Back to resultsCB-839 in Combination With Niraparib in Platinum Resistant BRCA -Wild-type Ovarian Cancer Patients (BRCA)
Primary Purpose
Ovarian Cancer, Resistant BRCA Wild-Type Ovarian Cancer
Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Cohort 1: Dose Escalation
Cohort 2: Dose Escalation
Sponsored by
About this trial
This is an interventional treatment trial for Ovarian Cancer focused on measuring BRCA Wild-Type, Resistant BRCA, Poly (ADP-ribose) polymerase (PARP) Inhibitor Therapy
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
Sites / Locations
- University of Alabama at Birmingham
- MAYO Clinic
- Allegheny Health Network Research Institute
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
Cohort 1: Dose Escalation using Niraparib and CB-839
Cohort 2: Dose Escalation using Niraparib and CB-839
Cohort 3: Expansion with Maximum Tolerated Dose (MTD)
Arm Description
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).
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.
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.
Outcomes
Primary Outcome Measures
Access toxicity as evidenced by the number and percent of treatment adverse events.
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.
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.
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.
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.
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.
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.
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
Determine the response rate by the percentage of patients that remain progression free as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
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).
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).
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).
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).
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).
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).
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).
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.
Full Information
NCT ID
NCT03944902
First Posted
May 1, 2019
Last Updated
September 28, 2023
Sponsor
University of Alabama at Birmingham
1. Study Identification
Unique Protocol Identification Number
NCT03944902
Brief Title
CB-839 in Combination With Niraparib in Platinum Resistant BRCA -Wild-type Ovarian Cancer Patients
Acronym
BRCA
Official Title
Phase 1 Trial of CB-839 in Combination With Niraparib in Platinum Resistant BRCA-wild-type Ovarian Cancer Patients
Study Type
Interventional
2. Study Status
Record Verification Date
April 2022
Overall Recruitment Status
Terminated
Why Stopped
will not resume. company choosing not to continue with drug. one participant now off study.
Study Start Date
September 1, 2021 (Actual)
Primary Completion Date
January 5, 2022 (Actual)
Study Completion Date
January 5, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Alabama at Birmingham
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ovarian Cancer, Resistant BRCA Wild-Type Ovarian Cancer
Keywords
BRCA Wild-Type, Resistant BRCA, Poly (ADP-ribose) polymerase (PARP) Inhibitor Therapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
1 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1: Dose Escalation using Niraparib and CB-839
Arm Type
Experimental
Arm Description
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).
Arm Title
Cohort 2: Dose Escalation using Niraparib and CB-839
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort 3: Expansion with Maximum Tolerated Dose (MTD)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Cohort 1: Dose Escalation
Other Intervention Name(s)
Niraparib, Zejula, CB-839, Glutaminase inhibitor
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Cohort 2: Dose Escalation
Other Intervention Name(s)
Niraparib, Zejula, CB-839, Glutaminase inhibitor
Intervention Description
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 Outcome Measure Information:
Title
Access toxicity as evidenced by the number and percent of treatment adverse events.
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.
Time Frame
Baseline through Week 1
Title
Access toxicity as evidenced by the number and percent of treatment adverse events.
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.
Time Frame
Baseline through Week 2
Title
Access toxicity as evidenced by the number and percent of treatment adverse events.
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.
Time Frame
Baseline through Week 3
Title
Access toxicity as evidenced by the number and percent of treatment adverse events.
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.
Time Frame
Baseline through Week 4
Title
Access toxicity as evidenced by the number and percent of treatment adverse events.
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.
Time Frame
Baseline through Week 12
Title
Access toxicity as evidenced by the number and percent of treatment adverse events.
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.
Time Frame
Baseline through Week 24
Title
Access toxicity as evidenced by the number and percent of treatment adverse events.
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.
Time Frame
Baseline through Week 48
Secondary Outcome Measure Information:
Title
Determine the response rate by the percentage of patients that remain progression free as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
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.
Time Frame
Baseline through 6 months
Title
Determine progression rate by the percentage of patients that have disease progression as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
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.
Time Frame
Baseline through 6 months
Title
Determine the response rate by the percentage of patients that remain progression free as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
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.
Time Frame
Baseline through 12 months
Title
Determine the progression rate by the percentage of patients that have disease progression as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
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.
Time Frame
Baseline through 12 months
Title
Determine the response rate by the percentage of patients that remain progression free as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
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.
Time Frame
Baseline through 18 months
Title
Determine the progression rate by the percentage of patients that have disease progression as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
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.
Time Frame
Baseline through 18 months
Title
Determine the response rate by the percentage of patients that remain progression free as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
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.
Time Frame
Baseline through 24 months
Title
Determine the progression rate by the percentage of patients that have disease progression as measured by the Response Evaluation Criteria in Solid Tumors (RECIST).
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.
Time Frame
Baseline through 24 months
10. Eligibility
Sex
Female
Gender Based
Yes
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rebecca Arend, MD
Organizational Affiliation
University of Alabama at Birmingham
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
MAYO Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Allegheny Health Network Research Institute
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing 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.
Learn more about this trial
CB-839 in Combination With Niraparib in Platinum Resistant BRCA -Wild-type Ovarian Cancer Patients
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