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
