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Intraventricular Administration of Rhenium-186 NanoLiposome for Leptomeningeal Metastases (ReSPECT-LM)
This is an open-label Phase I clinical study that will administer a single dose of 186RNL via
intraventricular catheter for treatment of Leptomeningeal Metastases (LM).
1. At least 18 years of age at time of screening.
2. Ability to understand the purposes and risks of the study and has signed a written
informed consent document approved by the site-specific IRB.
3. Subject has proven and documented LM that meets the requirements for the study:
• EANO-ESMO Clinical Practice Guidelines Type 1 and 2 (with the exception of 2D) LM of
any primary type.
4. Karnofsky performance status of 60 to 100
5. Acceptable liver function:
• Bilirubin ≤ 1.5 times upper limit of normal
• AST (SGOT) and ALT (SGPT) ≤ 3.0 times upper limit of normal for subjects with
normal liver.
* AST (SGOT) and ALT (SGPT) ≤ 5.0 times upper limit of normal for subjects with
liver metastasis
• Acceptable renal function with serum creatinine ≤ 2 times upper limit of normal
6. Acceptable hematologic status (without hematologic support):
• ANC ≥1000 cells µL
• Platelet count ≥75,000/µL
• Hemoglobin ≥9.0 g/dL
7. All women of childbearing potential must have a negative serum pregnancy test at
screening. Male and female subjects must agree to use effective means of contraception
(for example, surgical sterilization or the use of barrier contraception with either a
condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner
from entry into the study through 6 months after the last dose.
8. Subjects with a creatinine clearance greater than or equal to 60 mL/min (using the
Cockcroft-Gault Equation) for males and females.
Exclusion Criteria:
1. The subject has not recovered to National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE v5.0 Grade ≤ 1 from AEs (except alopecia, anemia
and lymphopenia) due to antineoplastic agents, investigational drugs, or other
medications that were administered prior to study.
2. Obstructive or symptomatic communicating hydrocephalus
3. Ventriculo-peritoneal or ventriculo-atrial shunts without programable valves or
contraindications to placement of Ommaya reservoir
4. Females of childbearing potential who are pregnant, breast feeding, or may possibly be
pregnant without a negative serum pregnancy test
5. Serious intercurrent illness, such as progressive systemic (extra leptomeningeal)
disease, clinically significant cardiac arrhythmias, uncontrolled systemic infection,
symptomatic congestive heart failure or unstable angina pectoris within 3 months prior
study drug, myocardial infarction, stroke, transient ischemic attack within 6 months,
seizure disorder with any seizure occurring within 14 days prior to consenting or
encephalopathy
6. Active severe non hematologic organ toxicity such as renal, cardiac, hepatic,
pulmonary, or gastrointestinal systemic toxicity grade 3 or above.
7. Significant coagulation abnormalities such as inherited bleeding diathesis or acquired
coagulopathy with unacceptable risks of bleeding.
8. Patients who had any dose to the spinal cord or whole brain radiation therapy,
regardless of when the radiation treatment was delivered.
9. Myelopathy following spinal irradiation greater than 3 weeks prior to the first dose
of 186RNL.
10. Systemic chemotherapeutic agents with CNS penetration (such as temozolomide,
carmustine, lomustine, capecitabine, carboplatin, vinorelbine, bevacizumab, irinotecan
or topotecan) unless they develop or have progressive or persistent leptomeningeal
metastases while on these agents.
11. Systemic therapy (including investigational agents and small-molecule kinase
inhibitors) within 14 days or 5 half-lives, whichever is shorter, prior first dose of
study drug (186RNL).
12. Nitrosoureas or mitomycin C within 42 days, or metronomic/protracted low-dose
chemotherapy within 14 days, or other cytotoxic chemotherapy within 28 days, prior to
first dose of study drug (186RNL).
13. Impaired CSF Flow Study performed on Day -4 to Day -2 based on study imaging and as
determined by the investigator.
Drug: 186RNL
Brain and Nervous System, Leptomeningeal Metastasis
Osteosarcoma Maintenance Therapy With OST31-164 (OST-164-01)
Up to 45 Patients aged 12 to 39 with osteosarcoma (bone cancer) that had recurred in the
lungs and has recently been surgically removed will be enrolled. Patients will receive
OST31-164 infusions every 3 weeks over 48 weeks and be followed after that for 3 years.
• Note: Patients enrolled on AOST2031 are eligible for enrollment in the present study.
Patients are eligible to be included in the study only if all the following criteria apply:
Age and Weight
1. Between 12 years of age and 39 years of age at the time the Informed Consent/ Assent
form is signed.
2. Weight at least 40 kg. Diagnosis
3. Has histologic confirmation of osteosarcoma at diagnosis.
4. Has at least one episode of disease recurrence in the lungs without limitation on the
number of episodes of recurrence as long as the following criteria are met:
1. Surgical resection of all possible sites of suspected pulmonary metastases to
achieve a complete remission within 8 weeks prior to study enrollment
2. Pathological confirmation of osteosarcoma from at least one resected tumor.
3. Patients will not require radiographic confirmation of complete remission for
enrollment. However, a postoperative CT chest scan is required as a baseline for
future comparisons.
https://members.childrensoncologygroup.org/files/Disc/surgery/handbooks/OsteoBoneHandb
ook.pdf) Performance Status
5. Patient must have a performance status corresponding to ECOG scores of 0, 1, or 2. Use
Karnofsky scale for patients > 16 years of age and Lansky scale for patients < years
of age Prior Therapy
6. Patient must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, radiotherapy, or surgery prior to entering this study.
Organ Function Requirements
7. Patient has adequate organ function as defined below:
a. Hematological: i. Absolute neutrophil count (ANC) is at least 1,000/µL without
transfusion or growth factor support. ii. Platelet count ≥ 50,000/µL without
transfusion or growth factor support. b. Adequate renal function defined as: i.
Creatine clearance or radioisotope glomerular filtration rate (GFR) > 70 mL/min/1.73
m2 or ii. A serum creatine based on age/gender as follows:
Maximum Serum Creatinine (mg/dL)
Age: 12 to < 13 years Male :1.2 Female:1.2 Age:13 to < 16 years Male :1.5 Female:1.4
Age: ≥ 16 years Male :1.7 Female:1.4 Note: the threshold for creatinine values in this
table were derived from the Schwartz formula for estimating GFR.
c. Adequate liver function defined as: i. Total bilirubin < 1.5 x upper limit of
normal (ULN) for age ii. Serum glutamic-pyruvic transaminase (SGPT) / alanine
aminotransferase (ALT) < 110 U/L (for the purpose of this study the ULN for SGPT is 45
U/L) iii. Serum albumin > 2 g/dL
d. Adequate coagulation i. International normalized ratio (INR) or prothrombin time
(PT) < 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or
INR is within therapeutic range of intended use of anticoagulants.
ii. Activated partial thromboplastin time (aPTT) < 1.5 x ULN unless patient is
receiving anticoagulant therapy as long as aPTT is within therapeutic range of
intended use of anticoagulants.
e. Adequate cardiac function defined as: i. Shortening fraction of > 27% by
echocardiogram, or ii. Ejection fraction of > 50% by radionuclide angiogram or
echocardiogram f. Adequate pulmonary function defined as: i. No evidence of dyspnea at
rest, no history of exercise intolerance, and a pulse oximetry of > 94%.
g. Central nervous system (CNS) function defined as: i. Patients with a known seizure
disorder may be enrolled if on anticonvulsants and/or are well-controlled.
ii. CNS toxicity including peripheral neuropathy < Grade 2.
8. Patient and/or patient's parent or legal guardian must be capable of understanding the
investigational nature, potential risks, and benefits of the study. The patient and/or
the parent or legal guardian must sign a written informed consent. Age-appropriate
assent will be obtained per institutional guidelines.
Contraception:
Female patients :
9. A female patient is eligible to participate if she is not pregnant, not breastfeeding,
and at least one of the following conditions applies:
1. Not a woman of childbearing potential (WOCBP) as defined in the protocol OR
2. A WOCBP who agrees to follow the contraceptive guidance in the protocol during
the treatment period and for at least 120 days after the last dose of study
treatment.
10. A female patient of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving any dose of study treatment. If the
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
be required.
Male patients:
11. A male patient is eligible to participate if he agrees to follow the contraceptive
guidance in the protocol during the study treatment period and for at least 120 days
after the last dose of study treatment.
Exclusion Criteria:
1. Has clinically evident metastatic or recurrent disease.
2. Has concurrent pulmonary recurrence and local recurrence at the primary tumor site.
3. Has primary refractory disease with progression of the primary tumor on
initial-therapy.
4. Has CNS or any extrapulmonary disease involvement at the time of the most recent
episode of disease recurrence proceeding enrollment.
5. Has active infection requiring systemic therapy or is dependent on or is currently
receiving systemic antibiotics that cannot be discontinued before dosing. (Note:
Patients who discontinue an antibiotic prior to dosing must wait at least 5 half-lives
after the last dose of antibiotic before receiving any OST31-164 infusion). Inhaled
prophylactic PJP (pneumocystis jiroveci pneumonia) treatment is acceptable per
Investigator discretion.
6. Is currently dependent on or has received corticosteroids within the past 4 weeks
(topical corticosteroids and occasional inhaled corticosteroids are allowed).
7. Is currently participating in or has participated in a study of an investigational
agent or is using an investigational device within 4 weeks of the first dose of
treatment.
8. Has a history of other active malignancy for < 2 years prior to enrollment. Basal cell
carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer
that has undergone potentially curative therapy or is felt by the Investigator to be
at low risk for recurrence is allowed.
9. Has an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents. Replacement therapy (e.g.,
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
pituitary insufficiency) is not considered a form of systemic treatment. Patients with
vitiligo or resolved childhood asthma/atopy would be an exception to this rule.
Patients who require intermittent use of bronchodilators or local steroid injections
will not be excluded from the study. Patients with hypothyroidism stable on hormone
replacement or Sjogren's syndrome will not be excluded from the study.
10. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
11. Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of study treatment.
12. Has a known allergy to any component of the study treatment(s) formulations.
13. Has a contraindication (e.g., sensitivity/allergy) to both trimethoprim/
sulfamethoxazole and amoxicillin.
14. Has contraindication to administration of NSAIDs.
15. Is currently receiving or will be receiving any chemotherapy, including PI3K
inhibitors, during the treatment phase.
16. Has had a prior monoclonal antibody therapy within 2 weeks prior to study Day 1.
17. Requires or anticipates requiring tumor necrosis factor (TNF) blocking agent (e.g.,
infliximab) therapy for diagnosis of rheumatologic disease or inflammatory bowel
disease (e.g., ankylosing spondylitis, Crohn's disease, plaque psoriasis, psoriatic
arthritis, rheumatoid arthritis, or ulcerative colitis).
18. Has previous history of listeriosis.
19. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
20. Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA
[qualitative] is detected).
21. Has received a live vaccine within 30 days prior to Study Day 1.
22. Patient is or has an immediate family member (spouse, children, or parent) who is
directly involved with this study or is employed by the investigational site or
Sponsor, unless prospective Institutional Review Board (IRB) approval (by chair or
designee) is given allowing exception to this criterion for a specific patient.
Regulatory Requirements:
1. All patients and/or their parents or legal guardians must sign a written informed
consent.
2. All institutional, FDA, and NCI requirements for human studies must be met.
Treatment Combination of Durvalumab, Tremelimumab and Enfortumab Vedotin or Durvalumab and Enfortumab Vedotin in Patients With Muscle Invasive Bladder Cancer Ineligible to Cisplatin (VOLGA)
A Global Study to Determine the Efficacy and Safety of Durvalumab in combination with
Tremelimumab and Enfortumab Vedotin or Durvalumab in Combination With Enfortumab Vedotin for
Perioperative Treatment in Patients Ineligible for Cisplatin Undergoing Radical Cystectomy
for Muscle Invasive Bladder Cancer
• Histologically or cytologically documented muscle-invasive TCC of the bladder with
clinical stage T2-T4aN0/1M0 with transitional and mixed transitional cell histology;
• Medically fit for cystectomy and able to receive neoadjuvant therapy;
• Patients who have not received prior systemic chemotherapy or immunotherapy for
treatment of MIBC;
• ECOG performance status of 0,1,2 at enrollment.
• Availability of tumor sample prior to study entry;
• Must have a life expectancy of at least 12 weeks at randomization.
Exclusion criteria:
• Evidence of lymph node (N2+) or metastatic TCC/UC disease at the time of screening.
• Active infection
• Uncontrolled intercurrent illness
• Prior exposure to immune-mediated therapy (with exclusion of Bacillus-Calmette Guerin
[BCG]), including but not limited to other anti-CTLA-4, anti--PD-1, anti PD-L1, or
anti-PD-L2 antibodies.
• Current or prior use of immunosuppressive medication within 14 days before the first
dose of IPs.
Study of Relugolix in Men With Metastatic Castration-Sensitive Prostate Cancer or Non-Metastatic or Metastatic Castration-Resistant Prostate Cancer
This study is being conducted to assess the safety and tolerability of relugolix with other
agents approved for use in combination with androgen deprivation therapy (ADT) for a 12-week
treatment period and an additional 40-week safety extension period in men with prostate
cancer, either metastatic castration-sensitive prostate cancer (mCSPC) or non-metastatic or
metastatic castration-resistant prostate cancer (nmCRPC or mCRPC).
1. A diagnosis of adenocarcinoma of the prostate confirmed by histologic or cytologic
evidence and with a documented medical history of either:
• mCSPC (Parts 1, 2, and 3) defined as having at least two of three risk factors at
the baseline (Day 1) visit:
• Total Gleason score of ≥ 6; and
• Presence of ≥ 2 metastatic lesions on bone scan; OR
• Radiologic evidence of measurable visceral metastases with exception of
hepatic metastases.
• nmCRPC (Part 2 only) defined as disease progression despite maintaining
castration levels of testosterone with androgen deprivation therapy (ADT), as
evidenced by an increase in consecutive prostate-specific antigen (PSA)
concentrations (2 measurements, at least one week apart).
• mCRPC (Parts 1 and 3) defined as disease progression despite maintaining
castration levels of testosterone with ADT:
• An increase in consecutive PSA (2 measurements at least 1 weeks apart);
• Worsening clinical symptoms;
• Radiologic evidence demonstrating enlarged metastatic lesions or the
development of new metastases.
2. Currently receiving standard-of-care treatment of leuprolide acetate (3-, 4-, or
6-month injections [intramuscular Lupron or subcutaneous Eligard]) or a
gonadotropin-releasing hormone (GnRH) receptor antagonist (such as degarelix) in
combination with:
• Part 1: abiraterone acetate 1000 mg or fine-particle abiraterone acetate 500 mg
once daily plus prednisone 5 mg once daily for participants with mCSPC or twice
daily for participants with mCRPC or methylprednisolone 4 mg once daily and in
whom abiraterone has been well tolerated (that is, without evidence of
hepatotoxicity requiring dose adjustment for abiraterone).
• Part 2: apalutamide 240 mg once daily and in whom apalutamide has been well
tolerated (that is, without a fracture, fall, or seizure episode or need to dose
adjust due to any adverse events).
• Part 3: docetaxel 75 mg/m2 and in whom docetaxel has been well tolerated (that
is, no evidence of hypersensitivity reaction, febrile neutropenia or neutrophils
< 500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions,
or moderate neurosensory signs and/or symptoms despite dose reduction).
Key
Exclusion Criteria:
A patient will not be eligible for inclusion in the study if any of the following criteria
apply:
1. A medical history of brain or hepatic metastases based on radiologic evidence or a
medical history of surgical castration;
2. Received combination treatment with a GnRH analog or GnRH receptor antagonist with
either abiraterone acetate plus a corticosteroid (Part 1) or apalutamide (Part 2) in
patients with mCSPC (Part 1 and Part 2) or nmCRPC (Part 2) for a total duration > 24
months or in patients with mCRPC (Part 1) for a total duration > 6 months;
3. Is scheduled or anticipates being scheduled for major surgery during the study
treatment period;
4. A current diagnosis of a malignancy other than prostate cancer, with the exception of
any of the following:
• Adequately treated basal cell carcinoma or squamous cell carcinoma of the skin,
or carcinoma in situ of any type;
• Adequately treated Stage I cancer that is currently in remission and has been in
remission for ≥ 2 years;
• Any other cancer from which the patient has been disease-free for ≥ 3 years;
5. Abnormal clinical laboratory test value(s) at the screening visit or prior to the
baseline (Day 1) visit including:
• Serum creatinine > 2.0 mg/dL;
• Platelets < 100 × 103/μL;
• Hemoglobin < 10.0 g/dL;
• Leukocytes (WBC) < 3 × 103/μL;
• Absolute neutrophil count < 1.5 × 103/μL;
• Hemoglobin A1c (HbA1c) > 8%; Note (Part 3 only): Transfusions and/or
administration of growth factors are permitted as indicated for the clinical
management of docetaxel-related hematologic effects and in accordance with the
investigator's judgement.
6. Known hepatic disease, including alcoholic liver disease or viral hepatitis such as
hepatitis A (hepatitis A virus IgM positive), chronic hepatitis B (HbsAg positive), or
chronic hepatitis C (HCV antibody positive, confirmed by HCV RNA) or clinical signs of
hepatic disease such as jaundice;
7. A medical history within 6 months prior to the screening visit or a current diagnosis
of any of the following:
• Myocardial infarction;
• Unstable angina;
• Unstable symptomatic ischemic heart disease;
• Congestive heart failure classified as NYHA class III or IV heart failure;
• Thromboembolic event(s) (eg, deep vein thrombosis, pulmonary embolism, or
symptomatic cerebrovascular event[s]);
• Any other significant cardiac condition (eg, pericardial effusion, restrictive
cardiomyopathy, severe untreated valvular stenosis, or severe congenital heart
disease);
8. An abnormal ECG
9. Uncontrolled hypertension
10. Hypotension
11. Bradycardia
12. Positive HIV
13. Medical history of a bleeding disorder or current clinical evidence of
gastrointestinal bleeding or active bleeding from another anatomical location.
14. A medical history within 1 year of the screening visit of drug or alcohol abuse
disorder according to Diagnostic and Statistical Manual of Mental Disorders V
15. Received an investigational drug within 28 days or 5 half-lives, whichever is longer,
prior to the baseline (Day 1) visit;
16. Prior use of any prohibited medication(s) and restrictive medication(s) without the
appropriate washout period or use of a prohibited medication during the study
treatment period is planned;
17. A contraindication or known history of hypersensitivity to any of the study treatments
or components thereof, or has a history of drug or other allergy that, in the opinion
of the investigator or medical monitor, contraindicates study participation;
18. Any other medical or psychiatric condition that, in the opinion of the investigator,
would interfere with accomplishing the study objectives or the patient completing the
study;
19. Is a study site employee or is a primary family member (spouse, parent, child, or
sibling) of a site employee involved in the conduct of the study.
Efficacy and Safety of KD025 in Subjects With cGVHD After At Least 2 Prior Lines of Systemic Therapy
This is a Phase 2, randomized, multicenter study to evaluate the efficacy and safety of KD025
in subjects with Chronic Graft Versus Host Disease (cGVHD) after at least 2 prior lines of
systemic therapy
1. Male and female subjects at least 12 years of age who have had allogenic hematopoietic
cell transplant (HCT).
2. Previously received at least 2 and not more than 5 lines of systemic therapy for cGVHD
3. Receiving glucocorticoid therapy with a stable dose over the 2 weeks prior to
screening
4. Have persistent cGVHD manifestations and systemic therapy is indicated
5. Karnofsky Performance Score of ≥ 60 (if aged 16 years or older); Lansky Performance
Score of ≥ 60 (if aged < 16 years)
6. Weight ≥ 40kg
Exclusion Criteria:
1. Subject has not been on a stable dose / regimen of systemic cGVHD treatments for at
least 2 weeks prior to screening. (Note: Concomitant corticosteroids, calcineurin
inhibitors, sirolimus, MMF, methotrexate, rituximab, and extracorporeal photophoresis
(ECP) are acceptable. Systemic investigational GVHD treatments are not permitted).
2. Histological relapse of the underlying cancer or post-transplant lymphoproliferative
disease at the time of screening.
3. Current treatment with ibrutinib. Prior treatment with ibrutinib is allowed with a
washout of at least 28 days prior to randomization.
Drug: Belumosudil (KD025)
Leukemia, Other, Hodgkins Lymphoma, Leukemia, Not Otherwise Specified, Lymphoid Leukemia, Other Hematopoietic, Chronic Graft-versus-host-disease
• Histological confirmed primary SCC of the vulva
• T1 tumor, not encroaching urethra/vagina/anus
• Depth of invasion > 1mm
• Tumor diameter < 4cm
• Unifocal tumor
• No enlarged (>1.5cm) or suspicious inguinofemoral lymph nodes at imaging
(CT/MRI/ultrasound)
• Possibility to obtain informed consent
• Metastatic sentinel lymph node; size of metastasis > 2mm and / or extracapsular
extension, or
• Metastatic sentinel lymph node: more than 1 SN with metastasis ≤ 2mm
• Patients are able to understand requirements of study, provide written informed
consent and comply with the study and follow-up procedures
• Adequate bone marrow, renal and liver function:
• Absolute neutrophil count ≥ 1.5 x 109 /L
• Platelet count ≥ 100 x 109 /L
• Creatinine clearance ≥ 40 ml/min measured by the Cockroft Gault formula
• Total bilirubin < 1.25 x ULN Aspartate transaminase (AST) and alanine
transaminase (ALT) ≤ 2.5 x ULN
• Performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Scale
(Appendix A)
• Age 18 years or older
• Life expectancy of ≥ 12 weeks
• Written informed consent
Exclusion Criteria:
• Inoperable tumors and tumors > 4cm
• Multifocal tumors
• Tumors with other pathology than squamous cell carcinoma
• Patients with enlarged / suspicious lymph nodes which are proven metastatic after fine
needle aspiration cytology
• No other carcinomas, other than basal cell carcinomas, within last 5 years
• History of pelvic radiotherapy
• History of any infection requiring hospitalization or antibiotics within 2 weeks
before enrollment
• Pregnant female or nursing mother
• Desire to become pregnant
• Known brain or spinal cord metastases unless adequately treated (surgery or
radiotherapy) with no evidence of progression and neurologically stable off
anticonvulsants and steroids
• Unstable angina, myocardial infarction, cerebrovascular accident, > Class II
congestive heart failure according to the New York Heart Association Classification
for Congestive Heart Failure (see Appendix B) within 6 months before enrollment
Radiation: Radiotherapy combined with cisplatin, Drug: Cisplatin
A Study to See if Memantine Protects the Brain During Radiation Therapy Treatment for a Brain Tumor
This phase III trial compares memantine to usual treatment in treating patients with brain
tumors that are newly diagnosed or have come back (recurrent). 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 brain tumor.
• >= 4 and < 18 years at time of study entry
• Patients must weigh 15 kg or greater at time of study entry
• Newly diagnosed or recurrent primary brain tumors that have not received prior cranial
radiotherapy
• Planned focal, cranial or craniospinal radiation treatment for a primary brain 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 memantine
• 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
• 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 computerized
neurocognitive assessments are not eligible to participate
• 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
Neoadjuvant Lenvatinib and Pembrolizumab for IVC Tumor Thrombus
This study will be evaluating safety and efficacy of the combination of lenvatinib and
pembolizumab neoaadjuvant therapy prior to surgical resection of locally advanced renal cell
carcinoma with IVC tumor thrombus.
• Male/female participants who are at least 18 years of age
• Have histologically confirmed cT3-4,N0-1,M0-1 (clinical stage III-IV) diagnosis of
renal cell carcinoma (any subtype) with level II-IV inferior vena cava tumor thrombus
• The primary tumor and thrombus may be assessed to be resectable or unresectable at the
time of enrollment
• Male participants: A male participant must agree to use a protocol-approved
contraception during the 120 day neoadjuvant treatment period and for at least 90 days
after the last dose of study treatment and refrain from donating sperm during this
period.
• Female participants: A female participant is eligible to participate if she is not
pregnant, not breastfeeding, and at least one of the following conditions applies:
1. Not a woman of childbearing potential (WOCBP) OR
2. A WOCBP who agrees to follow the protocol-approved contraceptive guidance during
the treatment period and for at least 30 days after the last dose of study
treatment.
• The participant (or legally acceptable representative if applicable) provides written
informed consent for the trial.
• Have measurable disease based on RECIST 1.1. Lesions situated in a previously
irradiated area are considered measurable if progression has been demonstrated in such
lesions.
• Have provided archival tumor tissue sample or newly obtained core or excisional biopsy
of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE)
tissue blocks are preferred to slides. Newly obtained biopsies are preferred to
archived tissue.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Evaluation of ECOG is to be performed within 7 days prior to the first dose of study
intervention.
• Have adequate organ function as defined in the following table. Specimens must be
collected within 10 days prior to the start of study intervention.
• Absolute neutrophil count (ANC): ≥1500/µL
• Platelets: ≥100 000/µL
• Hemoglobin: ≥9.0 g/dL or ≥ 5.6 mmol/La
• Creatinine OR Measured or calculated creatinine clearance (GFR can also be used in
place of creatinine or CrCl): ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine
levels >1.5 × institutional ULN
• Total bilirubin: ≤1.5 ×ULN OR direct bilirubin ≤ ULN for participants with total
bilirubin levels >1.5 × ULN
• AST (SGOT) and ALT (SGPT): ≤2.5 × ULN (≤5 × ULN for participants with liver
metastases)
• International normalized ratio (INR) OR prothrombin time (PT) OR Activated partial
thromboplastin time (aPTT): ≤1.5 × ULN unless participant is receiving anticoagulant
therapy as long as PT or aPTT is within therapeutic range of intended use of
anticoagulants
• ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST
(SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase);
GFR=glomerular filtration rate; ULN=upper limit of normal.
• Criteria must be met without erythropoietin dependency and without packed red blood
cell (pRBC) transfusion within last 2 weeks.
• Creatinine clearance (CrCl) should be calculated per institutional standard.
• Note: This includes eligibility-defining laboratory value requirements for treatment;
laboratory value requirements should be adapted according to local regulations and
guidelines for the administration of specific chemotherapies.
Exclusion Criteria:
• A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with
an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,
OX 40, CD137).
• Has received prior systemic anti-cancer therapy including investigational agents prior
to allocation.
• Has received prior radiotherapy within 2 weeks of start of study intervention.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. COVID-19
vaccines are permitted provided they are not live attenuated vaccines.
• Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study intervention.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Has a known additional malignancy that is progressing or has required active treatment
within the past year. Participants with basal cell carcinoma of the skin, squamous
cell carcinoma of the skin or carcinoma in situ (eg, breast carcinoma, cervical
cancer, bladder in situ) that have undergone potentially curative therapy are not
excluded.
• Has known active CNS metastases and/or carcinomatous meningitis. Participants with
previously treated brain metastases may participate provided they are radiologically
stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
(note that the repeat imaging should be performed during study screening), clinically
stable and without requirement of steroid treatment for at least 14 days prior to
first dose of study intervention.
• Has more than three different sites of metastatic renal cell carcinoma.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and lenvatinib and/or any of
its excipients.
• Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment and is allowed.
• Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participant's
participation for the full duration of the study, or is not in the best interest of
the participant to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
• Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of trial treatment.
• Has had an allogenic tissue/solid organ transplant.
• Has prolongation of QTcF interval to >480 ms.
• Has a left ventricular ejection fraction (LVEF) below the institutional (or local
laboratory) normal range, as determined by multigated acquisition (MUGA) or
echocardiogram (ECHO)
• Has clinically significant cardiovascular disease within 12 months from first dose of
study intervention, including New York Heart Association Class III or IV congestive
heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or
cardiac arrhythmia associated with hemodynamic instability. Note: Medically controlled
arrhythmia would be permitted
• Has urine protein ≥1 g/24 hours. Note: Participants with proteinuria ≥2+>1+ (≥100
mg/dL) on urine dipstick testing (urinalysis) will undergo 24-hour urine collection
for quantitative assessment of proteinuria.
• Uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in spite
of an optimized regimen of antihypertensive medication.
Niraparib in the Treatment of Patients With Advanced PALB2 Mutated Tumors (PAVO)
The purpose of this study is to further evaluate the efficacy and safety of niraparib in
patients with locally advanced or metastatic solid tumors and a pathogenic or likely
pathogenic tumor PALB2 (tPALB2) mutation.
• Participants must be at least 18 years of age or older.
• Participants must have a histologically or cytologically confirmed diagnosis of
locally advanced or metastatic solid tumor(s).
• Participants must have tested positive for a pathogenic or likely pathogenic tPALB2
gene mutation using a CLIA-certified laboratory as described in the Next-Generation
Sequencing (NGS) Laboratory Manual.
• Participants who have stable and asymptomatic Central Nervous System (CNS) disease
must be receiving a stable (for at least 7 days) or decreasing corticosteroid dose at
the time of study entry.
• Participants must submit fresh or archived (collected within 24 months of enrollment)
Formalin-Fixed Paraffin-Embedded (FFPE) tumor sample to the central laboratory for
post-enrollment confirmation of tPALB2 status.
• Participants must have received all standard therapies appropriate for their tumor
type and stage of disease or, in the opinion of the Investigator, the patient would be
unlikely to tolerate or derive clinically meaningful benefit from appropriate standard
of care therapy, or the participant has no satisfactory alternative treatments.
Exclusion Criteria:
• Participants have other active concomitant malignancy that warrants systemic,
biologic, or hormonal therapy.
• Participants who have ovarian or prostate cancer.
• Participants who have variants of undetermined significance (VUS), but not pathogenic
variants of PALB2, at the time of screening.
• Participants who relapsed while receiving platinum based therapy in the
adjuvant/curative setting.
• Participants progressing within 14-18 weeks while receiving platinum based therapy in
the metastatic setting.
• Participants who have received Poly (ADP-ribose) polymerase (PARP) inhibitor(s) in
prior lines of treatment.
• Participants with leptomeningeal disease, carcinomatous meningitis, symptomatic brain
metastases, or radiologic signs of CNS hemorrhage.
• Participants with germline or somatic BRCA1 or BRCA2 mutations.
• Participant has systolic blood pressure (BP) over 140 mmHg or diastolic BP over 90
mmHg, despite optimal medical therapy.
• Participants have previously or are currently participating in a treatment study of an
investigational agent within 3 weeks of the first dose of therapy preceding the study.
• Participants have received prior systemic cytotoxic chemotherapy, biological therapy,
or hormonal therapy for cancer, or received radiation therapy within 3 weeks of the
first dose therapy preceding the study.
Drug: Niraparib
Endometrial Cancer, Esophageal Cancer, Melanoma, Pancreatic Cancer, Metastatic Cancer, Head and Neck Cancer, Solid Tumor, Breast - Female, Colon, Corpus Uteri, Esophagus, Lung/Thoracic, Melanoma, skin, Other Urinary, Pancreas, Breast Tumor, Colon Tumor, Malignant, Lung Tumor, Urologic Cancer, Locally Advanced Solid Tumor
PALB2, Solid Tumor, Metastatic Solid Tumor, Locally Advanced Solid Tumor, Advanced Solid Tumor, Local Solid Tumor, PALB2 Mutation, Niraparib, tPALB2, tPALB2 Mutation, Pathogenic tumor, Lung Tumor, Breast Tumor, Colon Tumor, Zejula, Pancreatic Cancer, Urologic Cancer, Melanoma, Metastatic Cancer, Head and Neck Cancer, Endometrial Cancer, Esophageal Cancer
Response and Biology-Based Risk Factor-Guided Therapy in Treating Younger Patients With Non-high Risk Neuroblastoma
This phase III trial studies how well response and biology-based risk factor-guided therapy
works in treating younger patients with non-high risk neuroblastoma. Sometimes a tumor may
not need treatment until it progresses. In this case, observation may be sufficient.
Measuring biomarkers in tumor cells may help plan when effective treatment is necessary and
what the best treatment is. Response and biology-based risk factor-guided therapy may be
effective in treating patients with non-high risk neuroblastoma and may help to avoid some of
the risks and side effects related to standard treatment.
• Patients must be:
• < 12 months (< 365 days) of age at diagnosis with INRG stage L1; or
• < 18 months (< 547 days) of age at diagnosis with INRG stage L2 or stage Ms
neuroblastoma/ganglioneuroblastoma
• Enrollment on ANBL00B1 or APEC14B1 is required for all newly diagnosed patients
• Patients must have newly diagnosed v-myc avian myelocytomatosis viral oncogene
neuroblastoma derived homolog (MYCN) non-amplified neuroblastoma (International
Classification of Diseases for Oncology [ICD-O] morphology 9500/3) or MYCN
non-amplified ganglioneuroblastoma verified by histology
• Patients must meet the specified criteria for one of the treatment groups defined
below; genomic features include MYCN gene amplification, segmental chromosome
aberrations (somatic copy number loss at 1p, 3p, 4p, or 11q or somatic copy number
gain at 1q, 2p, or 17q) and deoxyribonucleic acid (DNA) index
• "Favorable" genomic features are defined by one or more whole-chromosome gains or
hyperdiploid tumor (DNA index > 1) in the absence of segmental chromosome
aberrations as defined above
• "Unfavorable" genomic features are defined by the presence of any segmental
chromosome aberration (somatic copy number loss at 1p, 3p, 4p, or 11q or somatic
copy number gain at 1q, 2p, or 17q) or diploid tumor (DNA index = 1); this
includes copy neutral loss of heterozygosity (LOH)
• Only patients with MYCN non-amplified tumors are eligible for this study
• Group A: patients < 12 months (< 365 days) of age with newly diagnosed INRG stage L1
neuroblastoma/ganglioneuroblastoma who meet the following criteria:
• Greatest tumor diameter < 5 cm of adrenal or non-adrenal origin
• Patients with non-adrenal primaries are eligible, but must have positive uptake
on metaiodobenzylguanidine (MIBG) scan or elevated catecholamine metabolites
(urine or serum) to support the diagnosis of neuroblastoma
• No prior tumor resection or biopsy
• Group A will be further split into two subsets, which are mutually exclusive, for
statistical purposes
• Group A1:
• > 6 months and < 12 months of age with an adrenal primary tumor < 5 cm in
greatest diameter OR
• Patients less than 6 months of age with an adrenal primary tumor > 3.1 and <
5 cm in greatest diameter OR
• < 12 months of age with a non-adrenal primary site < 5 cm in greatest
diameter
• Group A2: =< 6 months of age with an adrenal primary site and tumor =< 3.1 cm in
greatest diameter.
• Group B: patients < 18 months (< 547 days) of age with newly diagnosed INRG stage L2
neuroblastoma/ganglioneuroblastoma who meet the following criteria:
• No life threatening symptoms or no impending neurologic or other organ function
compromise (e.g. epidural or intraspinal tumors with existing or impending
neurologic impairment, periorbital or calvarial-based lesions with existing or
impending cranial nerve impairment, anatomic or mechanical compromise of critical
organ function by tumor [abdominal compartment syndrome, urinary obstruction,
etc.]); horner syndrome is not considered neurologic compromise
• No prior tumor resection, tumor biopsy ONLY
• Only patients with both favorable histology and favorable genomic features will
remain on study as part of Group B; the institution will be notified of
histologic and genomic results within 3 weeks of specimen submission on ANBL00B1
or APEC14B1
• Group C: patients < 18 months (< 547 days) of age with newly diagnosed INRG stage Ms
neuroblastoma/ganglioneuroblastoma
• No prior radiotherapy or chemotherapy, with the exception of dexamethasone, which is
allowed
• 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:
• Patients with MYCN amplified tumors are not eligible
• Group B and C patients who do not enroll on ANBL1232 within 4 weeks of definitive
diagnostic procedure
• Group A and C patients, not required to undergo tumor biopsy, who do not enroll on
ANBL1232 within 4 weeks of confirmatory imaging study
The iCat2, GAIN (Genomic Assessment Informs Novel Therapy) Consortium Study
This research study is evaluating the use of specialized testing of solid tumors including
sequencing. The process of performing these specialized tests is called tumor profiling. The
tumor profiling may result in identifying changes in genes of the tumor that indicate that a
particular therapy may have activity. This is called an individualized cancer therapy (iCat)
recommendation. The results of the tumor profiling and, if applicable, the iCat
recommendation will be returned.
• Age -- Age ≤ 30 years at time of initial qualifying solid tumor diagnosis
• Diagnosis -- Histologic diagnosis of solid malignancy (excluding brain tumors and
lymphoma) that meets at least one of the following criteria:
• Refractory, defined as tumor progression after initiation of standard first line
therapy without having achieved a prior partial or complete remission OR Biopsy
proven residual disease at the completion of planned standard initial front-line
therapy.
• Recurrent, defined as tumor progression after achieving a prior partial or
complete remission
• Newly diagnosed high risk disease, defined as having an expected event free
survival of < 50% at 2 years.
• Lacks definitive diagnosis or classical genomic findings after histologic review
and standard molecular testing (rare tumor group).
• Examples include (eligibility not limited to these examples):
• Histology typically associated with a fusion in which fusion is not detected.
• Ewing-like sarcoma
• Undifferentiated sarcoma
• Inflammatory myofibroblastic tumor without ALK fusion
• Infantile fibrosarcoma without NTRK fusion
• Specimen Samples
• Sufficient tumor specimen available to meet the minimum requirements for
profiling from diagnosis or progression / recurrence
--- OR
• Surgery / biopsy planned as part of clinical care that is anticipated to yield
sufficient material to meet the minimum requirements for profiling; OR
• Patient has already had molecular profiling and patient has not yet started
matched targeted therapy based on the report .
Exclusion Criteria:
• No Therapy Planned
-- Patients who have declined further anticancer therapy will be excluded.
• Performance Status
-- Patients with Lansky (age < 16 years) or Karnofsky (age ≥16 years) score < 50 will
be excluded.
• Life Expectancy -- Patients with anticipated life expectancy < 3 months will be
excluded.
Genetic: Genetic testing and GAIN report
Sarcoma, Pediatric Solid Tumor, Brain and Nervous System, Other, Eye and Orbit, Anklylosing Spondylitis, Anus, Bones and Joints, Breast - Female, Breast - Male, Carcinoid Tumor, Cervix, Colon, Corpus Uteri, Ear, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Nose, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Uterine (Endometrial), Vulva, Heart, Kaposis sarcoma, Small Intestine, Soft Tissue, Ill - Defined Sites
Computer Training Program for Younger Patients With a Brain Tumor Who Underwent Radiation Therapy
This randomized clinical trial studies how well an adaptive computerized cognitive training
program works compared to a non-adaptive computerized cognitive training program in treating
younger patients with brain tumor who underwent radiation therapy. Providing a computer
training program may improve the well-being and quality of life of patients with cognitive
(physical and mental) function difficulties caused by radiation therapy to the brain.
• Patient must be newly diagnosed or relapsed/progressed with a brain tumor that has not
previously been treated with CRT
• Note: COG therapeutic study participation is not required for ACCL10P1 enrollment
• Patient enrollment must occur within 4 calendar months following completion of CRT
• Reminder: after patient enrollment, baseline testing followed by randomization
must occur within 2-4 months after completion of CRT
• The patient must have an identified caregiver who is willing and able to oversee the
training practice during the intervention period (ie, for 5-9 weeks starting
approximately 3 months after completion of CRT)
• The patient must have access to a telephone and phone number where they can be reached
• The patient and caregiver must have reading, speaking and listening comprehension of
English
• All patients and/or their parents or legal guardians must sign a written informed
consent (patient assent is also recommended when applicable according to each
institution's policy)
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met
Exclusion Criteria:
• Patients with pontine glioma are not eligible
• Patients with an estimated survival of less than one year are not eligible
• Patients with a history of traumatic brain injury prior to tumor diagnosis are not
eligible
• Patients with a motor, visual, or auditory handicap that prevents computer use (e.g.,
unresolved posterior fossa syndrome) are not eligible to participate in this trial
• Patients with full-scale intelligence quotient (IQ) < 70 per previous testing OR
existing diagnosis of/educational classification as a student with an intellectual
disability are not eligible
Procedure: Cognitive Assessment, Other: Computer-Assisted Cognitive Training, Procedure: Psychosocial Assessment and Care, Other: Quality-of-Life Assessment, Other: Questionnaire Administration
Brain Neoplasm, Recurrent Brain Neoplasm, Brain and Nervous System
Safety Study of Cord Blood Units for Stem Cell Transplants
Background:
- Cord blood is blood that is taken from the umbilical cord and placenta of healthy newborns
after childbirth. The cord blood collected from a baby is called a cord blood unit. Cord
blood units are stored frozen in public cord blood banks. About 10,000 cord blood
transplants have been performed in children and adults for blood cancers and other diseases
in the world. These transplants have helped save lives and improve treatments. However, not
all available units of cord blood have been collected, stored, and licensed according to
specific government requirements. These unlicensed units can still be used in transplant,
but they can only be given as part of specific research studies. This study will evaluate
the safety of giving these unlicensed units by recording any problems that may occur during
and after giving the cord blood.
Objectives:
- To test the safety and effectiveness of unlicensed cord blood units in people who need
stem cell transplants.
Eligibility:
- Individuals who are scheduled to have a stem cell transplant.
Design:
- Participants will be screened with a medical history and physical exam.
- Participants will receive the cord blood unit as part of their stem cell transplant
procedure. The transplant will be performed according to the current standard of care
for the procedure.
- After the transplant, participants will be monitored for up to 1 year. Any problems or
side effects from the transplant will be treated as necessary. All outcomes will be
reported to the National Cord Blood Program and to the Center for International Blood
and Marrow Transplant.
• INCLUSION CRITERIA:
• Patients of any age or either gender with indications for receipt of investigational
HPC-CORD BLOOD who are participating in an NIH-IRB approved clinical trial for
unrelated hematopoietic stem cell transplantation.
• Signed informed consent (and assent when applicable).
EXCLUSION CRITERIA:
• Patients who are receiving licensed CB products (only)
• Patients who are receiving unlicensed CB products from other CB banks (i.e. NMDP)
Difluoromethylornithine (DFMO) will be used in an open label, single agent, multicenter,
study for patients with neuroblastoma in remission. In this study subjects will receive 730
Days of oral difluoromethylornithine (DFMO) at a dose of 750 mg/m2 ± 250 mg/m2 BID (strata 1,
2, 3, and 4) OR 2500 mg/m2 BID (stratum 1B) on each day of study. This study will focus on
the use of DFMO in high risk neuroblastoma patients that are in remission as a strategy to
prevent recurrence.
• All patients must have a pathologically confirmed diagnosis of neuroblastoma, < 30.99
years of age and classified as high risk at the time of diagnosis. Exception: patients
who are initially diagnosed as non-high-risk neuroblastoma, but later converted
(and/or relapsed) to high risk neuroblastoma are also eligible.
• All patients must be in complete remission (CR):
1. No evidence of residual disease on scan
2. No evidence of disease metastatic to bone marrow.
• Specific Criteria by Stratum:
Stratum 1/1B: All patients must have completed standard upfront therapy that replicates
treatment which patients who were enrolled on ANBL0032 received, including:
intensive induction chemotherapy and (if feasible) resection of primary tumor, followed by:
consolidation with high-dose chemotherapy with stem cell transplant and radiotherapy,
followed by: immunotherapy with Ch14.18/IL-2/GM-CSF (dinutuximab) and retinoic acid;.
All subjects on Stratum 1/B must have also met the following criteria:
• A pre-transplant disease status evaluation that met International Neuroblastoma Response
Criteria (INRC) for CR (complete response), VGPR (very good partial response), or PR
(partial response) for primary site, soft tissue metastases and bone metastases. Patients
who meet those criteria must also meet the protocol-specified criteria for bone marrow
response prior to transplant as outlined below: No more than 10% tumor involvement (based
on total nucleated cellular content) seen on any specimen from a bilateral bone marrow
aspirate/biopsy.
Stratum 2: Neuroblastoma that is in first complete remission following standard upfront
therapy different from that described for Stratum 1.
Stratum 3: Neuroblastoma that failed to have a response of at least PR following induction
chemotherapy and surgical resection of the primary tumor, but that has achieved CR
following additional therapy.
Stratum 4: Patients who have achieved a second or subsequent CR following relapse(s).
• Pre-enrollment tumor survey: Prior to enrollment on this study, a determination of
mandatory disease staging must be performed:
• Tumor imaging studies including
• Bilateral bone marrow aspirates and biopsy
• This disease assessment is required for eligibility and preferably should be done
within 2 weeks prior to enrollment, but must be done within a maximum of 4 weeks
before enrollment.
• Timing from prior therapy:
Stratum 1/1B: Enrollment no later than 60 days after completion of upfront therapy, (last
dose of cis-retinoic acid) with a maximum of 6 cycles of cis-retinoic acid maintenance
therapy.
Stratum 2, 3 and 4: Enrollment no later than 60 days from last dose of the most recent
therapy.
• Patients must have a Lansky or Karnofsky Performance Scale score of > 50% and patients
must have a life expectancy of ≥ 2 months.
• All clinical and laboratory studies for organ functions to determine eligibility must
be performed within 7 days prior to enrollment unless otherwise indicated below.
• Patients must have adequate organ functions at the time of registration:
• Hematological: Total absolute phagocyte count ≥1000/μL
• Liver: Subjects must have adequate liver function
• Renal: Adequate renal function
• Females of childbearing potential must have a negative pregnancy test. Patients of
childbearing potential must agree to use an effective birth control method. Female
patients who are lactating must agree to stop breast-feeding.
• Written informed consent in accordance with institutional and FDA (food and drug
administration) guidelines must be obtained from all subjects (or patients' legal
representative).
Exclusion Criteria:
• BSA (Body Surface Area) of <0.25 m2.
• Investigational Drugs: Subjects who are currently receiving another investigational
drug are excluded from participation.
• Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are
not eligible. Subjects must have fully recovered from hematological and bone marrow
suppression effects of prior chemotherapy.
• Infection: Subjects who have an uncontrolled infection are not eligible until the
infection is judged to be well controlled in the opinion of the investigator.
• Subjects who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study, or in whom compliance is likely to be
suboptimal, should be excluded.
Study of Carfilzomib in Combination With Induction Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia
The purpose of Phase 1b of this study is to:
- Asses the safety, tolerability and activity of carfilzomib, alone and in combination
with induction chemotherapy, in children with relapsed or refractory acute lymphoblastic
leukemia (ALL).
- Determine the maximum tolerated dose (MTD) and to recommend a phase 2 dose of
carfilzomib in combination with induction chemotherapy.
The purpose of Phase 2 of this study is to compare the rate of complete remission (CR) of
carfilzomib in combination with vincristine, dexamethasone, PEG asparaginase, daunorubicin
(VXLD) at the end of induction therapy to an appropriate external control.
1. Age 21 years or younger at the time of initial ALL diagnosis and age > 1 year at the
time of study treatment initiation.
2. Subjects must have a diagnosis of relapsed or refractory ALL with ≥ 5% blasts in the
bone marrow (M2 or M3 disease), with or without extramedullary disease.
-To be eligible, subjects must have had 1 or more prior therapeutic attempts, defined
as:
• Early first relapse (< 36 months from original diagnosis) after achieving a CR
(B-ALL) or first relapse any time following the original diagnosis after
achieving a CR (T-ALL)
• First refractory bone marrow relapse occurring any time after original diagnosis
after achieving a CR (ie, ≥1 failed attempt to induce a second remission) OR
• Relapse after achieving a CR following the first or subsequent relapse (i.e., ≥ 2
relapses) OR
• Failing to achieve a CR from original diagnosis after at least 1 induction
attempt
3. Subjects must have fully recovered from the acute toxic effects of all previous
chemotherapy, immunotherapy, or radiotherapy treatment before enrollment.
4. Subjects must have a serum creatinine level that is ≤ 1.5 × institutional upper limit
of normal (ULN) according to age. If serum creatinine level is > 1.5 × ULN, the
subject must have a calculated creatinine clearance or radioisotope glomerular
filtration rate (GFR) ≥ 70 mL/min/1.73 m2.
5. Adequate liver function, defined as both of the following:
• Total bilirubin ≤ 1.5 × institutional ULN except in the presence of Gilbert
Syndrome
• Alanine aminotransferase (ALT) ≤ 5 × institutional ULN
6. Performance status: Karnofsky or Lansky scores ≥ 50 for subjects > 16 years old or ≤
16 years old, respectively.
Phase 2
Inclusion Criteria:
1. Subject's legally acceptable representative has provided informed consent when the
subject is legally too young to provide informed consent and the subject has provided
written assent based on local regulations and/or guidelines prior to any
study-specific activities/procedures being initiated, except for standard of care
local testing as permitted per protocol.
2. Age greater than or equal to 1 month to less than 21 years. Subjects greater than or
equal to 18 years must have had their original diagnosis at less than 18 years of age.
3. Subjects must be diagnosed with relapsed or refractory relapsed ALL.
4. Subjects must have a documented first remission, less than 5% blasts in the bone
marrow (M1 bone marrow) and no evidence of extramedullary disease.
5. T-cell ALL with bone marrow relapse (defined as greater than or equal to 5% leukemia
blasts in bone marrow) or refractory relapse with or without extramedullary disease.
OR B-cell ALL bone marrow relapse or refractory relapse (defined as greater than or
equal to 5% leukemia blasts in bone marrow) after having received a targeted B-cell
immune therapy (eg, blinatumomab, inotuzumab or a CAR-T therapy) with or without
extramedullary disease..
6. Adequate liver function: bilirubin less than or equal to 1.5 x upper limit of normal
(ULN), alanine aminotransferase (ALT) less than or equal to 5 x ULN.
7. Adequate renal function: serum creatinine less than or equal to 1.5 x ULN or
glomerular filtration rate (GFR) greater than or equal to 70 mL/min/1.73 m^2; or for
children less than 2 years of age, greater than or equal to 50 mL/min/1.73 m^2.
8. Adequate cardiac function: shortening fraction greater than or equal to 30% or
ejection fraction greater than or equal to 50%.
9. Karnofsky (subjects greater than or equal to 16 years of age) or Lansky (subjects 12
months to less than 16 years of age) performance status greater than or equal to 50%.
10. Subjects must have fully recovered from the acute toxic effects of all previous
chemotherapy, immunotherapy, or radiotherapy treatment before enrollment (for example:
recovery from gastrointestinal toxicity may occur more rapidly than less reversible
organ toxicities such as sinusoidal obstruction syndrome or non-infectious
pneumonitis, for serious prior toxicities recommended discussion with Amgen medical
monitor).
11. Life expectancy of greater than 6 weeks per investigator's judgement at time of
screening.
Phase 1b Key
Exclusion Criteria:
1. Known allergy to any of the drugs used in the study (Subjects who have had a previous
allergy to PEG-asparaginase and if able, may receive Erwinia asparaginase at the
investigator's discretion)
2. Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
3. Left ventricular fractional shortening < 30%
4. History of ≥ Grade 2 pancreatitis
5. Active graft-versus-host disease requiring systemic treatment
6. Positive culture for or other clinical evidence of infection with bacteria or fungus
within 14 days of the initiation of study treatment
7. Down Syndrome
8. Prior therapy restrictions:
• Subjects must have completed therapy with granulocyte-colony stimulating factor
(G-CSF) or other myeloid growth factors at least 7 days before study treatment
initiation, or at least 14 days before study treatment initiation, if pegylated
myeloid growth factors were administered.
• Subjects must have completed any type of active immunotherapy (e.g., tumor
vaccines) at least 42 days before study treatment initiation.
• Subjects must have received the last dose of a non-monoclonal antibody biologic
agent at least 7 days before study treatment initiation.
• At least 3 antibody half-lives must have elapsed since the last dose of
monoclonal antibody (e.g., 66 days for rituximab and 69 days for epratuzumab)
before subjects may initiate study treatment.
• Subjects must not have received other antineoplastic agents with therapeutic
intent, excluding hydroxyurea and antimetabolites administered as part of
maintenance chemotherapy, within 7 days prior to study treatment initiation.
9. Hepatitis B infection with positive hepatitis B DNA
Phase 2
Exclusion Criteria:
1. Prior treatment with carfilzomib.
2. Intolerance, hypersensitivity, or inability to receive any of the chemotherapy
components of the VXLD regimen. An exception is allowed for allergy to asparaginase
products if Erwinia asparaginase is unable to be administered,
3. Autologous HSCT within 6 weeks prior to start of study treatment.
4. Allogeneic HSCT within 3 months prior to start of study treatment.
5. Active GVHD requiring systemic immune suppression.
6. Less than 30 days from discontinuation of immune suppressive therapy administered for
the treatment of acute or chronic GVHD.
7. Isolated extramedullary relapse.
8. Positive bacterial or fungal infection within 14 days of enrollment (except for
documented line infection, line has been removed, and blood culture after line removal
is negative for 5 days prior to first dose of induction therapy). Antibiotics may be
administered for prophylaxis as per institutional standards up to and after
enrollment.
9. Subjects with less than 3 antibody half-lives since the last dose of monoclonal
antibody (eg, 66 days for rituximab, 69 days for epratuzumab, inotuzumab for 36 days),
prior to first dose of investigational product must be discussed with the Amgen
medical monitor and may be allowed to enroll based on extent of disease or evidence of
rapidly rising peripheral or bone marrow blast counts.
10. Cell-based immunotherapy (eg, donor leucocyte infusion, CAR-T cells, tumor vaccines)
within 42 days prior to first dose of investigational product. If the Amgen medical
monitor agrees, an exception may be granted to the 42-day requirement for subjects
with rapidly rising peripheral or bone marrow blast counts.
11. Down's syndrome.
12. Presence of another active cancer.
13. History of grade greater than or equal to 2 pancreatitis within 6 months to screening.
14. Unresolved toxicities from prior anticancer therapy, defined as not having resolved to
CTCAE version 4.03 grade 1 or to levels dictated in the eligibility criteria apart
from alopecia or toxicities from prior anticancer therapy that are considered
irreversible and do not trigger another exclusion criterion (defined as having been
present and stable for greater than 4 weeks).
15. Antitumor therapy (chemotherapy, investigational agents, molecular-targeted therapy)
within 7 days of day 1 of induction. Exception: hydroxyurea to control peripheral
blood leukemic cell counts is allowed until start of investigational product.
16. Active viral infection, including but not limited to cytomegalovirus (CMV), Hepatitis
B infection with positive serum hepatitis surface antigen or hepatitis B DNA, HIV,
Hepatitis C with detectable hepatitis C RNA. Subjects who have previously received a
stem cell transplant must be screened for CMV infection, unless both subject and donor
are known to be CMV negative.
17. Currently receiving treatment in another investigational device or product study, or
less than 14 days since ending treatment on another investigational device or product
study.
18. Uncontrolled arrhythmias or screening ECG with corrected QT interval (QTc) of greater
than 470 msec.
19. History or evidence of any other clinically significant disorder, condition or disease
(with the exception of those outlined above) that, in the opinion of the investigator
or Amgen physician, if consulted, would pose a risk to subject safety or interfere
with the study evaluation, procedures or completion.
20. Female subject is pregnant or breastfeeding or planning to become pregnant or
breastfeed during treatment and for an additional 6 months after the last dose of any
study treatment or for 12 months after last dose of cyclophosphamide if administered
during optional consolidation cycle.
21. Female subjects of childbearing potential unwilling to use 1 highly effective method
of contraception during treatment and for an additional 6 months after the last dose
of any study treatment or for 12 months after last dose of cyclophosphamide if
administered during optional consolidation cycle.
22. Female subjects of childbearing potential with a positive pregnancy test assessed at
Screening by a serum or urine pregnancy test.
23. Male subjects with a female partner of childbearing potential who are unwilling to
practice sexual abstinence (refrain from heterosexual intercourse) or use a condom
with spermicide during treatment and for an additional 6 months after the last dose of
any study treatment, even if they have undergone a successful vasectomy.
24. Male subjects with a pregnant partner who are unwilling to practice abstinence or use
a condom with spermicide during treatment, for duration of pregnancy, and for an
additional 6 months after the last dose of any study treatment.
25. Male subjects unwilling to abstain from donating semen or sperm during treatment and
for an additional 6 months after the last dose of any study treatment.
26. Known allergy to captisol (a cyclodextrin derivative used to solubilize carfilzomib;
for a complete listing of Captisol-enabled drugs, see the Ligand Pharmaceuticals, Inc.
website).
A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors (GARNET)
This is a multicenter, open-label, first-in-human Phase 1 study evaluating the
anti-programmed death receptor 1 (anti-PD-1) antibody TSR-042 in patients with advanced solid
tumors who have limited available treatment options. The study will be conducted in 2 parts:
dose escalation and cohort expansion. The cohort expansion may include up to 5 tumor types,
including endometrial and Non-Small Cell Lung cancer.
• Patient is at least 18 years of age
• Patient with advanced or metastatic solid tumor and has disease progression after
treatment with available therapies that are known to confer clinical benefit or who
are intolerant to treatment that meets the following requirements for the part of the
study they will participate in:
1. Part 1: Patient with any advanced or metastatic solid tumor
2. Part 2A: Patient with any advanced or metastatic solid tumor
3. Part 2B: Patient with Non-Small Cell Lung Cancer (NSCLC) and Endometrial cancers
• Female patients, if of childbearing potential, must have a negative serum pregnancy
test within 72 hours prior to the date of the first dose of study medication.
• Female patients of childbearing potential must agree to use 2 adequate methods of
contraception with their partner starting with the screening visit through 150 days
after the last dose of study therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 for Part 1 and ≤ 1
for Part 2. Adequate organ function.
Exclusion Criteria:
• Patient has received prior therapy with an anti- programmed death receptor 1
(anti-PD-1), anti-PD-1- ligand-1 (anti-PD-L1), or anti-PD-1 ligand-2 (anti-PD- L2)
agent.
• Known uncontrolled central nervous system (CNS) metastases and/or carcinomatous
meningitis. Note: Patients with previously treated brain metastases may participate
provided they are stable (without evidence of progression by imaging for at least 4
weeks prior to the first dose of study treatment and any neurologic symptoms have
returned to baseline), have no evidence of new or enlarging brain metastases, and are
clinically stable off steroids for at least 7 days prior to study treatment.
Carcinomatous meningitis precludes a patient from study participation regardless of
clinical stability.
• Known additional malignancy that progressed or required active treatment within the
last 2 years. Exceptions include basal cell carcinoma of the skin, squamous cell
cancer (SqCC) of the skin that has undergone potentially curative therapy, or in situ
cervical cancer.
• Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
• Known active hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (eg, hepatitis C virus ribonucleic acid (HCV RNA) (qualitative) is
detected).
• Active autoimmune disease that has required systemic treatment in the past 2 years
(ie, with use of disease- modifying agents, corticosteroids, or immunosuppressive
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
• History of interstitial lung disease.
Inotuzumab Ozogamicin in Treating Younger Patients With B-Lymphoblastic Lymphoma or Relapsed or Refractory CD22 Positive B Acute Lymphoblastic Leukemia
This phase II trial studies how well inotuzumab ozogamicin works in treating younger patients
with B-lymphoblastic lymphoma or CD22 positive B acute lymphoblastic leukemia that has come
back (relapsed) or does not respond to treatment (refractory). Inotuzumab ozogamicin is a
monoclonal antibody, called inotuzumab, linked to a toxic agent called ozogamicin. Inotuzumab
attaches to CD22 positive cancer cells in a targeted way and delivers ozogamicin to kill
them.
• Patients must be >= 1 year and < 22 years of age at the time of enrollment
• Patients must have B-ALL, or previously diagnosed B lymphoblastic lymphoma (B-LL),
with >= 5% (M2 or M3) bone marrow blasts with or without extramedullary disease
• NOTE: Relapsed patients previously diagnosed with B-lymphoblastic lymphoma (B-LL)
are eligible if they have an M2 or M3 marrow at the time of enrollment on this
study
• Patients with ALL or B-LL who have M2 morphology must have local confirmatory testing
showing >= 5% blasts by flow cytometry, fluorescence in situ hybridization (FISH)
testing or other molecular method
• Leukemic blasts must demonstrate surface expression of CD22 at the time of relapse by
local/institutional flow cytometry of a bone marrow aspirate sample; (assessment of
CD22 using a bright fluorophore such as phycoerythrin [PE] is strongly recommended)
• In the case of an inadequate aspirate sample (dry tap) or if bone marrow aspirate
is unable to be performed due to patient clinical status, flow cytometry of
peripheral blood specimen may be substituted if the patient has at least 1,000/uL
circulating blasts; alternatively, CD22 expression may be documented by
immunohistochemistry of a bone marrow biopsy specimen
• Patients with one of the following:
• Second or greater relapse;
• Primary refractory disease with at least 2 prior induction attempts;
• First relapse refractory to at least one prior re-induction attempt
• Any relapse after HSCT (Cohort 1 ONLY)
Patients with Down syndrome are eligible ONLY for Cohort 1 with:
• Any of above disease status, OR
• First relapse with no prior re-induction attempt NOTE: Patients with Down syndrome or
prior HSCT are NOT eligible for Cohort 2 combination therapy
• Patients with Philadelphia chromosome (Ph)+ ALL must have had two prior therapy
attempts including two different tyrosine kinase inhibitors (TKIs)
• Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy, defined as resolution of all such toxicities to =< grade 2
or lower per the inclusion/exclusion criteria prior to entering this study. Apply
to Cohort 2:
• Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. 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.
• A waiting period prior to enrollment is not required for patients receiving
standard cytotoxic maintenance chemotherapy (i.e., corticosteroid, vincristine,
6MP, and/or methotrexate).
• A waiting period is not required for patients receiving a single dose of
intrathecal methotrexate, hydrocortisone, and/or cytarabine within 7 days prior
to enrollment
• >= 14 days must have elapsed after the completion of other cytotoxic therapy,
with the exception of hydroxyurea, for patients not receiving standard
maintenance therapy. For patients who previously received calaspargase pegol, >=
21 days must have elapsed after the last dose. 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.
• 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. 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.
• Anti-cancer agents that are 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.
• Corticosteroids: If used to modify immune adverse events related to prior therapy, >=
14 days must have elapsed since last dose of corticosteroid. A waiting period prior to
enrollment is not required for patients receiving corticosteroid for leukemia
therapy/cytoreduction.
• Radiotherapy: >= 2 weeks must have elapsed since local palliative radiation therapy
(XRT) (small port); >= 3 months must have elapsed if prior cranial or craniospinal XRT
was received, if >= 50% of the pelvis was irradiated, or if total body irradiation
(TBI) was received; >= 6 weeks must have elapsed if other substantial bone marrow
irradiation was given.
• Stem cell transplant or rescue without TBI: For Cohort 1, at least 90 days must have
elapsed since stem cell transplant and at least 30 days from donor lymphocyte
infusion. Patient must have had no more than one previous HSCT and currently have no
evidence of active graft vs. host disease (GVHD). For Cohort 2, no prior HSCT is
allowed.
• Chimeric antigen receptor (CAR) T cell therapy: At least 30 days must have elapsed
from the last CAR-T cell infusion
• 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
• 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:
• 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)
• 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)
• 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)
• 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)
• 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
• >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)
• Direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5
x ULN for age; for the purpose of this study, the ULN for ALT will be 45 U/L
Exclusion Criteria:
• Patients with any prior history of SOS irrespective of severity
• Patients with isolated central nervous system (CNS), testicular, or any other
extramedullary site of relapse
• Patients who have been previously treated with inotuzumab ozogamicin
• Patients who have previously received HSCT (Cohort 2 only)
• Patients with Down syndrome (Cohort 2 only)
• History of allergic reaction attributed to compounds of similar or biologic
composition to inotuzumab ozogamicin or other agents in the study
• Note: Patients with history of allergy to pegaspargase/calaspargase pegol are
eligible for enrollment on Cohort 2 (dose levels 1 and -1) if Erwinia formulation
of asparaginase can be obtained
• If Cohort 2 is enrolling at dose level -2, then patients who cannot receive
asparaginase due to prior allergy, toxicity, or lack of access may enroll
• NOTE: patients on AALL1621 are not eligible to co-enroll on AALL1931
• Patients with active optic nerve and/or retinal involvement are not eligible; patients
who are presenting with visual disturbances should have an ophthalmologic exam and, if
indicated, a magnetic resonance imaging (MRI) to assess optic nerve or retinal
involvement
• Patients who are currently receiving another investigational drug
• Patients who are currently receiving or plan to receive other anti-cancer agents
(except hydroxyurea, which may be continued until 24 hours prior to start of protocol
therapy, and intrathecal chemotherapy)
• Anti-GVHD or agents to prevent organ rejection post-transplant; patients who are
receiving cyclosporine, tacrolimus, or other agents to prevent either
graft-versus-host disease post bone marrow transplant or organ rejection
post-transplant are not eligible for this trial; at least 3 half-lives must have
elapsed after the last dose of GVHD or anti-rejection medications
• Patients who are currently receiving or plan to receive corticosteroids except as
described below
• Systemic corticosteroids may be administered for cytoreduction up to 24 hours
prior to the start of protocol therapy, (Cohort 1 only) for all patients,
corticosteroids may be administered as a premedication for inotuzumab ozogamicin
and as treatment for allergic reactions or for physiologic replacement/stress
dosing of hydrocortisone for documented adrenal insufficiency; corticosteroids
are not allowed for other indications
• Patients with known human immunodeficiency virus (HIV), hepatitis B or C infections;
testing to prove negative status is not required for enrollment unless it is deemed
necessary for usual medical care of the patient
• Patients who have an active uncontrolled infection defined as:
• Positive bacterial blood culture within 48 hours of study enrollment;
• Fever above 38.2 degree 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
• Patients known to have one of the following concomitant genetic syndromes: Bloom
syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Schwachman
(Schwachman-Diamond-Blackfan) syndrome or any other known bone marrow failure syndrome
• There have been no human studies of inotuzumab ozogamicin in pregnant women and no
reports of exposure in utero; based on nonclinical safety studies, inotuzumab
ozogamicin has the potential to impair human male and female fertility and to
adversely affect human embryo fetal development; women of childbearing potential
should be advised to avoid becoming pregnant while receiving inotuzumab ozogamicin;
there is no information regarding the presence of inotuzumab ozogamicin in human milk,
the effects on the breast-fed infant, or the effects on milk production; because of
the potential for adverse reactions in breast-fed infants, women should not
breast-feed during treatment with inotuzumab ozogamicin and for at least 2 months
after the final dose
• Female patients of childbearing potential are not eligible unless a negative
pregnancy test result has been obtained within 7 days prior to enrollment
• Female patients who are sexually active and of reproductive potential are not
eligible unless they agree to use an effective contraceptive method for the
duration of their study participation and for 8 months after the last dose of
inotuzumab ozogamicin
• Men with female partners of childbearing potential should use effective
contraception during treatment with inotuzumab ozogamicin and for at least 5
months after the last dose of inotuzumab ozogamicin
• Lactating females are not eligible unless they agree not to breastfeed their
infants
Recurrent B Acute Lymphoblastic Leukemia, Recurrent B Lymphoblastic Lymphoma, Refractory B Acute Lymphoblastic Leukemia, Refractory B Lymphoblastic Lymphoma
Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery
This partially randomized phase II/III trial studies how well, in combination with surgery,
cisplatin and combination chemotherapy works in treating children and young adults with
hepatoblastoma or hepatocellular carcinoma. Drugs used in chemotherapy, such as cisplatin,
doxorubicin, fluorouracil, vincristine sulfate, carboplatin, etoposide, irinotecan,
sorafenib, gemcitabine and oxaliplatin, 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. Giving combination chemotherapy may kill more tumor cells than one type of
chemotherapy alone.
• Patients in Group F must have a body surface area (BSA) >= 0.6 m^2
• 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
• Patients must be newly diagnosed with histologically-proven primary pediatric hepatic
malignancies including hepatoblastoma or hepatocellular carcinoma, except as noted
below; patients with a diagnosis of hepatocellular neoplasm, not otherwise specified,
should be classified and treated per hepatoblastoma treatment arms; note that rapid
central pathology review is required in some cases; please note: all patients with
histology as assessed by the institutional pathologist consistent with pure small cell
undifferentiated (SCU) HB will be required to have testing for INI1/SMARCB1 by
immunohistochemistry (IHC) according to the practices at the institution
• Patients with histology consistent with pure SCU must have positive INI1/SMARCB1
staining
• For all Group A patients, WDF status as determined by rapid review will be used to
further stratify patients to Group A1 or A2
• For Groups B, C and D, rapid review is required if patients are either >= 8 years
of age or have an alphafetoprotein (AFP) =< 100 at diagnosis
• For all Groups E and F patients, rapid central pathology review is required
• In emergency situations when a patient meets all other eligibility criteria and has
had baseline required observations, but is too ill to undergo a biopsy safely, the
patient may be enrolled without a biopsy
• Clinical situations in which emergent treatment may be indicated include, but are
not limited to, the following circumstances:
• Anatomic or mechanical compromise of critical organ function by tumor (e.g.,
respiratory distress/failure, abdominal compartment syndrome, urinary
obstruction, etc.)
• Uncorrectable coagulopathy
• For a patient to maintain eligibility for AHEP1531 when emergent treatment is
given, the following must occur:
• The patient must have a clinical diagnosis of hepatoblastoma, including an
elevated alphafetoprotein (AFP), and must meet all AHEP1531 eligibility
criteria at the time of emergent treatment
• Patient must be enrolled on AHEP1531 prior to initiating protocol therapy; a
patient will be ineligible if any chemotherapy is administered prior to
AHEP1531 enrollment
• Note: If the patient receives AHEP1531 chemotherapy emergently PRIOR to
undergoing a diagnostic biopsy, pathologic review of material obtained in the
future during either biopsy or surgical resection must either confirm the
diagnosis of hepatoblastoma or not reveal another pathological diagnosis to be
included in the analysis of the study aims
• Patients may have had surgical resection of the hepatic malignancy prior to
enrollment; all other anti-cancer therapy for the current liver lesion is prohibited
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60
mL/min/1.73 m^2 or
• A serum creatinine based on age/gender as follows:
• Age: maximum serum creatinine (mg/dL)
• 1 month to < 6 months: 0.4 (male and female)
• 6 months to < 1 year: 0.5 (male and female)
• 1 to < 2 years: 06 (male and female)
• 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)
• Total bilirubin =< 5 x upper limit of normal (ULN) for age
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 10 x upper limit of normal (ULN) for age
• Shortening fraction of >= 28% by echocardiogram (for patients on
doxorubicin-containing regimens [Groups C, D, E2, and F] assessed within 8 weeks prior
to study enrollment) or
• Ejection fraction of >= 47% by echocardiogram or radionuclide angiogram (for patients
on doxorubicin-containing regimens [Groups C, D, E2, and F] assessed within 8 weeks
prior to study enrollment)
• Group F patients only: QT/corrected QT (QTc) interval =< 450 milliseconds for males
and =< 470 milliseconds for females (assessed within 8 weeks prior to study
enrollment)
• Normal pulmonary function tests (including diffusion capacity of the lung for carbon
monoxide [DLCO]) if there is clinical indication for determination (e.g. dyspnea at
rest, known requirement for supplemental oxygen) (for patients receiving chemotherapy
[Groups A, B, C, D, E2, F]); for patients who do not have respiratory symptoms or
requirement for supplemental oxygen, pulmonary function tests (PFTs) are NOT required
• 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:
• Prior chemotherapy or tumor directed therapy (i.e. radiation therapy, biologic agents,
local therapy (embolization, radiofrequency ablation, and laser); therefore, patients
with a pre-disposition syndrome who have a prior malignancy are not eligible
• Patients who are currently receiving another investigational drug
• Patients who are currently receiving other anticancer agents
• Patients with uncontrolled infection
• Patients who previously received a solid organ transplant, other than those who
previously received an orthotopic liver transplantation (OLT) as primary treatment of
their hepatocellular carcinoma
• Patients with hypersensitivity to any drugs on their expected treatment arm
• Group C: Patients who have known deficiency of dihydropyrimidine dehydrogenase (DPD)
• Group D:
• Patients with chronic inflammatory bowel disease and/or bowel obstruction
• Patients with concomitant use of St. John's wort, which cannot be stopped prior
to the start of trial treatment
• Group F:
• Patients with peripheral sensitive neuropathy with functional impairment
• Patients with a personal or family history of congenital long QT syndrome
• These criteria apply ONLY to patients who may receive chemotherapy (all groups other
than Group E1):
• 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 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
• Note for Group F: patients of childbearing potential should use effective
birth control during treatment with sorafenib and for at least 2 weeks after
stopping treatment
Myeloma-Developing Regimens Using Genomics (MyDRUG) (MyDRUG)
The MyDRUG study is a type of Precision Medicine trial to treat patients with drugs targeted
to affect specific genes that are mutated as part of the disease. Mutations in genes can lead
to uncontrolled cell growth and cancer. Patients with a greater than 25% mutation to any of
the following genes; CDKN2C, FGFR3, KRAS, NRAS, BRAF V600E, IDH2 or T(11;14) can be enrolled
to one of the treatment arms. These arms have treatments specifically directed to the mutated
genes. Patients that do not have a greater than 25% mutation to the genes listed can be
enrolled to a non-actionable treatment arm.
The genetic sequencing of the patient's tumor is required via enrollment to the MMRF002
study: Clinical-grade Molecular Profiling of Patients with Multiple Myeloma and Related
Plasma Cell Malignancies. (NCT02884102).
• Willing to be registered into the pomalidomide (POMALYST®) Risk Evaluation and
Mitigation Strategy (REMS®) program
• Enrolled in the MMRF002 Molecular Profiling Protocol (NCT02884102) with report less
than 120 days old
• Disease free of prior malignancies for ≥ 3 years with exception of currently treated
basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or
breast, or prostate cancer not requiring therapy
• High risk patients with relapsed refractory multiple myeloma (RRMM), who have:
• received at least one prior but no more than 3 prior therapies
• exposed to both a PI and an IMiD
• had early relapse after initial treatment Early relapse as defined by at least
one of the following: (Relapse is defined as the IMWG uniform response)
1. Relapse within 3 years of initiation of induction chemo therapy for post
autologous stem cell transplantation (ASCT) followed by maintenance, or 18
months if unmaintained after ASCT
2. Within 18 months of initial non-ASCT based therapy
• Patients must have progressed after their most recent treatment and require therapy
for myeloma
• Females of reproductive potential must have a negative pregnancy test at baseline, be
non-lactating, and willing to adhere to scheduled pregnancy testing
• Females of reproductive potential and males must practice and acceptable method of
birth control
• Laboratory values obtained ≤ 14 days prior to registration:
• Absolute neutrophil count (ANC) ≥ 1000/ul
• Hemoglobin (Hgb) ≥ 8 g/dl
• Platelet (PLT) ≥ 75,000/ul
• Total bilirubin <1.5 x upper limit of normal (ULN) or if total bilirubin is >1.5
x ULN, the direct bilirubin must be ≤ 2.0 mg/dL
• Aspartate aminotransferase (AST) <3 x ULN
• Creatinine Clearance ≥ 30 mL/min
Measurable disease of Multiple Myeloma (MM) as defined by at least one of the following:
• Serum monoclonal protein ≥ 0.5 g by protein electrophoresis
• ≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis
• Serum immunoglobulin free light chain (FLC) ≥10 mg/dL AND abnormal serum
immunoglobulin kappa to lambda FLC ratio
• Monoclonal bone marrow plasmacytosis ≥30% (evaluable disease)
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1, or 2
• Ability to take aspirin, warfarin, or low molecular weight heparin
Sub-Protocol
Inclusion Criteria:
Refer to each respective Sub Protocol for additional inclusion criteria.
Exclusion Criteria:
Patients will be ineligible for this study if they meet any one of the following criteria:
• Aggressive multiple myeloma requiring immediate treatment as defined by:
• Lactate dehydrogenase (LDH) > 2 times ULN
• Presence of symptomatic extramedullary disease or central nervous system
involvement
• Hypercalcemia >11.5 mg/dl
• Acute worsening of renal function (CrCl < 30 ml/min) directly related to myeloma
relapse
• Any neurological emergency related to myeloma
• Clinical symptoms of hyperviscosity related to monoclonal protein
• Involved serum free light chain > 100 mg/dL (1000 mg/L) in the setting of prior
diagnosis of cast nephropathy
• Infection requiring systemic antibiotic therapy or other serious infection within 14
days of enrolment
• Known hypersensitivity or development of erythema nodosum if characterized by a
desquamating rash while taking thalidomide, lenalidomide, pomalidomide or similar
drug. Known allergy to any of the study medications, their analogues, or excipients in
the various formulations of the agents
• Prior Ixazomib/Pomalidomide/Dexamethasone combination therapy
• Pregnant or breast-feeding females
• Serious medical or psychiatric illness, active alcoholism, or drug addiction that may
hinder or confuse compliance, interfere in the completion of treatment per protocol,
or follow-up evaluation
• Active hepatitis A, B or C viral infection or known human immunodeficiency virus (HIV)
infection
• Concurrent symptomatic amyloidosis or plasma cell leukemia
• POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly,
endocrinopathy, monoclonal protein (M-protein) and skin changes]
• Residual side effects to previous therapy > Grade 1 prior to initiation of therapy
(Alopecia any grade and/or neuropathy Grade 2 without pain are permitted)
• Prior allogeneic or ASCT within 12 weeks of initiation of therapy. Prior allogeneic
stem cell transplant with active graft-versus-host disease (GVHD)
• Prior experimental therapy within 14 days of protocol treatment or 5 half-lives of the
investigational drug, whichever is longer
• Prior anticancer therapy within 14 days of initiation of protocol therapy
(Dexamethasone/ 40mg/day) for a maximum of 4 days before screening is allowed
• Prior major surgical procedure or radiation therapy within 4 weeks of the initiation
of therapy (this does not include limited course of radiation used for management of
bone pain within 7 days of initiation of therapy).
• Known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that
limit the ingestion or Gastro Intestinal (GI) absorption of drugs administered orally
• Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
unstable angina, or myocardial infarction within the past 6 months
• Other co-morbidity, which would interfere with patient's ability to participate in
trial or that confounds the ability to interpret data from the study
Sub-Protocol
Exclusion Criteria:
Refer to each respective Sub Protocol for additional exclusion criteria.
Trial of Curcumin to Prevent Progression of Low-risk Prostate Cancer Under Active Surveillance
This is a prospective study to determine if the use of curcumin randomized against placebo
will reduce cancer progression in patients with prostate cancer undergoing active
surveillance.
• Age between 40-89 years
• Biopsy proven, low-risk, localized prostate cancer (minimum of 8 cores)
• May have had biopsy within last 12 months ≤4 cores involved with cancer
• Gleason score ≤6 with no Gleason pattern 4
• Clinical stage T1c-T2a/b
• Serum PSA ≤15 ng/ml
• Life expectancy > 5 years
Exclusion Criteria:
• Any previous prostate cancer treatment (radiotherapy, chemotherapy, hormonal therapy,
oral glucocorticoids, GnRH analogues, prostatectomy)
• Concurrent or previous use within 6 months of screening of any 5α-reductase inhibitor
• Use of anabolic steroids or drugs with antiandrogenic properties
• Prostate volume >150 grams
• Patients who are taking antiplatelet, anticoagulant agents or have a history of a
bleeding disorder. Patients taking 81 mg of Aspirin will be allowed to enroll with
close observation
• History of gastric or duodenal ulcers or untreated hyperacidity syndromes. Patients on
stable doses (2 months of therapy) of GERD medication allowed.
• Patients who are currently taking Curcumin and are unwilling to stop or plan to take
Curcumin during the study
• Patients with a history of gallbladder problems or gallstones or biliary
obstruction,unless patient had cholecystectomy
Drug: Curcumin, Drug: Placebo
Prostate Cancer, Prostate
prostate cancer, active surveillance, curcumin
UT Southwestern; Parkland Health & Hospital System
A Phase I Dose Escalation Study of Single Fraction Ablative Pre-operative Partial Breast (S-PBI) for Early Stage Breast Cancer
The purpose of this phase I trial is to evaluate dose-limiting toxicity while dose escalating
single-fraction preoperative S-PBI to a presumed radioablative dose over 3 cohorts, starting
with 30Gy in 1 fraction and advancing to 34Gy and 38Gy in 1 fraction.
1. Invasive epithelial (ductal, medullary, lobular, papillary, mucinous (colloid), or
tubular) histologies of the breast 3 cm or less(T1-T2cN0) in women who have not
undergone surgery or neoadjuvant endocrine or chemotherapy for current breast cancer
diagnosis
2. Tumor must not involve the overlying skin based on imaging evaluation and/or clinical
exam
3. Age >/= 18 years old and female
4. Greatest Tumor dimension is 3cm or less based on US. MRI measurements can be included
only if performed BEFORE the biopsy
5. Tumor must be unifocal
6. The tumor must be visible on CT scan and/or preferably marked with clip(s) in tumor
7. Patients must undergo an MRI for work up to aid in tumor delineation and to rule out
additional foci of disease. If additional foci of disease are present, they need to
have a negative biopsy to proceed with treatment.If patient cannot have MRI, contrast
enhanced digital mammography (CEDM) is allowed in place of MRI.
8. Clinically and radiographically node negative on ultrasound of the axilla or MRI
9. Estrogen receptor positive or Progesterone receptor positive and Her2neu negative
10. Ability to understand and the willingness to sign a written informed consent.
11. Women of child-bearing potential must agree to use adequate contraception (hormonal or
barrier method of birth control) prior to the start of study and for the duration of
radiation therapy. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately
A female of child-bearing potential is any woman (regardless of sexual orientation, having
undergone a tubal ligation, or remaining celibate by choice) who meets the following
criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has
had menses at any time in the preceding 12 consecutive months
Exclusion Criteria:
1. Multi-centric disease
2. Prior RT to the involved breast
3. Tumor size >3cm
4. 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
5. Patients who are pregnant or lactating due to the potential exposure to the fetus to
radiation therapy and unknown effects of radiation therapy to lactating females
6. Patients unable to have an MRI or contrast enhanced digital mammography (CEDM)
7. Prior ipsilateral breast cancer
8. Tumor less than 5mm from the skin surface on clinical exam and/or radiographic imaging
9. Patients with active Lupus or scleroderma
Testing the Timing of Pembrolizumab Alone or With Chemotherapy as First Line Treatment and Maintenance in Non-small Cell Lung Cancer
This phase III trial studies whether pembrolizumab alone as a first-line treatment, followed
by pemetrexed and carboplatin with or without pembrolizumab after disease progression is
superior to induction with pembrolizumab, pemetrexed and carboplatin followed by
pembrolizumab and pemetrexed maintenance in treating patients with stage IV non-squamous
non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab,
may help the body's immune system attack the cancer, and may interfere with the ability of
tumor cells to grow and spread. Chemotherapy drugs, such as pemetrexed and carboplatin, 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. It is not yet known whether giving
first-line pembrolizumab followed by pemetrexed and carboplatin with or without pembrolizumab
works better in treating patients with non-squamous non-small cell cancer.
• Patients must have histologically or cytologically confirmed stage IV non-squamous
non-small cell lung cancer (NSCLC) (includes M1a, M1b, and M1c stage disease, American
Joint Committee on Cancer [AJCC] 8th edition). Patients with stage IIIB and IIIC
disease are eligible if they are not candidates for combined chemotherapy and
radiation. Prior chemo-radiation therapy (RT) for stage III with recurrence is allowed
• Patients must have PD-L1 expression Tumor Proportion Score (TPS) >= 1% in tumor cells.
If PD-L1 expression TPS is unevaluable or the testing could not be completed, the
patients are not eligible. The assay must have been performed by a Clinical Laboratory
Improvement Act (CLIA) (or equivalent) certified laboratory
• Patients must have measurable or non-measurable disease. The presence of malignant
pleural fluid alone is sufficient to satisfy this eligibility criterion. Baseline
imaging assessments and measurements used to evaluate all measurable or non-measurable
sites of disease must be done within 4 weeks prior to study registration
• NOTE: If patient receives pemetrexed, follow institutional guidelines to drain
fluids
• Patients must be >= 18 years of age
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 to 1
• Patients with treated brain metastases are eligible if follow-up brain imaging
obtained at least 14 days after central nervous system (CNS)-directed therapy shows no
evidence of progression. CNS progression counts as progression and patients must move
on to the next phase after CNS treatment. Patients with asymptomatic new (at
screening) or progressive brain metastases (active brain metastases at screening) are
eligible if the treating physician determines that immediate CNS specific treatment is
not required and is unlikely to be required during the first cycle of therapy
• Patients are eligible if off steroids for at least 14 days prior to protocol
treatment
• Anticonvulsants are allowed
• Patients with asymptomatic, sub-centimeter brain metastasis who at the discretion
of investigators do not need immediate CNS directed therapies are eligible
• Patients with prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class 2B or better
• Patients must use accepted and effective method(s) of contraception or by abstaining
from sexual intercourse from time of registration, while on study treatment, and
continue for 120 days after the last dose of study treatment
• Absolute neutrophil count (ANC) >= 1500/mm^3 (within 14 days prior to randomization)
• Platelets >= 100,000/mm^3 (within 14 days prior to randomization)
• Prothrombin time (PT)/international normalized ratio (INR) only if on active
anticoagulation with warfarin or any formulations of heparin) =< 3.0 (within 14 day
prior to randomization)
• Total bilirubin =< 1.5 mg/dL (obtained within 14 days prior to randomization)
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 5
x upper limit of normal (ULN) (obtained within 14 days prior to randomization)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 5 x
upper limit of normal (ULN) (obtained within 14 days prior to randomization)
• Calculated creatinine clearance >= 45 ml/min to be eligible to receive pemetrexed
(obtained within 14 days prior to randomization)
• Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) (obtained within
14 days prior to randomization)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable or on suppressive therapy, if indicated. Patients with a
history of hepatitis C virus (HCV) infection must have been treated and cured. For
patients with HCV infection who are currently on treatment, they are eligible if they
have an undetectable HCV viral load
Exclusion Criteria:
• Patients must NOT have received the following:
• Prior systemic chemotherapy or immunotherapy for advanced metastatic NSCLC.
Patients treated with any prior checkpoint inhibitors for metastatic lung cancer
are ineligible. Chemotherapy for non-metastatic disease (e.g. adjuvant therapy)
or immunotherapy for locally advanced Stage III disease, or treated with
neoadjuvant IO is allowed if at least 6 months have elapsed between the last dose
of the prior therapy and study registration. Local therapy, e.g. palliative
radiation, is allowed as long as a period of 14 days has passed between
completion of local therapy and the start of protocol treatment. Registration
prior to treatment during the 14 days is allowed. Palliative radiation must be to
non-target lesions. Palliative radiation to pre-existing lesions while on
protocol treatment is allowed as long as these areas have not grown to RECIST
defined progression. Development of any new metastasis is considered progression.
Concurrent radiation and protocol treatment is not allowed; protocol treatment
may resume after completion of radiation as long as patient does not have greater
than grade 2 side effects from radiation per physician discretion.
• Methotrexate (MTX) given in low doses for non-malignant conditions with last dose
at least 14 days prior to date of registration will be allowed. Other low dose
chemotherapeutics for non-malignant conditions will be considered, but review by
the study chair is required
• Palliative radiation to non-target lesions (bone metastasis) is allowed if the
patient develops symptoms
• Patients with known EGFR mutations (except exon 20 insertion), BRAF mutations (V600)
or ALK or ROS1 translocations or other driver mutations that can be treated with oral
tyrosine kinase inhibitors are excluded
• Patients must not have known pre-existing and clinically active interstitial lung
disease, or a known history of (non infectious) pneumonitis that required steroids, or
current pneumonitis
• Patients must not have significant gastrointestinal disorders with diarrhea as a major
symptom (e.g. Crohn's disease, malabsorption, etc.)
• Patients must not have history of auto-immune condition (including Guillain-Barre
Syndrome or Multiple Sclerosis) requiring ongoing or intermittent systemic treatment
in the past 2 years prior to registration (i.e., with use of disease modifying agents,
corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine,
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment
• Patients must not have any other concomitant serious illness or organ system
dysfunction that in the opinion of the investigator would either compromise patient
safety or interfere with the evaluation of the safety of the study drug
• Patients must not receive any other investigational agents during the course of
therapy
• Patients must not be pregnant or breast-feeding due to potential harm to the fetus or
infant from cytotoxic chemotherapy and the unknown risk of pembrolizumab (MK-3475).
All patients of childbearing potential must have a blood test or urine study within 72
hours prior to registration to rule out pregnancy. A patient of childbearing potential
is anyone, regardless of sexual orientation or whether they have undergone tubal
ligation, who meets the following criteria: 1) has achieved menarche at some point; 2)
has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been
naturally postmenopausal (amenorrhea following cancer therapy does not rule out
childbearing potential) for at least 24 consecutive months (i.e., has had menses at
any time in the preceding 24 consecutive months)
• Patients must not have a known history of active tuberculosis (TB)
• Patients must not have a diagnosis of immunodeficiency or receive systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to the
first dose of protocol treatment
• Patients must not have received a live vaccine within 30 days prior to randomization.
Patients are permitted to receive inactivated vaccines and any non-live vaccines
including those for the seasonal influenza and COVID-19 (Note: intranasal influenza
vaccines, such as Flu-Mist are live attenuated vaccines and are not allowed). If
possible, it is recommended to separate study drug administration from vaccine
administration by about a week (primarily, in order to minimize an overlap of adverse
events)
STRATA: Safe Testing of Risk for AsymptomaTic MicrohematuriA
To evaluate the clinical utility associated with the integration of Cxbladder into the
evaluation of subjects presenting with hematuria for evaluation of urothelial carcinoma (UC)
without compromising detection of UC.
• Patient is undergoing investigation of recent confirmed hematuria, as defined by the
AUA/SUFU Guideline (Barocas DA, Boorjian SA, Alvarez RD et al. Microhematuria:
AUA/SUFU guideline, J Urol 2020; 204:778) (by either flexible or rigid
cystoscopy/TURBT), including hematuria subjects referred due to suspicious/positive
imaging, in order to determine the presence of urothelial carcinoma.
• Able to provide a voided urine sample of the required minimum volume
• Able to give written consent
• Able and willing to comply with study requirements
• Aged 18 years or older
Exclusion Criteria
• Prior history of bladder malignancy or pelvic radiotherapy. Prior history prostate or
renal cell carcinoma within the last 5 years.
• Prior genitourinary manipulation (flexible or rigid cystoscopy / catheterisation,
urethral dilation) in the 14 days before urine collection,
• Known current pregnancy
A Study of the Drugs Selumetinib vs. Carboplatin and Vincristine in Patients With Low-Grade Glioma
This phase III trial compares the effect of selumetinib versus the standard of care treatment
with carboplatin and vincristine (CV) in treating patients with newly diagnosed or previously
untreated low-grade glioma (LGG) that does not have a genetic abnormality called BRAFV600E
mutation and is not associated with systemic neurofibromatosis type 1. Selumetinib works by
blocking some of the enzymes needed for cell growth and may kill tumor cells. Carboplatin and
vincristine are chemotherapy drugs that work in different ways to stop the growth of tumor
cells, either by killing the cells or by stopping them from dividing. The overall goal of
this study is to see if selumetinib works just as well as the standard treatment of CV for
patients with LGG. Another goal of this study is to compare the effects of selumetinib versus
CV in subjects with LGG to find out which is better. Additionally, this trial will also
examine if treatment with selumetinib improves the quality of life for subjects who take it.
• Patients must be >= 2 years and =< 21 years at the time of enrollment
• Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment
• Patients must have non-neurofibromatosis type 1 (non-NF1) low-grade glioma (LGG)
without a BRAFV600E mutation as confirmed by Rapid Central Pathology and Molecular
Screening Reviews performed on APEC14B1 (NCT02402244) and that has not been treated
with any modality besides surgery. Note: Patients may be newly-diagnosed OR previously
diagnosed, and there is no required time frame between biopsy/surgery and treatment
initiation.
• Patients with residual tumor after resection or progressive tumor after initial
diagnosis (with or without surgery) who have not received treatment (chemotherapy
and/or radiation) are eligible
• Patients must have two-dimensional measurable tumor >= 1 cm^2 to be eligible
• Eligible histologies will include all tumors considered low-grade glioma or low-grade
astrocytoma (World Health Organization [WHO] grade I and II) by 5th edition WHO
classification of central nervous system (CNS) tumors with the exception of
subependymal giant cell astrocytoma
• Patients with metastatic disease or multiple independent primary LGG are eligible
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows (performed within
7 days prior to enrollment):
• Age: Maximum Serum Creatinine (mg/dL)
• 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female)
• 6 to < 10 years: 1 mg/dL (male); 1 mg/dL (female)
• 10 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female)
• 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female)
• >= 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (performed within 7 days
prior to enrollment) (children with a diagnosis of Gilbert's syndrome will be allowed
on study regardless of their total and indirect [unconjugated] bilirubin levels as
long as their direct [conjugated] bilirubin is < 3.1 mg/dL)
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L
(performed within 7 days prior to enrollment). For the purpose of this study, the ULN
for SGPT is 45 U/L
• Albumin >= 2 g/dL (performed within 7 days prior to enrollment)
• Left ventricular ejection fraction (LVEF) >= 53% (or institutional normal; if the LVEF
result is given as a range of values, then the upper value of the range will be used)
by echocardiogram (performed within 4 weeks prior to enrollment)
• Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) (performed within
4 weeks prior to enrollment)
• Absolute neutrophil count >= 1,000/uL (unsupported) (performed within 7 days prior to
enrollment)
• Platelets >= 100,000/uL (unsupported) (performed within 7 days prior to enrollment)
• Hemoglobin >= 8 g/dL (may be supported) (performed within 7 days prior to enrollment)
• Patients with a known seizure disorder should be stable and should not have
experienced a significant increase in seizure frequency within 2 weeks prior to
enrollment
• Patients 2-17 years of age must have a blood pressure that is =< 95th percentile for
age, height, and gender at the time of enrollment (with or without the use of
anti-hypertensive medications)
• Patients >= 18 years of age must have a blood pressure =< 130/80 mmHg at the time of
enrollment (with or without the use of anti-hypertensive medications)
• Note for patients of all ages: Adequate blood pressure can be achieved using
medication for the treatment of hypertension
• All patients must have ophthalmology toxicity assessments performed within 4 weeks
prior to enrollment
• For all patients, a magnetic resonance imaging (MRI) of the brain (with orbital cuts
for optic pathway tumors) and/or spine (depending on the site(s) of primary disease)
with and without contrast must be performed within 4 weeks prior to enrollment
• Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age
• Patients must have the ability to swallow whole capsules
• All patients have signed an appropriate consent form and Health Insurance Portability
and Accountability Act (HIPAA) authorization form (if applicable)
• All patients and/or their parents or legal guardians must sign a written informed
consent
• All patients have been consented and enrolled on APEC14B1 (NCT02402244) followed by
enrollment on the ACNS1833 Pre-Enrollment Eligibility Screening (Step 0) on the same
day to complete the Rapid Central Review
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met
Exclusion Criteria:
• Patients must not have received any prior tumor-directed therapy including
chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Prior
surgical intervention is permitted
• Patients with a concurrent malignancy or history of treatment (other than surgery) for
another tumor within the last year are ineligible
• Patients with diffuse intrinsic pontine tumors as seen on MRI (> 2/3 of pons
involvement on imaging) are not eligible even if biopsy reveals grade I/II histology
• Patients may not be receiving any other investigational agents
• Patients with any serious medical or psychiatric illness/condition, including
substance use disorders or ophthalmological conditions, likely in the judgment of the
investigator to interfere or limit compliance with study requirements/treatment
• Patients who, in the opinion of the investigator, are not able to comply with the
study procedures are not eligible
• Female patients who are pregnant are not eligible since fetal toxicities and
teratogenic effects have been noted for several of the study drugs. A pregnancy test
is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants are not eligible
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation and for
12 weeks after stopping study therapy are not eligible.
• Note: Women of child-bearing potential and males with sexual partners who are
pregnant or who could become pregnant (i.e., women of child-bearing potential)
should use effective methods of contraception for the duration of the study and
for 12 weeks after stopping study therapy to avoid pregnancy and/or potential
adverse effects on the developing embryo
• Known genetic disorder that increases risk for coronary artery disease. Note: The
presence of dyslipidemia in a family with a history of myocardial infarction is not in
itself an exclusion unless there is a known genetic disorder documented
• Symptomatic heart failure
• New York Health Association (NYHA) class II-IV prior or current cardiomyopathy
• Severe valvular heart disease
• History of atrial fibrillation
• Current or past history of central serous retinopathy
• Current or past history of retinal vein occlusion or retinal detachment
• Patients with uncontrolled glaucoma
• If checking pressure is clinically indicated, patients with intraocular pressure
(IOP) > 22 mmHg or ULN adjusted by age are not eligible
• Supplementation with vitamin E greater than 100% of the daily recommended dose. Any
multivitamin containing vitamin E must be stopped prior to study enrollment even if
less than 100% of the daily recommended dosing for vitamin E
• Surgery within 2 weeks prior to enrollment, with the exception of surgical biopsy,
placement of a vascular access device or cerebral spinal fluid (CSF) diverting
procedure such as endoscopic third ventriculostomy (ETV) and ventriculoperitoneal (VP)
shunt.
• Note: Patients must have healed from any prior surgery
• Patients who have an uncontrolled infection are not eligible
Genetic Testing in Guiding Treatment for Patients With Brain Metastases
This phase II trial studies how well genetic testing works in guiding treatment for patients
with solid tumors that have spread to the brain. Several genes have been found to be altered
or mutated in brain metastases such as NTRK, ROS1, CDK or PI3K. Medications that target these
genes such as abemaciclib, paxalisib, and entrectinib may stop the growth of tumor cells by
blocking some of the enzymes needed for cell growth. Genetic testing may help doctors tailor
treatment for each mutation.
PRE-REGISTRATION ELIGIBILITY CRITERIA (ALL PATIENTS) • Tissue available for biomarker
testing (any brain metastasis tissue and extracranial site from any prior resection or
biopsy).
REGISTRATION ELIGIBILITY CRITERIA (ALL PATIENTS)
• Participants must have histologically confirmed parenchymal metastatic disease to the
brain from any solid tumor. Note: this includes patients that have controlled
extracranial disease with progressive intracranial metastasis, as well as patients
that have progressive intracranial and extracranial disease.
• New or progressive brain metastases are defined as any one of the following:
• Untreated measurable lesions in patients who have received surgery and/or
stereotactic radiosurgery (SRS) to one or more other lesions.
• Progressive measurable lesions after radiation, surgery, or prior systemic
therapy
• Residual or progressive lesions after surgery if asymptomatic.
• Patients who have had prior whole-brain radiotherapy (WBRT) and/or SRS and then
whose lesions have progressed by BM-RANO criteria or there are new lesions, are
eligible. Lesions treated with SRS may be eligible if there is unequivocal
evidence of progression. For patients with NTRK or ROS1 mutations, entrectinib
may be used for newly diagnosed brain metastases.
• Patients who have not previously been treated with cranial radiation (e.g. WBRT
or SRS) are eligible, but such patients must be asymptomatic or neurologically
stable from their CNS metastases.
• Measurable CNS disease (=> 10 mm).
• Ability to obtain magnetic resonance imaging (MRI)s with contrast
• No surgery within 2 weeks prior to or after registration.
• No chemotherapy within 14 days prior to registration (Note: for abemaciclib arm, a
21-day chemotherapy washout is required).
• For melanoma, patients must have progressed after prior immune checkpoint
blockade or for BRAF positive melanoma, BRAF/MEK inhibitors.
• For lung cancer, EGFR mutant patients must have failed EGFR therapies
• For HER2-positive breast cancer patients (regardless of ER/PR status), patients
must have received at least one prior HER-2 directed therapy in the metastatic
setting.
• For triple negative breast cancer (TNBC), patients must have received at least
one chemotherapy in the metastatic setting.
• For estrogen receptor (ER) and/or progesterone receptor (PR)+ HER2-negative
breast cancer, patients must have received at least one endocrine therapy in the
metastatic setting.
• Patients who have received prior treatment with any of the targeted treatments on
this study are not eligible for that specific treatment arm(s), but could be
eligible for other arms (e.g., a patient who has had prior treatment with
abemaciclib would not be eligible for the abemaciclib arm, but could be eligible
for another arm).
• Presence of clinically actionable alteration in NTRK, ROS1, or CDK pathway or PI3K
pathway in both a brain metastasis and extracranial site per central review.
• Not pregnant and not nursing, because this study involves investigational agents whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown. Therefore, for women of childbearing potential only, a negative pregnancy
test done =< 14 days prior to registration is required (Note: for abemaciclib arm,
pregnancy test is required =< 7 days prior to registration).
• No known current diffuse leptomeningeal involvement (diffuse defined as leptomeningeal
involvement throughout the CNS axis; if there is documented positive CSF cytology,
patient is ineligible).
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Adequate organ function.
• Absolute neutrophil count (ANC) >= 1,500/mm^3.
• Platelet count >= 100,000/mm^3.
• Total bilirubin =< 1.5 x upper limit of normal (ULN) except in patients with Gilbert's
disease. Patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and
direct bilirubin within normal limits are permitted.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
limit of normal (ULN).
• Creatinine =< 1.5 mg/dL OR calculated (Calc.) creatinine clearance > 45 mL/min.
• No uncontrolled medical comorbidities per investigator discretion (e.g. interstitial
lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal
impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical
resection involving the stomach or small bowel, or preexisting Crohn's disease or
ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or
higher diarrhea)
• Radiation to symptomatic non-target sites within neural axis is allowed prior to
registration without washout (provided there is at least one untreated target lesion
for measurement on study and radiation is completed prior to registration).
• Concurrent systemic corticosteroids are allowed if stable dose of dexamethasone for 7
days prior to registration. Baseline doses and changes in steroid dosing will be
captured.
• No concurrent administration of anticancer therapies (except for endocrine therapy or
continuation of hormonal therapy or trastuzumab in breast cancer patients). No
chemotherapy, targeted therapy or immunotherapy within 14 days prior to entering the
study (Note: For abemaciclib arm, a 21-day chemotherapy washout is required).
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this
study. Patients on strong CYP3A4 inhibitors must discontinue the drug 14 days prior to
registration on the study.
• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients
must discontinue the drug 14 days prior to the start of study treatment.
ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR PAXALISIB ARM
• Urine protein to creatinine (UPC) ratio < 1 or urine protein =< 1.
• Recent acute myocardial infarction in the last 6 months or current angina pectoris are
excluded. Patients with symptomatic bradycardia should have an electrocardiogram at
baseline. If QT interval > 470 msec, the patient is excluded.
• Patients with uncontrolled type I or II diabetes mellitus should be excluded.
Uncontrolled diabetes is defined as glycosylated hemoglobin (HbA1c) > 9% in addition
to fasting glucose > 140 mg/dL on at least 2 occasions within 14 days prior to
registration.
ADDITIONAL REGISTRATION ELIGIBILITY CRITERION FOR ENTRECTINIB ARM
• Concurrent use of H2 receptor antagonists, receptor antagonists, proton pump inhibitors
(PPIs), and/or antacids are prohibited.
ADDITIONAL REGISTRATION ELIGIBILITY CRITERION FOR ABEMACICLIB ARM
• Hemoglobin >= g/dL. Patients may receive erythrocyte transfusions to achieve this
hemoglobin level at the discretion of the investigator. Initial treatment must not
begin earlier than the day after the erythrocyte transfusion.
• Patients who received chemotherapy must have recovered (Common Terminology Criteria
for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for
residual alopecia or Grade 2 peripheral neuropathy prior to registration. A washout
period of at least 21 days is required between last chemotherapy dose and registration
(provided the patient did not receive radiotherapy).
• Patients who received adjuvant radiotherapy must have completed and fully recovered
from the acute effects of radiotherapy. A washout period of at least 14 days is
required between end of radiotherapy and registration.
• Breast cancer patients who have received ribociclib or palbociclib are eligible as
long as there is documentation of CDK4/6 pathway alteration on a biopsy or resection
at the point of progression post-ribociclib or palbociclib.
• For females of childbearing potential: A female of childbearing potential, must have a
negative serum pregnancy test within 7 days prior to registration and agree to use a
highly effective contraception method during the treatment period and for 3 weeks
following the last dose of abemaciclib. Contraceptive methods may include an
intrauterine device [IUD] or barrier method. If condoms are used as a barrier method,
a spermicidal agent should be added as a double barrier protection. Cases of pregnancy
that occur during maternal exposures to abemaciclib should be reported. If a patient
or spouse/partner is determined to be pregnant following abemaciclib initiation, she
must discontinue treatment immediately. Data on fetal outcome and breast-feeding are
to be collected for regulatory reporting and drug safety evaluation.
• Patients with active bacterial infection (requiring intravenous [IV] antibiotics at
time of initiating study treatment), fungal infection, or detectable viral infection
(such as known human immunodeficiency virus positivity or with known active hepatitis
B or C [for example, hepatitis B surface antigen positive] are excluded. Screening is
not required for enrollment.
• Patients with personal history of any of the following conditions: syncope of
cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but
not limited to, ventricular tachycardia and ventricular fibrillation), or sudden
cardiac arrest, are excluded.
Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, The PDIGREE Study
This phase III trial compares the usual treatment (treatment with ipilimumab and nivolumab
followed by nivolumab alone) to treatment with ipilimumab and nivolumab, followed by
nivolumab with cabozantinib in patients with untreated renal cell carcinoma that has spread
to other parts of the body. The addition of cabozantinib to the usual treatment may make it
work better. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may
help the body's immune system attack the cancer, and may interfere with the ability of tumor
cells to grow and spread. Cabozantinib may stop the growth of tumor cells by blocking some of
the enzymes needed for cell growth. It is not yet known how well the combination of
cabozantinib and nivolumab after initial treatment with ipilimumab and nivolumab works in
treating patients with renal cell cancer that has spread to other parts of the body.
• STEP I REGISTRATION CRITERIA
• Histologically documented renal cell carcinoma with clear cell component, including
patients who have sarcomatoid or rhabdoid features
• Any metastatic disease, including visceral, lymph node, other soft tissue and bone,
measurable per RECIST 1.1.
• Measurable disease as defined in the protocol.
• Must be intermediate or poor risk patient per International Metastatic Renal Cell
Carcinoma Database (IMDC) criteria (1 or more of the following): Karnofsky performance
status [KPS] < 80, < 1 year from diagnosis [including initial nephrectomy] to systemic
treatment for metastatic disease, hemoglobin less than lower limit of normal [LLN],
corrected calcium concentration greater than upper limit of normal [ULN], absolute
neutrophil count greater than ULN, platelet count > ULN).
• Central nervous system (CNS) disease permitted, if stable and not otherwise causing
symptoms or needing active treatment.
• Karnofsky performance status >= 70%.
• No prior treatment with PD-1, PD-L1, or CTLA-4 targeting agents (including but not
limited to nivolumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab,
tremelimumab, and ipilimumab), or any other drug or antibody specifically targeting
T-cell co-stimulation or checkpoint pathways. The only exception is for prior
treatment with nivolumab or other PD-1/PD-L1/CTLA-4 targeting therapy on pre- or
post-operative trials, as long as > 1 year since completion of systemic therapy.
• No prior previous systemic therapy for renal cell carcinoma (prior HD IL-2 [> 28 days]
and prior adjuvant sunitinib > 180 days since completion and prior immunotherapy as
above are allowed).
• No systemic cancer therapy less than 28 days prior to registration; no radiation
therapy less than 14 days prior to registration. There must be a complete recovery and
no ongoing complications from radiotherapy.
• Not pregnant and not nursing, because this study involves an agent that has known
genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing
potential only, a negative serum or urine pregnancy test done =< 14 days prior to
registration is required.
• Age >= 18 years
• Absolute neutrophil count (ANC) >= 1,500/mm^3.
• Platelet count >= 100,000/mm^3.
• Hemoglobin >= 8 g/dL.
• Calculated (Calc.) creatinine clearance >= 30 mL/min.
• Urine protein =< 1+ or urine protein to creatinine (UPC) ratio < 1.
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except for patients with known
or likely Gilbert's syndrome, for whom total bilirubin up to 3 mg/dL is allowed with
direct bilirubin =< 20% total bilirubin)
• Aspartate aminotransferase/alanine aminotransferase (AST/ALT) =< 2.5 x upper limit of
normal (ULN) or < 5 x ULN if hepatic metastases present.
• STEP 2 REGISTRATION ELIGIBILITY CRITERIA
• Successful completion of at least 1 cycle of ipilimumab/nivolumab.
• Resolution of any treatment-related adverse events to grade 1 or less per dose
modification section (this criteria does not include any adverse events [AEs] not
attributable to treatment which are present due to disease), with
prednisone-equivalent dosing at 10 mg daily or less. Exceptions for this criteria
include patients receiving replacement hormone treatments (such as levothyroxine for
treatment-related hypothyroidism or glucocorticoid replacement for adrenal
insufficiency). Please contact study chair if further discussion is needed.
• No more than 80 days from last dose of ipilimumab/nivolumab.
Exclusion Criteria:
• Active autoimmune disease requiring ongoing therapy.
• Ongoing acute toxicity > grade 2 from previous treatment.
• History of severe allergic, anaphylactic or other hypersensitivity reactions to
chimeric or humanized antibodies.
• Active hepatitis B/C, or active tuberculosis (PPD response without active TB is
allowed)
• Human immunodeficiency virus (HIV) -infected patients with detectable viral load
within 6 months prior to registration. Patients on effective anti-retroviral therapy
with undetectable viral load within 6 months prior to registration are eligible.
• Concurrent use of immunosuppressive medication including prednisone above 10 mg daily.
• Uncontrolled adrenal insufficiency.
• Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg or diastolic BP > 90
mmHg).
• Major surgery less than 28 days prior to registration.
• Any serious non-healing wound, ulcer, or bone fracture within 28 days prior to
registration.
• Any arterial thrombotic events within 180 days prior to registration.
• Clinically significant hematuria, hematemesis, or hemoptysis within 12 weeks prior to
registration.
• Cavitating pulmonary lesions or known endotracheal or endobronchial disease
manifestations.
• Lesions encasing or invading any major blood vessels (this does not include tumor
thrombus extending into/through renal vein/inferior vena cava [IVC]). Patients with
tumor thrombus extending into/through renal vein are considered eligible.
• Moderate of severe hepatic impairment (Child-Pugh B or C).
• Any history of untreated pulmonary embolism or deep venous thrombosis (DVT) in the 180
days prior to registration. (Any asymptomatic, treated pulmonary embolism or
asymptomatic, treated deep venous thrombosis > 30 days prior to registration allowed).
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms.
• Unstable cardiac arrhythmia within 6 months prior to registration.
• Any gastrointestinal (GI) bleeding =< 180 days, hemoptysis, or other signs of
pulmonary hemorrhage =< 90 days prior to registration.
• History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess,
bowel obstruction, or gastric outlet obstruction within 180 days prior to
registration.
• Active peptic ulcer disease, inflammatory bowel disease, or malabsorption syndrome
within 28 days prior to registration.
• Untreated hypothyroidism (treated hypothyroidism on thyroid replacement therapy is
allowed. Abnormal thyroid-stimulating hormone (TSH) is acceptable with normal T3/free
T4 if treated on thyroid replacement therapy)
• Evidence of pancreatitis, history of organ transplant, or history of congenital QT
syndrome.
• Active treatment with coumarin agents (e.g., warfarin), direct thrombin inhibitors
(e.g., dabigatran), direct Xa inhibitor betrixaban or platelet inhibitors (e.g.,
clopidogrel) within 5 days of registration. Allowed anticoagulants include:
prophylactic use of low-dose aspirin for cardio-protection (per local applicable
guidelines) and low-dose low molecular weight heparins (LMWH), therapeutic doses of
LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban,
apixaban. Allowed also in patients with known brain metastases who are on a stable
dose of the anticoagulant for at least 1 week prior to registration without clinically
significant hemorrhagic complications from the anticoagulation regimen or the tumor.
• Significant cardiac ischemia events (ST elevation myocardial infarction [STEMI] or
non-ST elevation myocardial infarction [NSTEMI]) within 6 months or active NY Heart
Association class 3-4 heart failure symptoms
Clear Cell Renal Cell Carcinoma, Metastatic Malignant Neoplasm in the Bone, Sarcomatoid Renal Cell Carcinoma, Metastatic Malignant Neoplasm in the Soft Tissues, Stage IV Renal Cell Cancer AJCC v8, Metastatic Malignant Neoplasm in the Viscera, Metastatic Malignant Neoplasm in the Lymph Nodes, Stage III Renal Cell Cancer AJCC v8
Maximum Tolerated Dose, Safety, and Efficacy of Rhenium Nanoliposomes in Recurrent Glioma (ReSPECT)
This is a multi-center, sequential cohort, open-label, volume and dose escalation study of
the safety, tolerability, and distribution of 186RNL given by convection enhanced delivery to
patients with recurrent or progressive malignant glioma after standard surgical, radiation,
and/or chemotherapy treatment. The study uses a modified Fibonacci dose escalation, followed
by an expansion at the maximum tolerated dose (MTD) to determine efficacy. The starting
absorbed dose is 1mCi in a volume of 0.660mL.
1. At least 18 years of age
2. Ability to understand the purposes and risks of the study and has signed a written
informed consent form approved by the investigator's IRB/Ethics Committee
3. Histologically confirmed glioma
4. Progression by Response Assessment in Neuro-Oncology (RANO) criteria following
standard treatment options with known survival benefit (Temozolomide, Radiation, and
Tumor Treating Fields [unless unwilling])
5. Patients who receive treatment with antiepileptic medications must have a two week
history of stable dose of antiepileptic without seizures prior to dosing
6. Patients with corticosteroid requirements to control cerebral edema must be maintained
at a stable or decreasing dose for a minimum of two weeks without progression of
clinical symptoms
7. A volume of enhancing tumor which falls within the treatment field volume being
evaluated in the respective cohort (see 4.1 Design)
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
9. Life expectancy of at least 2 months
10. Acceptable liver function:
• Bilirubin ≤ 1.5 times upper limit of normal
• AST (SGOT) and ALT (SGPT) ≤ 3.0 times upper limit of normal (ULN);
11. Acceptable renal function:
• Serum creatinine ≤1.5xULN
12. Acceptable hematologic status (without hematologic support):
• ANC ≥1000 cells/uL
• Platelet count ≥100,000/uL
• Hemoglobin ≥9.0 g/dL
13. All women of childbearing potential must have a negative serum pregnancy test and male
and female subjects must agree to use effective means of contraception (surgical
sterilization or the use or barrier contraception with either a condom or diaphragm in
conjunction with spermicidal gel or an IUD) with their partner from entry into the
study through 6 months after the last dose
For part 2:
14. Bevacizumab naïve glioblastoma with no more than 1 recurrence
Exclusion Criteria:
1. The subject has evidence of acute intracranial or intratumoral hemorrhage either by
MRI or computerized tomography (CT) scan. Subjects with resolving hemorrhage changes,
punctate hemorrhage, or hemosiderin are eligible.
2. The subject is unable to undergo MRI scan (eg, has pacemaker).
3. The subject has not recovered to National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) v4.0 Grade ≤ 1 from AEs (except alopecia, anemia
and lymphopenia) due to surgery, antineoplastic agents, investigational drugs, or
other medications that were administered prior to study.
4. The subject is pregnant or breast-feeding.
5. The subject has serious intercurrent illness, as determined by the treating physician,
that would compromise either patient safety or study outcomes such as:
• hypertension (two or more blood pressure readings performed at screening of > 150
mmHg systolic or > 100 mmHg diastolic) despite optimal treatment
• Non-healing wound, ulcer, or bone fracture
• Clinically significant cardiac arrhythmias
• Untreated hypothyroidism
• Uncontrolled systemic infection
• Symptomatic congestive heart failure or unstable angina pectoris within 3 months
prior study drug
• Myocardial infarction, stroke, transient ischemic attack within 6 months
• Known active malignancy (other than glioma) except non-melanoma skin cancer or
carcinoma in-situ in the cervix
6. The subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding
7. The subject has received any of the following prior anticancer therapy:
• Non-standard radiation therapy such as brachytherapy, systemic radioisotope
therapy, or intra-operative radiotherapy (IORT) to the target site.
• Radiation therapy within 12 weeks of screening
• Systemic therapy (including investigational agents and small-molecule kinase
inhibitors) or non-cytotoxic hormonal therapy (eg, tamoxifen) within 14 days or 5
half-lives, whichever is shorter, prior first dose of study drug
• Biologic agents (antibodies, immune modulators, vaccines, cytokines) within 21
days prior to first dose of study drug
• Nitrosoureas or mitomycin C within 42 days, or metronomic/protracted low-dose
chemotherapy within 14 days, or other cytotoxic chemotherapy within 28 days,
prior to first dose of study drug
• Prior treatment with carmustine wafers
• Patients who are currently receiving any other investigational agents and/or who
have received an investigational agent in the prior 28 days
8. Multifocal progression or involvement of the leptomeninges
9. Psychiatric illness/social situations that would limit compliance with the study
requirements
10. Infratentorial disease
A Study of LY3484356 in Participants With Advanced or Metastatic Breast Cancer or Endometrial Cancer (EMBER)
The reason for this study is to see if the study drug LY3484356 alone or in combination with
other anticancer therapies is safe and effective in participants with advanced or metastatic
breast cancer or endometrial cancer.
All study parts:
• Participants must be willing to provide adequate archival tissue sample
• Participants must be willing to use highly effective birth control
• Participants must have adequate organ function
• Participants must be able to swallow capsules
Dose escalation- Participants must have one of the following:
• Parts A and B: ER+ HER2- breast cancer with evidence of locally advanced unresectable
or metastatic disease who have had the following:
• Part A: may have had up to 1 prior regimen of any kind for in the advanced/metastatic
setting and no prior cyclin-dependent kinase 4/6 (CDK4/6) inhibitor therapy.
• Part B: may have had up to 2 prior regimens, no more than 1 of which may be endocrine
therapy in the advanced/metastatic setting, and must have received a prior CDK4/6
inhibitor
• Cohort E4: No prior everolimus.
• Cohort E5: No prior alpelisib and must have a phosphatidylinositol 3-kinase catalytic
α (PIK3Cα) mutation as determined by local testing.
• Part C: ER+, human epidermal growth factor receptor 2 positive (HER2+) breast cancer
with evidence of locally advanced unresectable or metastatic disease who have had at
least 2 HER2-directed therapies in any setting.
• Part D: ER+, EEC that has progressed after platinum containing chemotherapy and no
prior fulvestrant or aromatase inhibitor therapy.
• Part E: ER+ and HER2+ breast cancer with evidence of locally advanced, unresectable,
or metastatic disease.
• Part E: Participants must have received induction taxane chemotherapy combined with
trastuzumab + pertuzumab as first-line treatment for advanced/metastatic disease and
must not have progressed on this regimen.
• Part E: Participants must not have received more than 1 HER2-directed regimen or any
endocrine therapy for advanced disease or any prior CDK4/6 inhibitor therapy.
Participants with ER+/HER2- breast cancer enrolled in this study must have had evidence of
clinical benefit while on endocrine therapy for at least 24 months in the adjuvant setting
or at least 6 months in the advanced/metastatic setting or have untreated de novo
metastatic breast cancer
Exclusion Criteria:
• Participants must not have certain infections such as hepatitis or tuberculosis or HIV
that are not well controlled
• Participants must not have another serious medical condition
• Participants must not have cancer of the central nervous system that is unstable
• Participants must not be pregnant or breastfeeding
GEN3013, Epcoritamab Trial in Patients With Relapsed, Progressive or Refractory B-Cell Lymphoma EPCORE™ NHL-1
The trial is a global, multi-center safety trial of Epcoritamab, an antibody also known as
GEN3013 (DuoBody®-CD3xCD20). The trial consists of three parts: a dose-escalation part (Phase
1, first-in-human (FIH)), an expansion part (Phase 2a) and a dose optimization part (Phase
2a)
Main Inclusion Criteria Escalation Part (recruitment completed)
• Documented CD20+ mature B-cell neoplasm
1. Diffuse large B-cell lymphoma •de novo or transformed
2. High-grade B-cell lymphoma
3. Primary mediastinal large B-cell lymphoma
4. Follicular lymphoma
5. Mantle cell lymphoma
6. Small lymphocytic lymphoma
7. Marginal zone lymphoma (nodal, extranodal or mucosa associated)
• Relapsed, progressive and/or refractory disease following treatment with an anti-CD20
monoclonal antibody (e.g. rituximab) potentially in combination with chemotherapy
and/or relapsed after autologous stem cell rescue.
• ECOG performance status 0,1 or 2
• Patients must have measurable disease by CT, MRI or PET-CT scan
• Acceptable renal function
• Acceptable liver function
Main Inclusion Criteria Expansion and Optimization Parts
• Documented CD20 positive mature B cell neoplasm or CD20+ MCL
• Diffuse large B cell lymphoma, de novo or transformed (including double hit or triple
hit)
• Primary mediastinal large B cell lymphoma
• Follicular lymphoma grade 3B
• Histologic confirmed follicular lymphoma
• Marginal zone lymphomas
• Small lymphocytic lymphoma
• Mantle Cell Lymphoma (prior BTKi or intolerant to BTKi)
• At least 2 therapies including an anti CD20 monoclonal antibody containing
chemotherapy combination regimen
• Either failed prior autologous hematopoietic stem cell transplantation or ineligible
for autologous stem cell transplantation due to age or comorbidities
• At least 1 measurable site of disease based on CT, MRI or PET-CT scan with involvement
of 2 or more clearly demarcated lesions and or nodes
NOTE: Other protocol defined Inclusion criteria may apply.
Main Exclusion Criteria Escalation, Expansion and Optimization Parts
• Primary central nervous system (CNS) lymphoma or CNS involvement by lymphoma at
screening
• Known past or current malignancy other than inclusion diagnosis
• AST, and/or ALT >3 × upper limit of normal
• Total bilirubin >1.5 × upper limit of normal, unless bilirubin rise is due to
Gilbert's syndrome or of non-hepatic origin
• Estimated CrCl <45 mL/min
• Known clinically significant cardiovascular disease
• Ongoing active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
requiring systemic treatment (excluding prophylactic treatment). Past COVID-19
infection may be a risk factor
• Confirmed history or current autoimmune disease or other diseases resulting in
permanent immunosuppression or requiring permanent immunosuppressive therapy
• Seizure disorder requiring therapy (such as steroids or anti-epileptics)
• Any prior therapy with an investigational bispecific antibody targeting CD3 and CD20
• Prior treatment with chimeric antigen receptor T-cell (CAR-T) therapy within 30 days
prior to first epcoritamab administration
• Eligible for curative intensive salvage therapy followed by high dose chemotherapy
with HSCT rescue
• Autologous HSCT within 100 days prior to first epcoritamab administration, or any
prior allogeneic HSCT or solid organ transplantation
• Active hepatitis B (DNA PCR-positive) or hepatitis C (RNA PCR-positive infection).
Subjects with evidence of prior HBV but who are PCR-negative are permitted in
• Known human immunodeficiency virus (HIV) infection
• Exposed to live or live attenuated vaccine within 4 weeks prior to signing ICF
• Pregnancy or breast feeding
• Patient is known or suspected of not being able to comply with the study protocol or
has any condition for which, participation would not be in the best interest of the
patient
• Contraindication to all uric acid lowering agents
Biological: Epcoritamab
Small Lymphocytic Lymphoma, Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, Marginal Zone Lymphoma, Mantle Cell Lymphoma, Non-Hodgkins Lymphoma, High-grade B-cell Lymphoma, Primary Mediastinal Large B-cell Lymphoma
International Penile Advanced Cancer Trial (International Rare Cancers Initiative Study) (InPACT)
This is an international phase III trial, with a Bayesian design, incorporating two
sequential randomisations. It efficiently examines a series of questions that routinely arise
in the sequencing of treatment. The study design has evolved from lengthy international
consultation that has enabled us to build consensus over which questions arise from current
knowledge and practice. It will enable potential randomisation for the majority of patients
with inguinal lymph node metastases and will provide data to inform future clinical
decisions.
InPACT-neoadjuvant patients are stratified by disease burden as assessed by radiological
criteria. Treatment options are then defined according to the disease burden strata.
Treatment is allocated by randomisation. Patients may be allocated to one of three initial
treatments:
A. standard surgery (ILND); B. neoadjuvant chemotherapy followed by standard surgery (ILND);
or C. neoadjuvant chemoradiotherapy followed by standard surgery (ILND).
After ILND, patients are defined as being at low or high risk of recurrence based on
histological interpretation of the ILND specimen. Patients at high risk of relapse are
eligible for InPACT-pelvis, where they are randomised to either:
P. prophylactic PLND Q. no prophylactic PLND
1. Written informed consent
2. Measurable disease as determined by RECIST (version 1.1) criteria;
3. Histologically-proven squamous cell carcinoma of the penis,
4. Stage:
• any T, N1 (i.e. a palpable mobile unilateral inguinal lymph node), M0 or;
• any T, N2 (i.e. palpable mobile multiple or bilateral inguinal lymph nodes), M0
or;
• any T, N3 (i.e. fixed inguinal nodal mass or any pelvic lymphadenopathy), M0
5. Performance Status ECOG 0, 1 or 2.
Exclusion Criteria:
1. Pure verrucous carcinoma of the penis,
2. Nonsquamous malignancy of the penis,
3. Squamous carcinoma of the urethra,
4. Stage M1,
5. Previous chemotherapy or chemoradiotherapy,
6. Concurrent malignancy (other than SCC or Basal Cell Carcinoma of non-penile skin) that
has required surgical or non-surgical treatment in the last 3 years.