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

NCT03936465 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 19-040
• Study Type: interventional
• Target: 41
• Locations: 2 countries
• Sites: 6

Brief Summary

Arm 1 of this research study is studying an investigational drug called BMS-986158 as a possible treatment for pediatric solid tumors or lymphoma. Arm 2 of this research study is studying an investigational drug called BMS-986378 (also known as CC-90010) as a possible treatment for pediatric brain tumors or pediatric tumors that have spread to the brain.

Conditions

Solid Tumor, Childhood; Lymphoma; Brain Tumor, Pediatric

Keywords

Solid Tumor; Lymphoma; Neuroblastoma; Sarcoma; Medulloblastoma; MYC; MYCN; BRD4; BET inhibitor; Bromodomain

Outcome Measures

Primary Outcomes (2)

• Dose Limiting Toxicity Rate

  Dose limiting toxicity as defined in protocol

  28 days (first cycle)

• The Rate of Toxicities from Protocol Therapy

  Adverse events coded using CTCAE version 5

  2 years

Secondary Outcomes (6)

• Objective Response Rate

  2 years

• Pharmacokinetics of BMS-986158 (Arm 1) or BMS-986378 (Arm 2)

  2 years

• Pharmacodynamics of BMS-986158 (Arm 1) or BMS-986378 (Arm 2)

  2 years

• Blood Markers of Response

  2 years

• CSF Markers of Response

  2 years

Study Arms (4)

Arm 1 Cohort A

EXPERIMENTAL

* Patients will receive BMS-986158 monotherapy orally for 5 days on / 2 days off per week in 28-day cycles. * Patients with unselected relapsed or refractory solid tumors or lymphoma

Drug: BMS-986158

Arm 1 Cohort B

EXPERIMENTAL

* Patients will receive BMS-986158 monotherapy orally for 5 days on / 2 days off per week in 28-day cycles. * Patients with relapsed or refractory solid tumors or lymphoma that have defined molecular features predicted to increase sensitivity to BET inhibition

Drug: BMS-986158

Arm 2 Cohort A

EXPERIMENTAL

* Patients will receive BMS-986378 (also known as CC-90010) monotherapy orally for 4 days every 28 days. * Patients with relapsed or refractory CNS tumors or CNS metastatic tumors

Drug: BMS-986378

Arm 2 Cohort B

EXPERIMENTAL

* Patients will receive BMS-986378 (also known as CC-90010) monotherapy orally for 4 days every 28 days. * Patients with relapsed or refractory CNS tumors or CNS metastatic tumors that have defined molecular features predicted to increase sensitivity to BET inhibition

Drug: BMS-986378

Interventions

BMS-986158 DRUG

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.

Arm 1 Cohort A; Arm 1 Cohort B

BMS-986378 DRUG

BMS-986378 (also known as CC-90010) 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.

Also known as: CC-90010

Arm 2 Cohort A; Arm 2 Cohort B

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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 Arm 1, Cohort 1A, 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 Arm 1, Cohort 1B, participants must have histologically confirmed solid tumors or lymphoma 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
• BRD4 amplification or high copy number gain
• Histologic diagnosis of NUT midline carcinoma
• For Arm 2, Cohort 2A, participants must have histologically confirmed primary CNS p tumors or untreated CNS metastases 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 Arm 2, Cohort 2B, participants must have histologically confirmed primary CNS p tumors or untreated CNS metastases 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.

You may not qualify if:

• 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/or radiated without evidence of active CNS disease for 3 months preceding enrollment; NOTE: patients with primary CNS tumors or solid tumors with active CNS metastases will 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 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 and BMS-986378 (CC-90010) 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 or BMS-986378 (CC-90010).
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to BMS-986158 or BMS-986378 (CC-90010).
• 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 or BMS-986378 (CC-90010), such as bowel obstruction or inflammatory 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 rounding constraints.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Stand Up To Cancer: collaborator

Study Sites (6)

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

C.S. Mott Children's Hospital

Ann Arbor, Michigan, 48109, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

MeSH Terms

Conditions

Lymphoma; Brain Neoplasms; Neuroblastoma; Sarcoma; Medulloblastoma

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neoplasms, Connective and Soft Tissue; Glioma

Study Officials

• Steven G. DuBois, MD, MS

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 30, 2019
• First Posted: May 3, 2019
• Study Start: September 27, 2019
• Primary Completion: March 16, 2024
• Study Completion: October 1, 2024
• Last Updated: October 2, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1); US (5)