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

November 17, 2023 updated by: Rebecca Arend, University of Alabama at Birmingham

Phase 1 Trial of CB-839 in Combination With Niraparib in Platinum Resistant BRCA-wild-type Ovarian Cancer Patients

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

1

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35294
        • University of Alabama at Birmingham
    • California
      • San Francisco, California, United States, 94143
        • UCSF
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15224
        • Allegheny Health Network Research Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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).
Drug: 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.
Other Names:
  • Zejula
  • Glutaminase inhibitor
  • CB-839
  • Niraparib
Experimental: 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.
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.
Other Names:
  • Zejula
  • Glutaminase inhibitor
  • CB-839
  • Niraparib
Experimental: 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.
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.
Other Names:
  • Zejula
  • Glutaminase inhibitor
  • CB-839
  • Niraparib

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Access toxicity as evidenced by the number and percent of treatment adverse events.
Time Frame: 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.
Baseline through Week 1
Access toxicity as evidenced by the number and percent of treatment adverse events.
Time Frame: 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.
Baseline through Week 2
Access toxicity as evidenced by the number and percent of treatment adverse events.
Time Frame: 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.
Baseline through Week 3
Access toxicity as evidenced by the number and percent of treatment adverse events.
Time Frame: 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.
Baseline through Week 4
Access toxicity as evidenced by the number and percent of treatment adverse events.
Time Frame: 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.
Baseline through Week 12
Access toxicity as evidenced by the number and percent of treatment adverse events.
Time Frame: 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.
Baseline through Week 24
Access toxicity as evidenced by the number and percent of treatment adverse events.
Time Frame: 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.
Baseline through Week 48

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
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.
Baseline through 6 months
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
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.
Baseline through 6 months
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
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.
Baseline through 12 months
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
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.
Baseline through 12 months
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
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.
Baseline through 18 months
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
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.
Baseline through 18 months
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
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.
Baseline through 24 months
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
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.
Baseline through 24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Alabama at Birmingham

Investigators

  • Principal Investigator: Rebecca Arend, MD, University of Alabama at Birmingham

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2021

Primary Completion (Actual)

January 5, 2022

Study Completion (Actual)

January 5, 2022

Study Registration Dates

First Submitted

May 1, 2019

First Submitted That Met QC Criteria

May 7, 2019

First Posted (Actual)

May 10, 2019

Study Record Updates

Last Update Posted (Actual)

November 21, 2023

Last Update Submitted That Met QC Criteria

November 17, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB-300002530

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

To be determined.

IPD Sharing Time Frame

The above documents will be posted on CT.gov and available as long as study record is posted.

IPD Sharing Access Criteria

To be determined.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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