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

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ClinicalTrials.gov Identifier: NCT03944902
Recruitment Status : Not yet recruiting
First Posted : May 10, 2019
Last Update Posted : May 10, 2019
Sponsor:
Information provided by (Responsible Party):
Michael Birrer, University of Alabama at Birmingham

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.

Condition or disease Intervention/treatment Phase
Ovarian Cancer Resistant BRCA Wild-Type Ovarian Cancer Drug: Cohort 1: Dose Escalation Drug: Cohort 2: Dose Escalation Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 33 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: CB-839 in Combination With Niraparib in Platinum Resistant BRCA-wild-type Ovarian Cancer Patients
Estimated Study Start Date : July 31, 2019
Estimated Primary Completion Date : September 1, 2021
Estimated Study Completion Date : September 1, 2022


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:
  • Niraparib
  • Zejula
  • CB-839
  • Glutaminase inhibitor

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:
  • Niraparib
  • Zejula
  • CB-839
  • Glutaminase inhibitor

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:
  • Niraparib
  • Zejula
  • CB-839
  • Glutaminase inhibitor




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03944902


Contacts
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Contact: Rebecca Arrend, MD 205-934-4986 rarend@uab.edu

Locations
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United States, Alabama
University of Alabama at Birmingham Not yet recruiting
Birmingham, Alabama, United States, 35294
Contact: Rebecca Arend, MD    205-934-4986    rarend@uab.edu   
Principal Investigator: Michael Birrer, MD         
Sponsors and Collaborators
University of Alabama at Birmingham
Investigators
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Principal Investigator: Michael Birrer, MD University of Alabama at Birmingham

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Responsible Party: Michael Birrer, Primary Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT03944902     History of Changes
Other Study ID Numbers: IRB-300002530
First Posted: May 10, 2019    Key Record Dates
Last Update Posted: May 10, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: To be determined.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: The above documents will be posted on CT.gov and available as long as study record is posted.
Access Criteria: To be determined.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Michael Birrer, University of Alabama at Birmingham:
BRCA Wild-Type
Resistant BRCA
Poly (ADP-ribose) polymerase (PARP) Inhibitor Therapy
Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Ovarian Diseases
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Niraparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents