BMS-986158 for the Treatment of Recurrent or Refractory Solid Tumors, Central Nervous System Tumors, or Lymphoma

Status: Active

Description

This phase I trial studies the side effects and best dose of BMS-986158 in treating patients with solid tumors, central nervous system tumors, or lymphoma that has come back (recurrent) or does not respond to treatment (refractory). BMS-986158 may stop the growth of tumor cells by blocking some of the proteins needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • Karnofsky performance status >= 50% for patients >= 16 years of age or Lansky >= 50% for patients < 16 years of age
  • Participants must have evaluable or measurable disease
  • 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 BRD3 or BRD4
  • Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy except organ function. 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 radiotherapy (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 bone marrow (BM) radiation ** At least 42 days must have passed since last iobenguane (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 principal investigator (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 ventriculoperitoneal (VP) shunt placement/revision * BET inhibitors: Patients must not have received prior treatment with a BET inhibitor
  • For patients without documented bone marrow involvement by disease: Hemoglobin >= 8 g/dL (may be transfused)
  • For patients without documented bone marrow involvement by disease: Absolute neutrophil count >= 1,000 /uL
  • For patients without documented bone marrow involvement by disease: Platelets >= 100,000 /uL and transfusion independent, defined as not receiving a platelet transfusion for at least 5 days prior to complete blood count (CBC) documenting eligibility
  • For patients with documented bone marrow involvement by disease: Hemoglobin >= 8 g/dL (may be transfused)
  • For patients with documented bone marrow involvement by disease: Absolute neutrophil count >= 750 /uL
  • For patients with documented bone marrow involvement by disease: Platelets >= 75,000 /uL and transfusion independent, defined as not receiving a platelet transfusion for at least 5 days prior to CBC documenting eligibility
  • 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)
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x upper limit of normal
  • Serum albumin >= 2 g/dL
  • Lipase < upper limit of normal
  • Diarrhea =< grade 1 by Common Terminology Criteria for Adverse Events (CTCAE) version 5
  • International normalized ratio (INR) =< 1.5 Note: For patients having labs drawn via heparinized catheters, it is important to request heparin-absorbed values
  • Partial thromboplastin time (PTT) =< 1.5 times upper limit of normal * Note: For patients having labs drawn via heparinized catheters, it is important to request heparin-absorbed values
  • Corrected QT (QTc) =< 480 msec
  • Serum creatinine based on age/sex as follows: * 1 to < 2 years: maximum serum creatinine (mg/dL) male = 0.6; female = 0.6 * 2 to < 6 years: maximum serum creatinine (mg/dL) male = 0.8; female = 0.8 * 6 to < 10 years: maximum serum creatinine (mg/dL) male = 1; female = 1 * 10 to < 13 years: male = maximum serum creatinine (mg/dL) 1.2; female = 1.2 * 13 to < 16 years: maximum serum creatinine (mg/dL) male = 1.5; female = 1.4 * >= 16 years: maximum serum creatinine (mg/dL) male = 1.7; female = 1.4 OR * Creatinine clearance >= 60 mL/min/1.73 m^2 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

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 cerebrospinal fluid (CSF) involvement
  • Patients receiving any of the following prohibited foods and medications: * Prohibited concomitant medications 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 investigational new drug (IND)
  • Pregnant participants will not be entered on this study given that the effects of BM-S986158 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 human immunodeficiency virus (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 body surface area (BSA) < 0.3 m^2

Locations & Contacts

Massachusetts

Boston
Boston Children's Hospital
Status: Active
Contact: Steven G. DuBois
Phone: 617-632-5460
Email: SDUBOIS2@PARTNERS.ORG
Dana-Farber Cancer Institute
Status: Active
Contact: Steven G. DuBois
Phone: 617-632-5460
Email: SDUBOIS2@PARTNERS.ORG

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the recommended pediatric phase 2 dose of BET inhibitor BMS-986158 (BMS-986158) in children with relapsed or refractory solid tumors, central nervous system (CNS) tumors, or lymphoma.

II. To describe the toxicities of BMS-986158 in this population.

SECONDARY OBJECTIVES:

I. To describe the objective response rate of BMS-986158 in this population.

II. To describe the pharmacokinetics and pharmacodynamics of BMS-986158 in this population.

III. To investigate tumor, peripheral blood, and cerebrospinal fluid biomarkers associated with response to BMS-986158 in this population.

EXPLORATORY OBJECTIVE:

I. To bank tumor material, germline deoxyribonucleic acid (DNA), peripheral blood, and cerebrospinal fluid for potential future research for participating subjects who provide additional consent.

OUTLINE: This is a dose-escalation study.

Patients receive BET inhibitor BMS-986158 orally (PO) once daily (QD) on days 1-5, 8-12, 15-19, and 22-26. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Steven G. DuBois

Trial IDs

Primary ID 19-040
Secondary IDs NCI-2019-05496
Clinicaltrials.gov ID NCT03936465