Clinical Trials /

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

NCT03944902

Description:

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.

Related Conditions:
  • Ovarian Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: CB-839 in Combination With Niraparib in Platinum Resistant Breast Cancer (BRCA) -Wild-type Ovarian Cancer Patients
  • Official Title: CB-839 in Combination With Niraparib in Platinum Resistant BRCA-wild-type Ovarian Cancer Patients

Clinical Trial IDs

  • ORG STUDY ID: IRB-300002530
  • NCT ID: NCT03944902

Conditions

  • Ovarian Cancer
  • Resistant BRCA Wild-Type Ovarian Cancer

Interventions

DrugSynonymsArms
Cohort 1: Dose EscalationNiraparib, Zejula, CB-839, Glutaminase inhibitorCohort 1: Dose Escalation using Niraparib and CB-839
Cohort 2: Dose EscalationNiraparib, Zejula, CB-839, Glutaminase inhibitorCohort 2: Dose Escalation using Niraparib and CB-839

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1: Dose Escalation using Niraparib and CB-839ExperimentalThe 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).
  • Cohort 1: Dose Escalation
Cohort 2: Dose Escalation using Niraparib and CB-839ExperimentalIf 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.
  • Cohort 2: Dose Escalation
Cohort 3: Expansion with Maximum Tolerated Dose (MTD)ExperimentalPatients 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.
  • Cohort 2: Dose Escalation

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Access toxicity as evidenced by the number and percent of treatment adverse events.
Time Frame:Baseline through Week 1
Safety Issue:
Description: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

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).
Time Frame:Baseline through 6 months
Safety Issue:
Description: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.
Measure:Determine progression rate by the percentage of patients that have disease progression as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
Time Frame:Baseline through 6 months
Safety Issue:
Description: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.
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).
Time Frame:Baseline through 12 months
Safety Issue:
Description: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.
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).
Time Frame:Baseline through 12 months
Safety Issue:
Description: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.
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).
Time Frame:Baseline through 18 months
Safety Issue:
Description: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.
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).
Time Frame:Baseline through 18 months
Safety Issue:
Description: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.
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).
Time Frame:Baseline through 24 months
Safety Issue:
Description: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.
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).
Time Frame:Baseline through 24 months
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Alabama at Birmingham

Trial Keywords

  • BRCA Wild-Type
  • Resistant BRCA
  • Poly (ADP-ribose) polymerase (PARP) Inhibitor Therapy

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