Study of the Bromodomain (BRD) and Extra-Terminal Domain (BET) Inhibitors BMS-986158 and BMS-986378 in Pediatric Cancer

Inclusion Criteria:

• Age ≤ 21 years at time of enrollment. Note the requirement in section 3.1.6 that allpatients must be able to swallow intact capsules.

• Karnofsky performance status ≥ 50% for patients ≥16 years of age or Lansky ≥ 50% forpatients <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 standardcurative measures do not exist or are no longer effective.

• For Arm 1, Cohort 1A, participants must have histologically confirmed non-CNSprimary solid tumors or lymphoma based upon biopsy or surgery atrelapse/progression. Patients without biopsy or surgery at relapse/progressionand with tissue only available from initial diagnosis may still be consideredafter discussion with the overall Primary Investigator.

• For Arm 1, Cohort 1B, participants must have histologically confirmed solidtumors or lymphoma based upon biopsy or surgery at relapse/progression as wellas documentation of one of the following confirmed tumor molecular featuresobtained in a laboratory certified to return results for clinical purposes.Patients without biopsy or surgery at relapse/progression and with tissue onlyavailable from initial diagnosis may still be considered after discussion withthe 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

• BRD4 amplification or high copy number gain

• Histologic diagnosis of NUT midline carcinoma

• For Arm 2, Cohort 2A, participants must have histologically confirmed primaryCNS p tumors or untreated CNS metastases based upon biopsy or surgery atrelapse/progression. Patients without biopsy or surgery at relapse/progressionand with tissue only available from initial diagnosis may still be consideredafter discussion with the overall Primary Investigator.

• For Arm 2, Cohort 2B, participants must have histologically confirmed primaryCNS p tumors or untreated CNS metastases based upon biopsy or surgery atrelapse/progression as well as documentation of one of the following confirmedtumor molecular features obtained in a laboratory certified to return resultsfor clinical purposes. Patients without biopsy or surgery atrelapse/progression and with tissue only available from initial diagnosis maystill 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

• BRD4 amplification or high copy number gain

• Histologic diagnosis of NUT midline carcinoma

• Patients must have fully recovered from the acute toxic effects of all prioranti-cancer therapy except organ function as noted in Section 3.1.5. Patients mustmeet the following minimum washout periods prior to enrollment:

• Myelosuppressive chemotherapy: At least 21 days after the last dose ofmyelosuppressive 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, or if >50% radiation ofpelvis;

• At least 180 days must have elapsed after prior craniospinal XRT;

• At least 42 days must have elapsed if other substantial BM radiation;

• At least 42 days must have passed since last MIBG or other radionuclidetherapy.

• Small molecule biologic therapy: At least 7 days following the last dose of a smallmolecule biologic agent. For agents with known adverse events occurring beyond 7days, this duration must be extended beyond the time in which adverse events areknown to occur. If extended duration is required, this must be discussed with andapproved by the overall PI.

• Monoclonal antibody: At least 28 days must have elapsed after the last dose oftherapeutic monoclonal antibody.

• Myeloid growth factors: At least 14 days following the last dose of long-actinggrowth factor (e.g. Neulasta) or 7 days following short-acting growth factor.

• Autologous hematopoietic stem cell transplant and stem cell boost: Patients must beat least 60 days from day 0 of an autologous stem cell transplant or autologous stemcell boost.

• Cellular therapies (including CAR-T cells) and other non-cellular, non-antibodyimmunotherapies (e.g., vaccines): At least 42 days must have elapsed after lastdose.

• Major Surgery: At least 2 weeks from prior major surgical procedure. Note: Majorsurgical procedure will be considered all surgical procedures aside from thefollowing: Biopsy; central line placement/removal; bone marrow aspirate/biopsy;lumbar puncture; dental procedures; gastrostomy tube placement; and VP shuntplacement/revision.

• BET inhibitors: Patients must not have received prior treatment with a BETinhibitor, except patients with CNS tumors or CNS metastasis previously treated onArm 1 of the trial who discontinued protocol therapy due to disease progression andnot due to toxicity. Such patients may participate in Arm 2 of the trial.

• 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 aplatelet 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 aplatelet 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 knownGilbert's may be considered after discussion with overall PI and if directbilirubin 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 requestheparin-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 levelsgreater than the above age/sex maximum allowed values.

• Able to swallow intact capsules (BMS-986158) or tablets (BMS-986378, also known asCC-90010).

• Patient (or parent or legally authorized representative, if minor) is able tounderstand and willing to provide informed consent, using an institutionallyapproved informed consent procedure.

• Participants of childbearing or child-fathering potential must agree to use adequatecontraception 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 are not eligible for Arm 1, except:

--Patients with a history of CNS metastatic disease that has been resected and/orradiated without evidence of active CNS disease for 3 months preceding enrollment;NOTE: patients with primary CNS tumors or solid tumors with active CNS metastaseswill be eligible for Arm 2.

• 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 toenrollment

• Non-steroidal anti-inflammatory drugs, oral anticoagulants, and therapeuticheparins (unfractionated or low molecular weight heparin) at the time ofenrollment. Note: Use of heparin to maintain patency of a central or peripheralcatheter is allowed

• Other investigational agents being administered under an IND.

• Pregnant participants will not be entered on this study given that the effects ofBMS-986158 and BMS-986378 (CC-90010) on the developing human fetus are unknown.Female participants of childbearing potential must have a documented negativepregnancy exam within 24 hours prior to dosing.

• Breastfeeding mothers are not eligible, because there is an unknown risk for adverseevents in nursing infants secondary to treatment of the mother with BMS-986158 orBMS-986378 (CC-90010).

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to BMS-986158 or BMS-986378 (CC-90010).

• Uncontrolled intercurrent illness including, but not limited to, ongoing oruncontrolled infection, symptomatic congestive heart failure, unstable anginapectoris, cardiac arrhythmia, or psychiatric illness/social situations that wouldlimit compliance with study requirements.

• Patients with a known history of HIV, hepatitis B, and/or hepatitis C (testing notrequired as part of screening).

• Patients with gastrointestinal disease or disorder that could interfere withabsorption of BMS-986158 or BMS-986378 (CC-90010), such as bowel obstruction orinflammatory bowel disease.

• For Arm 1: Patients with BSA < 0.3 m2 for all dose levels except Dose Level -2 or -2i for which patients with BSA < 0.71 m2 will be excluded due to dose roundingconstraints.

• For Arm 2: Patients with BSA < 0.65 m2.