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

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.

• Cohort 1: Dose Escalation (Drug), also known as Niraparib, Zejula, CB-839, Glutaminase inhibitor: 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 (Drug), also known as Niraparib, Zejula, CB-839, Glutaminase inhibitor: 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.

Primary outcomes

• Access toxicity as evidenced by the number and percent of treatment adverse events. [Baseline through Week 1]: 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.
• Access toxicity as evidenced by the number and percent of treatment adverse events. [Baseline through Week 2]: 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.
• Access toxicity as evidenced by the number and percent of treatment adverse events. [Baseline through Week 3]: 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.
• Access toxicity as evidenced by the number and percent of treatment adverse events. [Baseline through Week 4]: 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.
• Access toxicity as evidenced by the number and percent of treatment adverse events. [Baseline through Week 12]: 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.
• Access toxicity as evidenced by the number and percent of treatment adverse events. [Baseline through Week 24]: 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.
• 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 outcomes

• 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 6 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 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 12 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 12 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 18 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 18 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.

Sex: Female, ages: 18 Years to any

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

• Rebecca Arend, MD, Principal investigator, University of Alabama at Birmingham