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

Phase 1

Terminated

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.

Recruitment & Eligibility

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

Primary Outcome Measures

Name	Time	Method
Access toxicity as evidenced by the number and percent of treatment adverse events.	Baseline through Week 48	Any CTCAE v4.0 grade 3 except with some identified exceptions: Grade 3-4 nausea, vomiting and diarrhea, Grade 3 transaminitis present for \<= 7 days, Grade 3 laboratory abnormalities (correctable \& asymptomatic), Grade 3 ALT or AST elevation, Grade 3 thrombocytopenia or neutropenia, and Grade 4 anemia.

Secondary Outcome Measures

Name	Time	Method
Determine progression rate by the percentage of patients that have disease progression as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).	Baseline through 6 months	Progression will be evaluated by the revised RECIST. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes. Assessment of association among biomarkers will be carried out by dose level and cycle.
Determine the response rate by the percentage of patients that remain progression free as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).	Baseline through 24 months	Response will be evaluated by the revised RECIST. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes. Assessment of association among biomarkers will be carried out by dose level and cycle.
Determine the progression rate by the percentage of patients that have disease progression as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).	Baseline through 24 months	Progression will be evaluated by the revised RECIST. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes. Assessment of association among biomarkers will be carried out by dose level and cycle.

Locations (4): Allegheny Health Network Research Institute
🇺🇸
Pittsburgh, Pennsylvania, United States
University of Alabama at Birmingham
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Birmingham, Alabama, United States
UCSF
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San Francisco, California, United States
MAYO Clinic
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Rochester, Minnesota, United States