CB-839 in Combination With Niraparib in Platinum Resistant BRCA -Wild-type Ovarian Cancer Patients

NCT ID: NCT03944902

Last Updated: 2023-11-21

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 1 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-09-01
• Study Completion Date: 2022-01-05

Brief Summary

The purpose of this protocol is to investigate the efficacy of the combination of CB-839 with Niraparib in platinum resistant BRCA wild-type ovarian cancer patients. The primary and secondary objectives are to determine the maximum tolerated dose of CB-839 in combination with Niraparib and to determine the response rate and percentage of participants who remain progression free at 6 months.

Detailed Description

Based on the scientific rationale, pre-clinical data, and clinical data available to date, and the need for further treatment options in patients that are platinum resistance that are specifically BRCA wild-type. Only patients carrying wild type BRCA genes will be enrolled in the study. The proposed research tests a new therapeutic strategy for ovarian cancer with a very novel mechanistic target: metabolic dependency of ovarian cancer. Pre-clinical results indicate that both serous and clear cells ovarian cancers have upregulation of Hypoxia Inducible Factors (HIF) HIF1a and Hypoxia Inducible Factors (HIF) HIF2a regulated genes. In addition, cell line models of these tumors display sensitivity to CB-839 in vitro. Ovarian cancers resistant to standard platinum chemotherapy may thus respond to treatment with this glutaminase inhibitor. The majority of patients do not present mutations in BRCA or any other genes of the Fanconi pathway, but their tumors may respond to CB-839, which in turn may lead to genomic instabilities due to nucleotide deprivation; therefore, CB-839 could sensitize the tumors to treatment with Niraparib.

Conditions

Ovarian Cancer; Resistant BRCA Wild-Type Ovarian Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort 1: Dose Escalation using Niraparib and CB-839

The first phase will be a 3+3 design, 3 participants will be enrolled in the first cohort with a fixed dose of Niraparib and CB-839, 600 mg. If there are no dose limiting toxicities (DLT), 3 additional participants will be enrolled in the next cohort (CB-839, 800mg). If 1 of the 3 in the first cohort experiences DLT's, then the additional participants will be enrolled in the same cohort (CB-839, 600mg).

Group Type: EXPERIMENTAL

Cohort 1: Dose Escalation

Intervention Type: DRUG

The first 3 participants will be enrolled on a fixed dose of Niraparib and CB-839, 600mg. Participants will be evaluated for DLT's, if there are none, they will be enrolled in the next cohort.

Cohort 2: Dose Escalation using Niraparib and CB-839

If there are no DLT's, 3 additional participants will be enrolled in the next cohort with a fixed dose of Niraparib and CB-839, 800mg.

Group Type: EXPERIMENTAL

Cohort 2: Dose Escalation

Intervention Type: DRUG

If no dose limiting toxicities, 3 additional participants will be enrolled in this cohort. Participants will receive a fixed dose of Niraparib and CB-839, 800mg.

Cohort 3: Expansion with Maximum Tolerated Dose (MTD)

Patients in this expansion cohort will continue study treatment with the MTD until they experience disease progression, unacceptable toxicity or withdraw consent. Patients who discontinue study treatment for reasons other than Progressive-Free Survival (PFS) will continue to have PFS follow-up visits every 2 months for the first 6 months after treatment, and every 3 months until disease progression, death, or start of another anticancer therapy.

Group Type: EXPERIMENTAL

Cohort 2: Dose Escalation

Intervention Type: DRUG

If no dose limiting toxicities, 3 additional participants will be enrolled in this cohort. Participants will receive a fixed dose of Niraparib and CB-839, 800mg.

Interventions

Cohort 1: Dose Escalation

The first 3 participants will be enrolled on a fixed dose of Niraparib and CB-839, 600mg. Participants will be evaluated for DLT's, if there are none, they will be enrolled in the next cohort.

Intervention Type: DRUG

Cohort 2: Dose Escalation

If no dose limiting toxicities, 3 additional participants will be enrolled in this cohort. Participants will receive a fixed dose of Niraparib and CB-839, 800mg.

Intervention Type: DRUG

Other Intervention Names

Niraparib; Zejula; CB-839; Glutaminase inhibitor; Niraparib; Zejula; CB-839; Glutaminase inhibitor

Eligibility Criteria

Inclusion Criteria

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
• Estimated life expectancy of at least 3 months
• Measurable disease; at least one tumor lesion/lymph node that meets the RECIST 1.1 criteria for measurability
• Negative serum or urine pregnancy test within 3 days prior to the first dose
• Serum creatinine <= 2.0 x upper limit of normal (ULN)
• Adequate hematological function
• Alanine aminotransferase (ALT) & aspartate aminotransferase (AST) <3.0 x ULN
• Total bilirubin <=1.5 x ULN

Exclusion Criteria

• Prior treatment with CB-839 or a PARP inhibitor
• Receipt of any anticancer therapy within the following windows:
• Small molecule tyrosine kinase inhibitor therapy (including investigational) within 2 weeks or 5 half-lives, whichever is longer
• Any type of anti-cancer antibody within 4 weeks
• Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before randomization
• Subjects with clinically relevant ongoing complications from prior radiation therapy
• Other investigational therapy within 2 weeks or 5 half-lives, whichever is longer
• Any other current or previous malignancy within he past three years except:
• Adequately treated basal cell or squamous cell skin cancer
• Carcinoma in situ of the cervix
• Prostate cancer with stable prostate specific antigen (PSA) levels for >3 years
• Other neoplasm that, in the opinion of the Principal Investigator, will not interfere with the study-specific endpoints

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

University of Alabama at Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Rebecca Arend

Primary Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Rebecca Arend, MD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

UCSF

San Francisco, California, United States

MAYO Clinic

Rochester, Minnesota, United States

Allegheny Health Network Research Institute

Pittsburgh, Pennsylvania, United States

Countries

United States

Other Identifiers

IRB-300002530

Identifier Type: -

Identifier Source: org_study_id