Clinical trial NCT03944902: CB-839 in Combination With Niraparib in Platinum Resistant BRCA -Wild-type Ovarian Cancer Patients
Official title: Phase 1 Trial of CB-839 in Combination With Niraparib in Platinum Resistant BRCA-wild-type Ovarian Cancer Patients
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Ovarian Cancer
Resistant BRCA Wild-Type Ovarian Cancer
Keywords: BRCA Wild-Type
Resistant BRCA
Poly (ADP-ribose) polymerase (PARP) Inhibitor Therapy
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
First posted: 2019-05-10
Enrollment: 1
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Access toxicity as evidenced by the number and percent of treatment adverse events.
timeFrame: Baseline through Week 1
measure: Access toxicity as evidenced by the number and percent of treatment adverse events.
timeFrame: Baseline through Week 2
measure: Access toxicity as evidenced by the number and percent of treatment adverse events.
timeFrame: Baseline through Week 3
measure: Access toxicity as evidenced by the number and percent of treatment adverse events.
timeFrame: Baseline through Week 4
measure: Access toxicity as evidenced by the number and percent of treatment adverse events.
timeFrame: Baseline through Week 12
measure: Access toxicity as evidenced by the number and percent of treatment adverse events.
timeFrame: Baseline through Week 24
measure: Access toxicity as evidenced by the number and percent of treatment adverse events.
timeFrame: Baseline through Week 48
Secondary outcomes:
measure: Determine the response rate by the percentage of patients that remain progression free as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
timeFrame: Baseline through 6 months
measure: Determine progression rate by the percentage of patients that have disease progression as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
timeFrame: Baseline through 6 months
measure: Determine the response rate by the percentage of patients that remain progression free as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
timeFrame: Baseline through 12 months
measure: Determine the progression rate by the percentage of patients that have disease progression as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
timeFrame: Baseline through 12 months
measure: Determine the response rate by the percentage of patients that remain progression free as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
timeFrame: Baseline through 18 months
measure: Determine the progression rate by the percentage of patients that have disease progression as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
timeFrame: Baseline through 18 months
measure: Determine the response rate by the percentage of patients that remain progression free as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
timeFrame: Baseline through 24 months
measure: Determine the progression rate by the percentage of patients that have disease progression as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
timeFrame: Baseline through 24 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: San Francisco
country: United States
facility: UCSF
state: California
city: Rochester
country: United States
facility: MAYO Clinic
state: Minnesota
city: Pittsburgh
country: United States
facility: Allegheny Health Network Research Institute
state: Pennsylvania
Study officials:
affiliation: University of Alabama at Birmingham
name: Rebecca Arend, MD
role: PRINCIPAL_INVESTIGATOR
References: