulmonary artery thrombosis
* Chronic kidney disease
* Chronic inflammatory or an autoimmune disorder (such as systemic lupus erythematosus, juvenile rheumatoid disorder, inflammatory bowel disease, and sickle cell disease)
* A metabolic or endocrinological disorder such as diabetes mellitus or thyroid disorder
* History of or active cancer
* Pregnant
* Musculoskeletal limitations to exercise expected to be present uptil 4 months post-diagnosis
* Weight ≥ 300 lbs
* Contraindications to magnetic resonance imaging
* Frequent severe exacerbations of asthma defined by two or more bursts of systemic glucocorticoids (more than three days each) in the previous year or at least one hospitalization, intensive care unit stay or mechanical ventilation in the previous year. Patients should also be excluded if there are daily symptoms of asthma requiring daily use of short-acting bronchodilators such as albuterol or levalbuterol administration. The use of controller medications such as daily inhaled corticosteroids for mild persistent asthma is not exclusionary.
* Has any other medical condition, which in the opinion of the investigator may potentially compromise the safety or compliance of the patient or may preclude the patient's successful completion of the clinical study
Additional exclusion criteria for participants with PE:
* Prior history of DVT or PE (upper extremity, cerebral sinus venous thrombosis and abdominal thromboses encountered as a neonate are not exclusion criteria)
* Lack of anticoagulant treatment for the acute VTE due to contraindications
Enasidenib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia Patients With an IDH2 Mutation
This phase II trial studies the side effects of enasidenib and sees how well it works in treating pediatric patients with acute myeloid leukemia that has come back after treatment (relapsed) or has been difficult to treat with chemotherapy (refractory). Patients must also have a specific genetic change, also called a mutation, in a protein called IDH2. Enasidenib may stop the growth of cancer cells by blocking the mutated IDH2 protein, which is needed for leukemia cell growth.
* Patients must be \>= 24 months and \< 21 years of age at the time of study enrollment
* Patient must have AML with an IDH2 mutation identified from a peripheral blood or bone marrow sample at the time of diagnosis and/or relapsed/refractory disease
* Patient must have bone marrow assessment (aspiration or biopsy) with \> 5% leukemic blasts by morphology and/or flow cytometry in at least one of the following clinical scenarios:
* Second or greater relapse after chemotherapy or hematopoietic stem cell transplant (HSCT)
* Refractory after \>= 2 attempts at induction therapy
* Relapsed patients
* Must not have received prior re-induction therapy for this relapse
* Each block of chemotherapy (i.e., cytarabine, daunorubicin and etoposide \[ADE\], cytarabine and mitoxantrone \[MA\]) is a separate re-induction attempt
* Donor lymphocyte infusion (DLI) is considered a re-induction attempt
* Refractory patients
* Each attempt at induction therapy may include up to two chemotherapy courses
* Karnofsky \>= 50% for patients \> 16 years of age and Lansky \>= 50 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
* Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
* Evaluation of cerebrospinal fluid (CSF) is only required if there is a clinical suspicion of central nervous system (CNS) involvement by leukemia during eligibility screening. Should a patient be found to have CNS2 or CNS3 status by CSF prior to eligibility screening, patient may receive intrathecal chemotherapy \> 72 hours prior to starting study drug. CNS1 status must be established before starting study drug
* 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 numerical eligibility criteria are met, e.g., blood count criteria, the patient is considered to have recovered adequately
* Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
* \>= 14 days must have elapsed after the completion of other cytotoxic therapy with the exception of hydroxyurea. Additionally, patients must have fully recovered from all acute toxic effects of prior therapy. NOTE: Cytoreduction with hydroxyurea must be discontinued \>= 24 hours prior to the start of protocol therapy
* Intrathecal chemotherapy must be completed \>= 72 hours prior to the start of the first cycle of treatment
* 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. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
* 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
* Corticosteroids: If used to modify immune adverse events related to prior therapy, \>= 14 days must have elapsed since last dose of corticosteroid
* 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 research coordinator
* Interleukins, interferons and cytokines (other than hematopoietic growth factors): \>= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
* Stem cell Infusions (with or without total body irradiation \[TBI\]):
* Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion:
* \>= 60 days after infusion for bone marrow or stem cell transplant and
* \>= 4 weeks after infusion for any stem cell infusion including DLI or boost infusion
* There must be no evidence of graft versus host disease (GVHD)
* Autologous stem cell infusion including boost infusion: \>= 42 days
* Cellular Therapy: \>= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer \[NK\] cells, dendritic cells, etc.)
* XRT/external beam irradiation including protons: \>= 14 days after local XRT; \>= 150 days after TBI, craniospinal XRT or if radiation to \>= 50% of the pelvis; \>= 42 days if other substantial bone marrow (BM) radiation
* Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-metaiodobenzylguanidine \[MIBG\]): \>= 42 days after systemically administered radiopharmaceutical therapy
* Study-specific limitations on prior therapy: small molecule investigational agents: \>= 14 days or \> 5 half-lives must have elapsed from the last dose of the agent, whichever is greater
* Platelet count \>= 20,000/mm\^3 (may receive platelet transfusions)
* Hemoglobin \>= 8.0 g/dL at baseline (may receive red blood cell \[RBC\] transfusions)
* 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: Maximum serum creatinine (mg/dL)
* 2 to \< 6 years: 0.8 (male and female)
* 6 to \< 10 years: 1 (male and female)
* 10 to \< 13 years: 1.2 (male and female)
* 13 to \< 16 years: 1.5 (male); 1.4 (female)
* \>= 16 years: 1.7 (male); 1.4 (female)
* Bilirubin (sum of conjugated + unconjugated) =\< 1.5 x upper limit of normal (ULN) for age
* Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 225 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L
* Serum albumin \>= 2 g/dL
* Left ventricular ejection fraction of \>= 50% by echocardiogram
* Regulatory Requirements
* All patients and/or their parents or legal authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Exclusion Criteria:
* AML associated with Down syndrome or t(15;17) is not eligible for study
* Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study therapy and for 2 months after the last dose of enasidenib. Abstinence is an acceptable method of birth control. It is not known if enasidenib is present in breast milk. Breastfeeding is not recommended during therapy or for at least 30 days after the last dose of enasidenib
* Concomitant Medications:
* Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. If used to modify immune adverse events related to prior therapy, \>= 14 days must have elapsed since last dose of corticosteroid. The use of corticosteroids to manage the side effect of IDH inhibitor-associated differentiation syndrome (IDH-DS), is permitted on study
* Investigational drugs: Patients who are currently receiving another investigational drug are not eligible
* Anti-cancer agents: Patients who are currently receiving other anti-cancer agents are not eligible (except leukemia patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy; the use of hydroxyurea to manage the side effect of IDH-DS, is permitted on study)
* 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
* Patients must be able to swallow intact tablets whole or use the alternate enasidenib formulation.
* Patients with known hypersensitivity to any of the components of enasidenib are not eligible.
* Patients with prior exposure to enasidenib or another IDH2 inhibitor are not eligible.
* Patients taking the following drugs will be excluded from study entry unless these drugs are discontinued or patients are transferred to a medically acceptable alternative \> 5 half-lives before the first dose of enasidenib.
* Drugs with a narrow therapeutic range that are sensitive substrates of the following cytochrome P450 (CYP) enzymes: CYP2C8 (e.g. paclitaxel), 2C9 (e.g. phenytoin and warfarin), 2C19 (e.g. s-mephenytoin), 2D6 (e.g. thioridazine), and 1A2 (e.g. theophylline and tizanidine).
* Breast cancer resistant protein (BCRP) transporter-sensitive substrate rosuvastatin
* Patients with the following leukemia complications are not eligible for this trial:
* No intrathecal chemotherapy is permitted on study. Prior to study enrollment, cerebrospinal fluid (CSF) evaluation is only required if there is a clinical suspicion for CNS leukemia. Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome) are not eligible for this trial
* Immediately life-threatening, severe complications of leukemia including uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation
* Patients who have received a prior solid organ transplantation are not eligible
* Infection: Patients who have an uncontrolled infection or patients with known human immunodeficiency virus (HIV) or active hepatitis B or C are not eligible
* Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
PROCEDURE: Biospecimen Collection, PROCEDURE: Bone Marrow Aspiration, PROCEDURE: Bone Marrow Biopsy, DRUG: Enasidenib, DRUG: Enasidenib Mesylate
Refractory Acute Myeloid Leukemia, Recurrent Acute Myeloid Leukemia, Leukemia, Other
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
• Participant is able and willing to provide informed consent (≥18 years), or informed consent is obtained by the parent or legal guardian for minor participants, with the minor providing age appropriate assent, according to local law and regulations;
• Life expectancy ≥ 12 weeks;
• Known high-risk neuroblastoma OR previously intermediate-risk neuroblastoma that has relapsed or progressed to high-risk, with failure to achieve complete response with standard therapy (defined as at least 4 cycles of aggressive multi-drug induction chemotherapy with or without radiation and surgery, or according to a standard high-risk treatment/neuroblastoma protocol), OR who are medically ineligible to receive standard treatment OR who are intolerant to standard treatment;
• Adequate recovery from acute toxic effects of any prior therapy, as deemed by the Investigator or treating Sub-Investigator;
• Adequate liver function as defined by the following laboratory values obtained within 28 days prior to administration of 64Cu-SARTATE: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3.0 x upper limit of normal (ULN);
• Adequate renal function;
• Adequate laboratory parameters: Absolute neutrophil count \> 1.0 x 10 9/L; Platelet count \> 50 x 10 9/L; Total bilirubin \<1.5 x ULN;
• Karnofsky or Lansky performance status ≥50;
• All participants must have a hematopoietic stem cell product available (minimum CD34+ cell dose is ≥2 x 10 6 cells/kg);
• Sexually active participants of reproductive potential must practice an effective method of birth control while participating on this study, to avoid possible damage to the fetus. Abstinence is considered acceptable;
• 64Cu-SARTATE uptake on the 4 hour scan (SUVmax) of any lesion equal to or higher than that of the liver in order to move on to the therapy phase of the study.
Exclusion Criteria:
• Participants with disease of any major organ system that would compromise their ability to tolerate therapy, as deemed by the Investigator or treating Sub-Investigator;
• Any other active malignancy, or a history of prior malignancy within the past 3 years;
• History of cardiac failure as evidenced by: dyspnea at rest, exercise intolerance, oxygen requirement, clinically significant cardiac dysfunction;
• Planned administration of chemotherapy, anti-cancer cytokine therapy, immunotherapy or radiotherapy within 2 weeks prior to the administration of 64Cu-SARTATE;
• Administration of therapeutic dose of 131I-MIBG within 8 weeks prior to the administration of 64Cu-SARTATE;
• External beam radiation therapy (EBRT) to both kidneys or a single functioning kidney within 12 months prior to the administration of 64Cu-SARTATE;
• Administration of any investigational agents within 21 days prior to administration of 64Cu-SARTATE;
• Treatment with long acting somatostatin analogues (administered within 28 days prior to the administration of 64Cu-SARTATE), or short acting somatostatin analogues (administered within 24 hours prior to the administration of 64Cu-SARTATE);
• Known sensitivity or allergy to somatostatin analogues;
• Previous peptide receptor radionuclide therapy (PRRT);
• Female participants who are pregnant or lactating;
• Participants who are on hemodialysis;
• QTc interval ≥ 0.45 seconds as measured by Screening ECG;
• Participants with uncontrolled infection(s);
• Any medical condition which the Investigator feels may interfere with the procedures or evaluations of the study;
• Participants 12 months and younger will be excluded from cohorts where the planned single or cumulative administered activity is modelled to deliver a radiation dose to the marrow that exceeds 2 Gy.
DRUG: 67Cu-SARTATE, DRUG: 64Cu-SARTATE
Neuroblastoma, Refractory Neuroblastoma, Relapsed Neuroblastoma, Brain and Nervous System
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.
A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors (LIBRETTO-121)
This is an open-label, multi-center Phase 1/2 study of oral LOXO-292 in pediatric
participants with an activating rearranged during transfection (RET) alteration and an
advanced solid or primary CNS tumor.
• Advanced or metastatic solid or primary CNS tumor which has failed standard of care
therapies
• Evidence of an activating RET gene alteration in the tumor and/or blood
• Measurable or non-measurable disease
• Karnofsky (participants 16 years and older) or Lansky (participants younger than 16)
performance score of at least 50
• Participant with primary CNS tumors or cerebral metastases must be neurologically
stable for 7 days prior and must not have required increasing doses of steroids within
the last 7 days
• Adequate hematologic, hepatic and renal function.
• Ability to receive study drug therapy orally or via gastric access
• Willingness of men and women of reproductive potential to observe conventional and
effective birth control
Exclusion Criteria:
• Major surgery within two weeks prior to planned start of LOXO-292
• Clinically significant, uncontrolled cardiac, cardiovascular disease or history of
myocardial infarction within 6 months prior to planned start of LOXO-292
• Active uncontrolled systemic bacterial, viral, fungal or parasitic infection
• Clinically significant active malabsorption syndrome
• Pregnancy or lactation
• Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e. the participant
required a modification to current thyroid medication in the 7 days before start of
LOXO-292)
• Uncontrolled symptomatic hypercalcemia or hypocalcemia
• Known hypersensitivity to any of the components of the investigational agent, LOXO-292
or Ora-Sweet® SF and OraPlus®, for participants who will receive LOXO-292 suspension
• Prior treatment with a selective RET inhibitor(s) (including investigational selective
RET inhibitor[s])
Study of Efficacy and Safety of Tisagenlecleucel in HR B-ALL EOC MRD Positive Patients (CASSIOPEIA)
This is a single arm, open-label, multi-center, phase II study to determine the efficacy and
safety of tisagenlecleucel in de novo HR pediatric and young adult B-ALL patients who
received first-line treatment and are EOC MRD positive. The study will have the following
sequential phases: screening, pre-treatment, treatment & follow-up, and survival. After
tisagenlecleucel infusion, patient will have assessments performed more frequently in the
first month and then at Day 29, then every 3 months for the first year, every 6 months for
the second year, then yearly until the end of the study. Efficacy and safety will be assessed
at study visits and as clinically indicated throughout the study. The study is expected to
end in approximately 8 years after first patient first treatment (FPFT). A post-study long
term follow-up safety will continue under a separate protocol per health authority
guidelines.
• CD19 expressing B-cell Acute Lymphoblastic Leukemia
• De novo NCI HR B-ALL who received first-line treatment and are MRD ≥ 0.01% at EOC. EOC
bone marrow MRD will be collected prior to screening and will be assessed by
multi-parameter flow cytometry using central laboratory analysis.
• Age 1 to 25 years at the time of screening
• Lansky (age < 16 years) or Karnofsky (age ≥ 16 years) performance status ≥ 60%
• Adequate organ function during the screening period:
A. Renal function based on age/gender B. ALT ≤ 5 times ULN for age C. AST ≤ 5 times
ULN for age D. Total bilirubin < 2 mg/dL (for Gilbert's Syndrome subjects total
bilirubin < 4 mg/dL)
E. Adequate pulmonary function defined as:
• no or mild dyspnea (≤ Grade 1)
• oxygen saturation of > 90% on room air F. Adequate cardiac function defined as
LVSF ≥ 28% confirmed by echocardiogram or LVEF ≥ 45% confirmed by echocardiogram
or MUGA within 6 weeks of screening
• Prior induction and consolidation chemotherapy allowed: 1st line subjects: ≤ 3 blocks
of standard chemotherapy for first-line B-ALL, defined as 4-drug induction,
Berlin-Frankfurt-Münster (BFM) consolidation or Phase 1b, and interim maintenance with
high-dose methotrexate.
Exclusion Criteria:
• M3 marrow at the completion of 1st line induction therapy
• M2 or M3 marrow or persistent extramedullary disease at the completion of first-line
consolidation therapy or evidence of disease progression in the peripheral blood or
new extramedullary disease prior to enrollment. Patients with previous CNS disease are
eligible if there is no active CNS involvement of leukemia at the time of screening.
• Philadelphia chromosome positive ALL
• Hypodiploid: less than 44 chromosomes and/or DNA index < 0.81, or other clear evidence
of a hypodiploid clone
• Prior tyrosine kinase inhibitor therapy
• Subjects with concomitant genetic syndromes associated with bone marrow failure
states: such as subjects with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or
any other known bone marrow failure syndrome. Subjects with Down syndrome will not be
excluded.
• Subjects with Burkitt's lymphoma/leukemia (i.e. subjects with mature B-ALL, leukemia
with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3
morphology and /or a MYC translocation)
• Has had treatment with any prior anti-CD19 therapy 9. Treatment with any prior gene or
engineered T cell therapy
Other protocol-defined inclusion/exclusion may apply.
CTL019, Kymriah, B-Cell Acute Lymphoblastic Leukemia, ALL, tisagenlecleucel, HR B-ALL EOC MRD, Minimal Residual Disease (MRD), Positive at the End of Consolidation (EOC)