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Study Description

Brief Summary:

This research study is studying an investigational drug called BMS-986158 as a possible treatment for pediatric solid tumors, lymphoma, or brain tumors.

Detailed Description:

This is a Phase I clinical trial, which tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug to use for further studies. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved BMS-986158 as a treatment for any disease.

BMS-986158 is currently still being studied in adults. This is the first time that BMS-986158 will be evaluated in younger children, though children 12-17 years of age may also be included in parts of adult studies of BMS-986158.

Research in the laboratory has shown that BMS-986158 may have activity against cancer cells. BMS-986158 belongs to a group of drugs called Bromodomain (BRD) and Extra-Terminal Domain (BET) inhibitors. These drugs block proteins that are important in reading DNA, which is a process important for cancer cells.

Inclusion Criteria

• Age ≤ 21 years at time of enrollment. Note the requirement in section 3.1.6 that all patients must be able to swallow intact capsules.
• Karnofsky performance status ≥ 50% for patients ≥16 years of age or Lansky ≥ 50% for patients <16 years of age (see Appendix A)

• Diagnosis requirement

  • Participants must have evaluable or measurable disease (see Section 11).
  • Must have disease that is relapsed or refractory and for which standard curative measures do not exist or are no longer effective.
  • For Cohort A, participants must have histologically confirmed non-CNS primary solid tumors or lymphoma based upon biopsy or surgery at relapse/progression. Patients without biopsy or surgery at relapse/progression and with tissue only available from initial diagnosis may still be considered after discussion with the overall Primary Investigator.
  • For Cohort B, participants must have histologically confirmed solid tumors, lymphoma, or primary CNS tumor based upon biopsy or surgery at relapse/progression as well as documentation of one of the following confirmed tumor molecular features obtained in a laboratory certified to return results for clinical purposes. Patients without biopsy or surgery at relapse/progression and with tissue only available from initial diagnosis may still be considered after discussion with the overall Primary Investigator.
  • MYCN amplification or high copy number gain
  • MYC amplification or high copy number gain
  • Translocation involving MYC or MYCN
  • Translocation involving BRD4 or BRD3
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy except organ function as noted in Section 3.1.5. Patients must meet the following minimum washout periods prior to enrollment:
• Myelosuppressive chemotherapy: At least 14 days after the last dose of myelosuppressive chemotherapy (42 days for nitrosourea or mitomycin C).

• Radiotherapy:

  • At least 14 days after local XRT (small port, including cranial radiation);
  • At least 90 days must have elapsed after prior TBI, craniospinal XRT or if >50% radiation of pelvis;
  • At least 42 days must have elapsed if other substantial BM radiation;
  • At least 42 days must have passed since last MIBG or other radionuclide therapy.
• Small molecule biologic therapy: At least 7 days following the last dose of a small molecule biologic agent. For agents with known adverse events occurring beyond 7 days, this duration must be extended beyond the time in which adverse events are known to occur. If extended duration is required, this must be discussed with and approved by the overall PI.
• Monoclonal antibody: At least 28 days must have elapsed after the last dose of therapeutic monoclonal antibody.
• Myeloid growth factors: At least 14 days following the last dose of long-acting growth factor (e.g. Neulasta) or 7 days following short-acting growth factor.
• Autologous hematopoietic stem cell transplant and stem cell boost: Patients must be at least 60 days from day 0 of an autologous stem cell transplant or autologous stem cell boost.
• Cellular therapies (including CAR-T cells) and other non-cellular, non-antibody immunotherapies (e.g., vaccines): At least 42 days must have elapsed after last dose.
• Major Surgery: At least 2 weeks from prior major surgical procedure. Note: Major surgical procedure will be considered all surgical procedures aside from the following: Biopsy; central line placement/removal; bone marrow aspirate/biopsy; lumbar puncture; dental procedures; gastrostomy tube placement; and VP shunt placement/revision.
• BET inhibitors: Patients must not have received prior treatment with a BET inhibitor.
• Participants must have normal organ function as defined below.
• Bone Marrow Function

• For Patients without Documented Bone Marrow Involvement by Disease:

  • Hemoglobin > 8 g/dL (may be transfused)
  • Absolute neutrophil count ≥ 1,000 /uL
  • Platelets ≥ 100,000 /uL and transfusion independent, defined as not receiving a platelet transfusion for at least 5 days prior to CBC documenting eligibility.

• For Patients with Documented Bone Marrow Involvement by Disease:

  • Hemoglobin > 8 g/dL (may be transfused)
  • Absolute neutrophil count ≥ 750 /uL
  • Platelets ≥ 75,000 /uL and transfusion independent, defined as not receiving a platelet transfusion for at least 5 days prior to CBC documenting eligibility.

• Hepatic Function:

  • Total bilirubin ≤ 1.5 x upper limit of normal for age (patients with known Gilbert's may be considered after discussion with overall PI and if direct bilirubin is at or below the upper limit of normal for age)
  • ALT (SGPT) ≤ 3 x upper limit of normal (135 U/L) For the purpose of this study, the ULN for ALT is 45 U/L
  • Serum albumin > 2 g/dL

• Adequate Pancreatic Function:

  --Lipase < upper limit of normal

• Adequate GI Function:

  --Diarrhea < grade 1 by CTCAE version 5

• Coagulation Factors:

  • International Normalized Ratio (INR) < 1.5
  • Partial thromboplastin time (PTT) < 1.5 times upper limit of normal
• For patients having labs drawn via heparinized catheters, it is important to request heparin-absorbed values.

• Adequate Cardiac Function:

  --QTc < 480 msec

• Renal Function:

  • A serum creatinine within protocol limits based on age/sex.

OR

• Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels greater than the above age/sex maximum allowed values.
• Able to swallow intact capsules.
• Patient (or parent or legally authorized representative, if minor) is able to understand and willing to provide informed consent, using an institutionally approved informed consent procedure.
• Participants of childbearing or child-fathering potential must agree to use adequate contraception throughout their participation following the guidance in Appendix H.

Exclusion Criteria

• Prior solid organ or allogeneic stem cell transplantation.

• Patients with primary or metastatic CNS tumors, except:

  • Patients with primary CNS tumor meeting definition for Cohort B;
  • Patients with a history of CNS metastatic disease that has been resected and/or radiated without evidence of active CNS disease for 3 months preceding enrollment;
  • Patients with lymphoma and CSF involvement.

• Patients receiving any of the following prohibited foods and medications:

  • Agents listed in Appendix B within 7 days prior to enrollment
  • Grapefruit or Seville oranges and/or their juices within 7 days prior to enrollment
  • Non-steroidal anti-inflammatory drugs, oral anticoagulants, and therapeutic heparins (unfractionated or low molecular weight heparin) at the time of enrollment. Note: Use of heparin to maintain patency of a central or peripheral catheter is allowed
  • Other investigational agents being administered under an IND.
• Pregnant participants will not be entered on this study given that the effects of BMS-986158 on the developing human fetus are unknown. Female participants of childbearing potential must have a documented negative pregnancy exam within 24 hours prior to dosing.
• Breastfeeding mothers are not eligible, because there is an unknown risk for adverse events in nursing infants secondary to treatment of the mother with BMS-986158.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to BMS-986158.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients with a known history of HIV, hepatitis B, and/or hepatitis C (testing not required as part of screening).
• Patients with gastrointestinal disease or disorder that could interfere with absorption of BMS-986158, such as bowel obstruction or inflammatory bowel disease.
• Patients with a body surface area < 0.3 m2

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Study Description

This phase III trial compares the effect of vinorelbine with vincristine, dactinomycin, and cyclophosphamide (VAC) followed by vinorelbine and cyclophosphamide versus VAC followed by vinorelbine and cyclophosphamide for the treatment of high risk rhabdomyosarcoma. Chemotherapy drugs, such as vinorelbine, vincristine, dactinomycin, and cyclophosphamide, 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 vinorelbine and VAC may kill more tumor cells. Adding maintenance therapy (vinorelbine and cyclophosphamide) after VAC therapy, with or without vinorelbine, may help get rid of the cancer and/or lower the chance that the cancer comes back.

PRIMARY OBJECTIVE:

I. To compare event-free survival (EFS) of patients with high-risk rhabdomyosarcoma (HR-RMS) treated with vinorelbine, dactinomycin and cyclophosphamide (VINO AC) followed by 24 weeks of vinorelbine and oral cyclophosphamide (VINO-CPO) maintenance therapy to that of patients treated with vincristine, dactinomycin and cyclophosphamide (VAC) followed by 24 weeks of VINO-CPO maintenance therapy.

SECONDARY OBJECTIVES:

I. To assess the safety and feasibility of administering VINO-AC in newly diagnosed patients with HR-RMS.

II. To describe the toxicity experience of patients with HR-RMS treated with VINO-AC compared to VAC.

III. To compare overall survival (OS) of patients with HR-RMS treated with VINO AC followed by 24 weeks of VINO-CPO maintenance therapy to that of patients treated with VAC followed by 24 weeks of VINO-CPO maintenance therapy.

IV. To compare objective radiologic response rates at week 12 between patients with HR-RMS treated with VINO-AC to those treated with VAC.

V. To determine whether the addition of 24 weeks of VINO-CPO maintenance therapy improves EFS in patients with HR-RMS when compared to historical controls.

EXPLORATORY OBJECTIVE:

I. To collect serial blood samples and tumor tissue for banking at baseline, during treatment, at the end of therapy, and at the time of progression for future tumor and liquid biopsy studies.

OUTLINE: Patients are randomized to 1 of 2 arms.

• ARM A: Patients receive vincristine sulfate intravenously (IV) on days 1, 8 and 15 of cycles 1-4, 7, 8, 11, and 12, and day 1 of cycles 6, 9, 10, 13, and 14. Patients also receive dactinomycin IV over 1-15 minutes on day 1 of cycles 1-5 and 8-14, and cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on weeks 13 and 40.
• ARM B: Patients receive vinorelbine tartrate IV over 6-10 minutes on days 1 and 8, vincristine sulfate IV on day 15, dactinomycin IV over 1-15 minutes on day 1 of cycles 1-5 and 8-14, and cyclophosphamide IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on weeks 13 and 40.

MAINTENANCE: All patients receive vinorelbine tartrate IV over 6-10 minutes on days 1, 8, and 15, and cyclophosphamide orally (PO) on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for year 1, every 4 months for years 2-3, and every 6 months for year 4.

Inclusion Criteria

• Patients must be =< 50 years of age at the time of enrollment
• Patients with newly diagnosed RMS of any subtype, except adult-type pleomorphic, based upon institutional histopathologic classification are eligible to enroll on the study based upon Stage, Group, and age, as below. FOXO1 fusion status must be determined by week 4 (day 28) of therapy. RMS types included under embryonal RMS (ERMS) include those classified in the 1995 International Classification of Rhabdomyosarcoma (ICR) as ERMS (classic, spindle cell, and botryoid variants), which are reclassified in the 2020 World Health Organization (WHO) Classification as ERMS (classic, dense and botryoid variants) and spindle cell/sclerosing RMS (encompassing the historical spindle cell ERMS variant and the newly recognized sclerosing RMS variant). Classification of alveolar RMS (ARMS) in the 2020 WHO Classification is the same as in the ICR and includes classic and solid variants
  • ERMS
    • Stage 4, group IV, >= 10 years of age
  • ARMS
    • Stage 4, group IV Patients will be eligible to remain on protocol therapy based upon stage, group, and age
• Bone marrow metastatic disease is based on morphologic evidence of RMS based on hematoxylin and eosin (H&E) stains. In the absence of morphologic evidence of marrow involvement on H&E, patients with bone marrow involvement detected ONLY by flow cytometry, reverse transcriptase (RT)-polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), or immunohistochemistry will NOT be considered to have clinical bone marrow involvement for the purposes of this study
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
  • Age; Maximum serum creatinine (mg/dL)
  • 1 month to < 6 months; 0.4 mg/dL (male); 0.4 mg/dL (female)
  • 6 months to < 1 year; 0.5 mg/dL (male); 0.5 mg/dL (female)
  • 1 to < 2 years; 0.6 mg/dL (male); 0.6 mg/dL (female)
  • 2 to < 6 years; 0.8 mg/dL (male); 0.8 mg/dL (female)
  • 6 to < 10 years; 1 mg/dL (male); 1 mg/dL (female)
  • 10 to < 13 years; 1.2 mg/dL (male); 1.2 mg/dL (female)
  • 13 to < 16 years; 1.5 mg/dL (male); 1.4 mg/dL (female)
  • >= 16 years; 1.7 mg/dL (male); 1.4 mg/dL (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
  • If there is evidence of biliary obstruction by tumor, then total bilirubin must be < 3 x ULN for age
• 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

Additional inclusion and exclusion criteria may apply 

Exclusion Criteria

• Patients with evidence of uncontrolled infection are not eligible
• RMS that is considered a second malignancy and previous cancer(s) that were treated with chemotherapy and/or radiation. Surgical resection alone of previous cancer(s) is allowed
• Patients with central nervous system involvement of RMS as defined below:
  • Malignant cells detected in cerebrospinal fluid
  • Intra-parenchymal brain metastasis separate and distinct from primary tumor (i.e., direct extension from parameningeal primary tumors is allowed).
  • Diffuse leptomeningeal disease
• Patients who have received any chemotherapy (excluding steroids) and/or radiation therapy for RMS prior to enrollment.
  • Note: the following exception:
    • Patients requiring emergency radiation therapy for RMS. These patients are eligible, provided they are consented to ARST2031 prior to administration of radiation
  • Note: Patients who have received or are receiving chemotherapy or radiation for non-malignant conditions (e.g. autoimmune diseases) are eligible. Patients must discontinue chemotherapy for non-malignant conditions prior to starting protocol therapy
• Vincristine and vinorelbine are sensitive substrates of CYP450 3A4 isozyme. Patients must not have received drugs that are moderate to strong CYP3A4 inhibitors and inducers within 7 days prior to study enrollment
• 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

Additional inclusion and exclusion criteria may apply 

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Study Description

The primary purpose of this study is to assess the safety and tolerability of RP-6306 in patients with eligible advanced solid tumors, determine the maximum tolerated dose (MTD) and assess preliminary anti-tumor activity.

Phase 1, multi-center, open-label, dose-escalation study to:

• Evaluate the safety profile and MTD of RP-6306 when administered orally to establish the recommended Phase 2 dose and schedule
• Characterize the PK and pharmacodynamics of RP-6306 monotherapy
• Assess preliminary anti-tumor activity associated with RP-6306 monotherapy

Inclusion Criteria

• Male or female and ≥12 years-of-age at the time of informed consent.
• Lansky performance status ≥50% for patients ≤16 years of age, or ECOG score of 0, 1, or 2 for patients >16 years of age.
• Locally advanced or metastatic resistant or refractory solid tumors.
• Patients <18 years of age must weigh at least 40 kg.
• Submission of available tumor tissue at screening or willingness to have a biopsy performed if safe and feasible
• Next generation sequencing (NGS) report obtained in a CLIA-certified or equivalent laboratory demonstrating eligible tumor biomarker.
  • CCNE1 amplification (non-equivocal) as determined by tumor NGS or FISH
  • FBXW7 deleterious mutations (e.g., hotspot, truncating, splice site, frameshift) identified by either a tumor or plasma NGS test
  • PPP2R1A deleterious mutations (e.g., hotspot, truncating, splice site, frameshift) identified by either a tumor or plasma NGS test
• Measurable disease as per RECIST v1.1.
• Ability to swallow and retain oral medications.
• Acceptable hematologic and organ function at screening.
• Negative pregnancy test (serum) for women of childbearing potential (WOCBP) at Screening.
• Resolution of all toxicities of prior therapy or surgical procedures.
• Any prior radiation must have been completed at least 7 days prior to the start of study drugs, and patients must have recovered from any acute adverse effects prior to the start of study treatment.

Exclusion Criteria

• Chemotherapy or small molecule antineoplastic agent given within 21 days or <5 half-lives, whichever is shorter, prior to first dose of study drug.
• History or current condition, therapy, or laboratory abnormality that might confound the study results or interfere with the patient's participation for the full duration of the study treatment.
• Patients who are pregnant or breastfeeding.
• Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction or other reasons which, in the investigator's opinion, could compromise the participating patient's safety.
• Major surgery within 4 weeks prior to first dose of RP-6306.
• Uncontrolled, symptomatic brain metastases.
• Uncontrolled hypertension.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.

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Study Description

This phase II trial studies how well reduced doses of radiation therapy to the brain and spine (craniospinal) and chemotherapy work in treating patients with newly diagnosed type of brain tumor called WNT)/Wingless (WNT)-driven medulloblastoma. Recent studies using chemotherapy and radiation therapy have been shown to be effective in treating patients with WNT-driven medulloblastoma. However, there is a concern about the late side effects of treatment, such as learning difficulties, lower amounts of hormones, or other problems in performing daily activities. Radiotherapy uses high-energy radiation from x-rays to kill cancer cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, vincristine sulfate, cyclophosphamide and lomustine, 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 reduced craniospinal radiation therapy and chemotherapy may kill tumor cells and may also reduce the late side effects of treatment.

Inclusion Criteria

• Patients must be newly diagnosed and have:

  • Eligibility confirmed by rapid central pathology and molecular screening review on APEC14B1:

    • Classical histologic type (non LC/A) WNT medulloblastoma
    • Positive nuclear beta-catenin by immunohistochemistry (IHC)
    • Positive for CTNNB1 mutation
    • Negative for MYC and MYCN by fluorescence in situ hybridization (FISH)
• Patient must have negative lumbar cerebrospinal fluid (CSF) cytology
  • Note: CSF cytology for staging should be performed no sooner than 14 days post operatively to avoid false positive CSF; ideally, CSF should be obtained between day 14 and day 21 to allow for final staging status before enrollment onto the study; patients with positive CSF cytology obtained 0 to 14 days after surgery should have cytology repeated to determine eligibility and final CSF status; patients with negative CSF cytology from lumbar puncture obtained 0 to 14 days after surgery do not need cytology repeated; patients with negative CSF cytology from lumbar puncture obtained prior to surgery do not need cytology repeated post-operatively
• Patients must have eligibility confirmed by Rapid Central Imaging Review on APEC14B1; patients must have =< 1.5 cm^2 maximal cross-sectional area of residual tumor; whole brain magnetic resonance imaging (MRI) with and without gadolinium and spine MRI with gadolinium must be performed
• Patients must be enrolled, and protocol therapy must be projected to begin, no later than 36 days after definitive diagnostic surgery (day 0)
• Peripheral absolute neutrophil count (ANC) >= 1000/uL
• Platelet count >= 100,000/uL (transfusion independent)
• Hemoglobin >= 10.0 g/dL (may receive red blood cell [RBC] transfusions)
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
  • 3 to < 6 years of age: maximum (max) serum creatinine 0.8 mg/dL (males and females)
  • 6 to < 10 years of age: max serum creatinine 1 mg/dL (males and females)
  • 10 to < 13 years of age: max serum creatinine 1.2 mg/dL (males and females)
  • 13 to < 16 years of age: max serum creatinine 1.5 md/dL (males) and 1.4 md/dL (females)
  • >= 16 years of age: max serum creatinine 1.7 mg/dL (males) and 1.4 mg/dL (females)
    • The threshold creatinine values were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control and Prevention (CDC)
• Total or direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
• Serum glutamate pyruvate (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (3x ULN); for the purpose of this study, the ULN for SGPT is 45 U/L
• Central nervous system function defined as:
  • Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
  • Patients must not be in status epilepticus, a coma or on assisted ventilation at the time of study enrollment
• Patients must have receptive and expressive language skills in English, French, or Spanish to complete the QoL and neurocognitive assessments; if a patient meets these criteria but the parent/guardian speaks a language other than English, French, or Spanish, the patient may still be enrolled and tested, and the parent-report measures should be omitted
• All patients and/or their parents or legal guardians must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria

• Patients with metastatic disease by either MRI evaluation (brain and spine) or lumbar CSF cytology are not eligible; patients who are unable to undergo a lumbar puncture for assessment of CSF cytology are ineligible
• Patients must not have received any prior radiation therapy or chemotherapy (tumor-directed therapy) other than surgical intervention and/or corticosteroids
• Pregnancy and Breast Feeding
  • Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies
  • Lactating females are not eligible unless they have agreed not to breastfeed their infants
  • Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
  • Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation
• Patients with a history of moderate to profound intellectual disability (i.e., intelligence quotient [Q)]=< 55) are not eligible for enrollment; PLEASE NOTE: Children with a prior history of attention deficit hyperactivity disorder (ADHD) or a specific learning disability (e.g., dyslexia) are eligible for this study

Multiple other inclusion and exclusion criteria could apply and will be reviewed by your treating team.

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Study Description

The purpose of this study is to assess the safety and tolerability of epcoritamab in pediatric participants with relapsed/refractory aggressive mature B-cell neoplasms and young adult participants with Burkitt's or Burkitt-like lymphoma/leukemia. Adverse events and change in disease activity will be assessed.

Epcoritamab is an investigational drug being developed for the treatment of relapsed/refractory aggressive mature B-cell neoplasms. Participants will receive subcutaneous (SC) of epcoritamab. Approximately 15 pediatric participants with a diagnosis of relapsed/refractory aggressive mature B-cell neoplasms and and young adult participants, ages of 18-25, with a diagnosis of Burkitt's or Burkitt-like lymphoma/leukemia will be enrolled at 50 sites globally.

Participants will receive subcutaneous epcoritamab in 28-day cycles. Participants will be followed for a minimum of 3 years after enrollment.

Inclusion Criteria

• Participants >= 1 and < 18 years old at time of primary diagnosis with Burkitt's or Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma (DLBCL), or other aggressive mature (CD20+) B-cell lymphomas. Participants up to 25 years of age with Burkitt's or Burkitt-like lymphoma/leukemia are also eligible.
• Disease pathologically confirmed (tumor tissue) by local testing.

• Relapsed or primary refractory disease meeting any of the following criteria:

  • Progressive disease at any time during second-line chemoimmunotherapy (CIT).
  • Best response of stable disease (SD) after a minimum of 2 cycles of second-line CIT.
  • Best response of partial response (PR) after a minimum of 3 cycles of second-line CIT.
  • Complete Response (CR) after a minimum of 3 cycles of second-line CIT therapy but unfit or ineligible for consolidation with cell therapy.
  • Not in CR and unable to initiate or tolerate (i.e., must discontinue) second-line CIT.
  • Have received cell therapy (allogeneic or autologous transplant or chimeric antigen receptor T-cell (CAR-T) therapy) as consolidation but have not obtained or maintained a CR.
• Recovery from toxic effects of prior chemoimmunotherapy.
• Performance status by Lansky (< 16 years old at evaluation) or Karnofsky (>= 16 years old at evaluation) score >= 50 or Eastern Cooperative Oncology Group (ECOG) score <= 2 .
• Adequate bone marrow, hepatic, and renal function.

Other inclusion criteria may apply

Exclusion Criteria

• Known central nervous system (CNS) involvement by lymphoma at screening as confirmed by screening magnetic resonance imaging (MRI)/computed tomography (CT)/positron emission tomography (PET) brain scans (participants with evidence of CNS disease only in the cerebrospinal fluid (CSF) will be eligible).
• Other malignancy requiring therapy.
• Currently receiving anti-cancer therapy, including chemotherapy (excluding intrathecal therapy), radiotherapy, small molecules, monoclonal antibodies, cell therapy, or other investigational agents.

Other exclusion criteria may apply

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Study Description

Phase 1 dose escalation will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of SNDX-5613 in patients with acute leukemia. There are 3 arms in Phase 1 as follows: 

• Arm A: Patients not receiving any strong cytochrome P450 3A4 (CYP3A4) inhibitor/ inducers.
• Arm B: Patients receiving strong cytochrome P450 3A4 (CY3A4) inhibitors for antifungal prophylaxis.
• Arm C: Patients receiving SNDX-5613 in combination with cobicistat.

In Phase 2, patients will be enrolled in 3 indication-specific expansion cohorts to determine the efficacy, short- and long-term safety, and tolerability of SNDX-5613. There are 3 cohorts in Phase 2 as follows: 

• Cohort 2A: Patients with MLLr acute lymphoblastic leukemia (ALL)/mixed phenotype acute leukemia (MPAL).
• Cohort 2B: Patients with MLLr AML.
• Cohort 2C: Patients with NPM1c AML.

Inclusion Criteria

Patients must have active acute leukemia (bone marrow blasts ≥ 5% or reappearance of blasts in peripheral blood) as defined by the National Comprehensive Cancer Network (NCCN) in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia (Version 1.2020) and Acute Myeloid Leukemia (Version 3.2020).

• Phase 1: Documented R/R acute leukemia harboring MLL rearrangement or NPM1c mutation.

  • Arm A: Patients not receiving any strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducers.
  • Arm B: Patients receiving strong cytochrome P450 3A4 inhibitors for antifungal prophylaxis.
  • Arm C: Patients receiving SNDX-5613 in combination with cobicistat.

• Phase 2:

  • Cohort 2A: Documented R/R ALL/MPAL with an MLLr translocation.
  • Cohort 2B: Documented R/R AML with an MLLr translocation.
  • Cohort 2C: Documented R/R AML with NPM1c.
• WBC must be below 50,000/ μL at time of enrollment. Patients may receive cytoreduction prior to enrollment.
• Male or female patient aged ≥30 days old.
• Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 or Karnofsky/Lansky score ≥40.
• Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 neuropathy or alopecia.
• Radiation Therapy: At least 60 days from prior total body irradiation (TBI), craniospinal radiation and/or ≥50% radiation of the pelvis, or at least 14 days from local palliative radiation therapy (small port).
• Stem Cell Infusion: At least 60 days must have elapsed from HSCT and at least 4 weeks (from first dose) must have elapsed from donor lymphocyte infusion (DLI) without conditioning.
• Immunotherapy: At least 42 days since prior immunotherapy, including tumor vaccines and checkpoint inhibitors, and at least 21 days since receipt of chimeric antigen receptor therapy or other modified T cell therapy.
• Myelosuppressive Chemotherapy: At least 14 days since the completion of cytotoxic/myelosuppressive therapy.
• Hematopoietic Growth Factors: At least 7 days since the completion of therapy with short-acting hematopoietic growth factors and 14 days with long-acting growth factors.
• Biologics: At least 7 days or 5 half-lives, whichever is longer, since the completion of therapy with a biologic agent.
• Steroids: At least 7 days since systemic glucocorticoid therapy, unless receiving physiologic dosing (equivalent to ≤10 mg prednisone daily) or cytoreductive therapy.
• Adequate organ function.
• If of childbearing potential, willing to use a highly effective method of contraception or double barrier method from the time of enrollment through 120 days following the last study drug dose.

Exclusion Criteria

• Active diagnosis of acute promyelocytic leukemia.
• Isolated extramedullary relapse.
• Known CNS involvement (cytologic or radiographic).
• Detectable human immunodeficiency virus (HIV) viral load within the previous 6 months. Patients with a known history of HIV 1/2 antibodies must have viral load testing prior to study enrollment.
• Hepatitis B or C.
• Pregnant or nursing women.
• Cardiac Disease: Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Classification Class ≥II), life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack.
  • - QTc >450 msec for males and QTc >450 msec for females.

• Gastrointestinal Disease:

  • Chronic diarrhea or other gastrointestinal issue that might affect oral drug absorption or ingestion (ie, short-gut syndrome, gastroparesis, etc).
  • Cirrhosis with a Child-Pugh score of B or C.
• Graft-Versus-Host Disease (GVHD): Signs or symptoms of acute or chronic GVHD >Grade 0 within 4 weeks of enrollment. All transplant patients must have been off all systemic immunosuppressive therapy and calcineurin inhibitors for at least 4 weeks prior to enrollment. Patients may be on physiological doses of steroids.
• Concurrent malignancy in the previous 2 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ, melanoma in situ) treated with potentially curative therapy. Concurrent malignancy must be in complete remission or no evidence of disease during this timeframe.
• Participation in another therapeutic interventional clinical study within 30 days of enrollment.

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Study Description

This is a Phase 1/2, multicenter, open-label trial of avapritinib in patients aged 2 to less than 18 years of age with with relapsed/refractory (R/R) solid tumors with mutations (including non-synonymous point mutations, insertions, and deletions) in KIT or PDGFRA, or gliomas with the H3K27M mutation, and no available alternative treatment options. This is a single-arm trial in which all patients will receive avapritinib. The study consists of 2 parts: dose confirmation, safety, and PK (Part 1) and initial efficacy, safety, and PK at the Part 2 recommended dose (Part 2).

Inclusion Criteria

• Patient has confirmed diagnosis of a R/R solid or CNS tumor with a mutation in KIT or PDGFRA (confirmed by local mutational testing of tumor sample) that has progressed despite standard therapy and no alternative treatment option is available OR Confirmed diagnosis of H3K27M mutant glioma that has failed standard therapy or for which no standard therapy that may convey clinical benefit exists, as judged by the Investigator.
• Patients with CNS disease should be on a stable dose (≤10% change) of corticosteroids for at least 7 days prior to first dose of avapritinib, with no plans for dose escalation.
• Disease extent

  1. Part 1: All patients must have at least 1 measurable lesion as defined by RECIST v1.1 or RANO (for CNS tumors). If radiation therapy has been administered, at least 1 measurable lesion must not have been irradiated, or must have clearly progressed since being irradiated.

  2. Part 2: At least one measurable lesion as defined by RECIST v1.1 (RANO for CNS tumors). If radiation therapy has been administered, at least 1 measurable lesion must not have been irradiated within the previous 12 weeks, or must have clearly progressed since being radiated (per RANO). For up to 5 patients with H3K27M mutant gliomas where there is no standard therapy that may convey clinical benefit as judged by the investigator, progression of disease of a measurable lesion after irradiation is not required.
• A Lansky (≤16 years of age) or Karnofsky (>16 years of age) score of at least 50. If the patient is unable to walk due to paralysis, but is mobile in a wheelchair, the patient is considered ambulatory for the purpose of assessing their performance status.
• Patient agrees to utilize contraception consistent with local regulations

Exclusion Criteria

• Patient has any of the following within 14 days before the first dose of study treatment:

  1. Platelet count <75 × 109/L (<100 × 109/L if a CNS tumor).
  2. Absolute neutrophil count (ANC) <1.0 × 109/L.
  3. Hemoglobin <8.0 g/dL (RBC transfusion ≥14 days before test is permitted to meet criterion).
  4. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × the upper limit of normal (ULN) for age; except in patients with tumor involvement of the liver who must not have AST and ALT >5 × ULN for age.
  5. Total bilirubin >1.5 mg/dL for age; and in presence of Gilbert's syndrome, total bilirubin > 3 × ULN or direct bilirubin > 1.5 × ULN.
  6. Serum creatinine >1.5 × ULN for age.
  7. International normalized ratio (INR) or prothrombin time (PT) >ULN (>1.5 × ULN if on prophylactic reversible anticoagulants).
• Patient has a QT interval corrected using Fridericia's formula (QTcF) >470 msec. Patient has a familial or personal history of prolonged QT syndrome or Torsades de pointes.
• Patient has clinically significant, uncontrolled, cardiovascular disease including congestive heart failure Grade III or IV according to the New York Heart Association (NYHA) classification; myocardial infarction or unstable angina within the previous 6 months, uncontrolled hypertension (>99th percentile for age), or clinically significant, uncontrolled arrhythmias, including bradyarrhythmias that may cause QT prolongation (eg, Type II second degree heart block or third-degree heart block).
• Patient received the following systemic antineoplastic therapies:
  1. Systemic antineoplastic therapy (including experimental therapy within 5 half-lives or 28 days [6 weeks if prior nitrosurea], whichever is shorter).
  2. Focal external beam radiotherapy, including stereotactic radiosurgery, within 6 weeks prior to the first dose of avapritinib to either target or non-target lesions. Systemic radiopharmaceuticals, including nonstereotactic radiosurgery, within 2 weeks of the first dose of avapritinib (within 6 weeks for patients with CNS tumors). Craniospinal irradiation within 12 weeks prior to the first dose of avapritinib.
  3. All AEs related to other antineoplastic therapies (eg, systemic antineoplastics, radiotherapy) must have resolved to Grade ≤1 (Grade ≤2 for peripheral neuopathy and/or ototoxicity) prior to the first dose of avapritinib.
• Patient has previously received treatment with avapritinib.
• Patient received autologous stem cell transplant (SCT) following myeloablative therapy or chimeric antigen receptor T cell (CAR-T) therapy within 3 months prior to the first dose of avapritinib or prior allogeneic SCT within 1 year and no evidence of Grade 1 or greater graft-versus-host disease and no immunosuppressants for graft-versus-host disease (steroids for primary malignancy being permitted). Patients who received stem cell reinfusion following nonmyeloablative therapy are eligible once they meet the peripheral blood count criteria in Exclusion Criterion #1.
• Patient requires on going treatment or has received treatment within 28 days before the start of avapritinib administration with drugs or foods that are strong CYP3A inhibitors or inducers or EIAEDs (eg, carbamazepine, phenytoin, phenobarbital, and primidone). Please refer to Appendix 1 for a list of these drugs and/or foods.
• Patient has had a major surgical procedure within 14 days of the first dose of study treatment (procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures).
• Patient has a history of another primary malignancy that has been diagnosed or required therapy within 3 years before the first dose of avapritinib. The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site.
• Female subjects of childbearing potential who are unwilling, if not post-menopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of informed consent and for at least 6 weeks after the last dose of study treatment. Male subjects who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of informed consent and for at least 6 weeks after the last dose of study treatment. Refer to Section 5.4.2 for acceptable methods of contraception.
• Patient is pregnant
• Patient is breastfeeding.
• Patient has prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator's opinion, could affect the safety of the patient; alter the absorption, distribution, metabolism, or excretion of the study drug; or impair the assessment of study results.
• History of thrombosis requiring treatment within the past 6 months.
• Patients who require anticoagulants, with the exception of stable doses of prophylactic reversible anticoagulants.
• Patients who are unable to swallow tablets (in Part 1) or mini-tablets (in Part 2) within the sprinkle capsules.
• Patients with a known risk of intracranial bleeding, such as a brain aneurysm that has not been removed or repaired, or a history of intracranial bleeding within the past year, or radiographic evidence of hemorrhage on Screening MRI. Exceptions are patients with primary CNS tumors who are eligible unless CNS bleeding has occurred within 2 weeks of the first dose of avapritinib and patients with punctate hemorrhages <3 mm.
• History of a seizure disorder that is not well controlled on current antiepileptic medications. EIAEDs carbamazepine, phenytoin, phenobarbital, and primidone are prohibited.
• Patient is unwilling or unable to comply with scheduled visits, treatment administration plan, laboratory tests, or other study procedures and study restrictions

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Study Description

This study includes a dose-escalation phase in Part A to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) followed by 5 monotherapy expansion arms in Part B to further evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of 23ME-00610 in patients with solid malignancies. Only Part B is open at pediatric sites. 

Primary Outcome Measures:

1. Part A: Incidence and severity of dose-limiting toxicities (DLTs) 
2. Part B adolescents: Incidence and severity of dose-limiting toxicities (DLTs) 
3. Part A: Incidence and severity of adverse events (AEs) 
4. Part B adolescents: Incidence and severity of adverse events (AEs)
5. Part A: Incidence and severity of serious adverse events (SAEs) 
6. Part B adolescents: Incidence and severity of serious adverse events (SAEs) 
7. Part A: Incidence of withdrawals due to AEs
8. Part B adolescents: Incidence of withdrawals due to AEs 
9. Part B: Objective response rate (ORR) 

   ORR based on investigator assessment against RECIST 1.1 criteria

Secondary Outcome Measures:

1. Prevalence and incidence of antidrug antibodies (ADA) to 23ME-00610 [ Time Frame: Up to 5 days post treatment discontinuation ]
2. Part A: Objective response rate (ORR) [ Time Frame: From baseline until disease progression (up to 5 years) ]

   ORR based on investigator assessment against RECIST 1.1 criteria

3. Duration of response (DoR) [ Time Frame: Up to 5 years ]

   Duration of response based on investigator assessment against RECIST 1:1 criteria

4. Disease Control Rate (DCR) [ Time Frame: Up to 5 years ]

   Disease control rate based on investigator assessment against RECIST 1:1 criteria

5. Progression free survival (PFS) [ Time Frame: Up to 5 years ]

   Progression free survival based on investigator assessment against RECIST 1:1 criteria

6. Overall survival (OS) [ Time Frame: Up to 5 years ]
7. Maximum serum concentration (Cmax) following a single dose of 23ME-00610 
8. Time of maximum serum concentration (Tmax) following a single dose of 23ME-00610 
9. Area under the concentration-time curve from zero to the last measurable concentration (AUClast) following a single dose of 23ME-00610 
10. Last measurable serum concentration (Clast) following a single dose of 23ME-00610
11. Area under the concentration-time curve from zero extrapolated to infinity (AUCinf) following a single dose of 23ME-00610 
12. Terminal half-life (T1/2) following a single dose of 23ME-00610
13. Maximum serum concentration (Cmax) following multiple doses of 23ME-00610
14. Time of maximum serum concentration (Tmax) following multiple doses of 23ME-00610
15. Area under the concentration-time curve from time zero to the end of the dosing interval (AUCtau) following multiple doses of 23ME-00610
16. Serum concentration at the end of the dosing interval (Ctau) following multiple doses of 23ME-00610
17. Terminal half-life (T1/2) following multiple doses of 23ME-00610

Inclusion Criteria

• Part A: Adults ≥ 18 years of age; Part B: ≥ 12 to years of age, weighing at least 40 kg (total body weight)
• Histologically-diagnosed locally advanced (unresectable), or metastatic solid cancer that has progressed after all available standard therapy for the specific tumor type, or for which all available standard therapy has proven to be ineffective or if no further standard therapy exists.
• Part A: Adults 18+: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1; Part B: Adolescents ≥ 12 to < 16 years of age: Lansky Play Scale ≥ 50; Adolescents ≥ 16 years of age: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1;
• Life expectancy ≥ 12 weeks
• Part A: Patients without RECIST measurable disease (e.g., evaluable disease only) will be eligible for enrollment in Part A, regardless of tumor type; Part B: Patients enrolled in Part B must have measurable disease by per RECIST 1.1 and have ≥ 1 site of measurable disease that has not been previously irradiated.

Additional inclusion or exclusion criteria may apply and will be discussed with you by the study team 

Exclusion Criteria

1. Females who are pregnant (positive serum pregnancy test within 7 days prior to study drug administration) or breastfeeding.
2. Immune Related Medical History:
   • Active autoimmune disease that has required systemic disease-modifying or immunosuppressive treatment within the last 2 years
   • Receipt of systemic immunosuppressive therapy (e.g. steroids) within 4 weeks prior to the start of study drug administration
   • History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia, non-infectious pneumonia that required steroids, or evidence of active, non-infectious pneumonitis
   • History of Grade ≥ 3 immune-mediated toxicity
3. Prior allogeneic or autologous bone marrow transplant, or other solid organ transplant.
4. History of a positive test for:
   • Hepatitis C virus (HCV) infection, except for those who have completed curative therapy for HCV and have undetectable HCV RNA
   • Hepatitis B virus (HBV) infection, except for those who are receiving treatment with HBV-active nucleos(t)ide antiviral therapy at the time of study entry and have undetectable HBV DNA
   • Human Immunodeficiency Virus (HIV) infection, except those who meet the following criteria: CD4+ T cells ≥ 350 cells/μL, no history of Acquired Immunodeficiency Syndrome (AIDS)-defining opportunistic infections, HIV RNA < 50 copies/mL, and on a stable antiretroviral regimen for at least 3 months.
5. Prior radiation therapy with an inadequate washout between the last dose and the start of study drug, defined as follows: 1) at least 2 weeks for palliative radiation to the extremities for osseous bone metastases is required; 2) at least 4 weeks for radiation to the chest, brain, or visceral organs is required; and 3) at least 6 weeks for large-field radiation is required.
6. Prior anticancer therapy, including chemotherapy, targeted therapy, biological therapy or immune-checkpoint inhibitors within 4 weeks or 5 drug half-lives (whichever is shorter)
7. History of another malignancy in the previous 2 years, unless cured by surgery alone and continuously disease free.
8. Recent history of cardiovascular disease
9. Uncontrolled or symptomatic CNS (central nervous system) metastases and/or carcinomatous meningitis

Additional inclusion or exclusion criteria may apply and will be discussed with you by the study team