Study of CB-839 in Combination w/ Paclitaxel in Participants of African Ancestry and Non-African Ancestry With Advanced Triple Negative Breast Cancer (TNBC)

Study Overview
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Brief Summary
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CX-839-007 is an open-label Phase 2 study of the combination of CB-839 with paclitaxel in participants of African ancestry and non-African ancestry with advanced triple negative breast cancer. Multiple single-arm cohorts will be enrolled in which 800 mg twice daily (BID) CB-839 will be administered in combination with the full approved dose of paclitaxel.

Detailed Description
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Participants will be enrolled into 4 cohorts, as follows: Cohort 1: patients of African ancestry with 2 or more lines of prior therapy for metastatic disease Cohort 2: patients of African ancestry with no prior lines of therapy for metastatic disease Cohort 3: same as cohort 1 but in patients of non-African ancestry Cohort 4: same as cohort 2 but in patients of non-African ancestry

Official Title
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A Multicenter Phase 2 Study of the Glutaminase Inhibitor CB-839 in Combination With Paclitaxel in Patients With Advanced Triple Negative Breast Cancer (TNBC) Including Patients of African Ancestry and Non-African Ancestry

Conditions
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Triple Negative Breast Cancer, TNBC - Triple-Negative Breast Cancer

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: CB-839


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Meets criteria for 1 of the 4 defined study cohorts TNBC, defined as estrogen receptor (ER) and progesterone receptor (PR) negative (< 1% by immunohistochemistry) and human epidermal growth factor receptor 2 (HER2)-negative (immunohistochemistry 0 to 1+ or fluorescence in situ hybridization [FISH] negative) Metastatic disease or locally-advanced disease not amenable to curative intent treatment Adequate hepatic, renal, cardiac, and hematologic function Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Recovery to baseline or ≤ Grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version.4.0 Key Exclusion Criteria: Known brain metastases or central nervous system (CNS) cancer unless adequately treated with radiotherapy and/or surgery and stable for ≥ 2 mo Unable to receive oral medications Known hypersensitivity to Cremophor®-based agents Major surgery within 28 days of Cycle 1 Day 1

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be assigned to one of 4 arms depending on the number of prior lines of therapy they have received and whether or not they have African ancestry
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - African ancestry, 3rd line+<br>Intervention = Paclitaxel- CB-839 (Pac-CB) combination Participants must self-identify as African ancestry (includes African American). At least 2 prior lines of systemic therapy for advanced/metastatic disease including a taxane. Prior taxane (paclitaxel, docetaxel, or nab-paclitaxel) for advanced/metastatic disease is required but must not have been received in the immediate prior line of therapy. Systemic neoadjuvant and/or adjuvant therapy is considered a line of therapy for advanced/metastatic disease if the time to recurrence from completion of treatment was ≤ 12 mo. | Drug: Paclitaxel<br>* standard weekly paclitaxel in 28-day cycles<br>* Other names: Taxane;Drug: CB-839<br>* CB-839 administered as oral tablets twice daily (BID)<br>* Other names: telaglenastat;|
| Experimental: Cohort 2 - African ancestry, 1st line<br>Intervention = Pac-CB combination Participants must self-identify as African ancestry (includes African American). No prior systemic therapy for advanced or metastatic disease. Systemic neoadjuvant or adjuvant therapy, including taxane, is allowed if time to recurrence was > 12 mo. | Drug: Paclitaxel<br>* standard weekly paclitaxel in 28-day cycles<br>* Other names: Taxane;Drug: CB-839<br>* CB-839 administered as oral tablets twice daily (BID)<br>* Other names: telaglenastat;|
| Experimental: Cohort 3 - Non-African ancestry, 3rd line+<br>Intervention = Pac-CB combination Participants do not self-identify as African ancestry. Otherwise have the same criteria as Cohort 1. | Drug: Paclitaxel<br>* standard weekly paclitaxel in 28-day cycles<br>* Other names: Taxane;Drug: CB-839<br>* CB-839 administered as oral tablets twice daily (BID)<br>* Other names: telaglenastat;|
| Experimental: Cohort 4 - Non-African ancestry, 1st line<br>Intervention = Pac-CB combination Participants do not self-identify as African ancestry. Otherwise have the same criteria as Cohort 2. | Drug: Paclitaxel<br>* standard weekly paclitaxel in 28-day cycles<br>* Other names: Taxane;Drug: CB-839<br>* CB-839 administered as oral tablets twice daily (BID)<br>* Other names: telaglenastat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is defined as the percentage of patients with complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by repeat assessment performed no less than 4 weeks after the criteria for response were first met. | Maximum duration of follow-up for ORR was 14.8 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) as Assessed by Investigator | PFS was defined as time from the first dose date to the earlier of either progression of disease per RECIST v1.1 or death from any cause. The duration of progression-free survival was censored at the date of last radiographic disease if the patient was alive and progression free at the time of analysis data cutoff, disease progression or death occurred after missing data for 2 consecutive radiographic disease assessments, or patient received non-protocol TNBC treatment prior to documentation of disease progression. Kaplan-Meier product-limit estimates. Brookmeyer-Crowley methodology for a non-parametric 95% confidence interval (CI) is used. Progressive Disease (PD) per RECIST 1.1: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition, the sum must also demonstrate an absolute increase of at least 5 mm. | Maximum duration of follow-up for PFS was 17.0 months. | 
| Overall Survival (OS) | Overall survival is defined as the time from the first dose date to death due to any cause. For patients alive at time of analysis, overall survival will be censored at the time when the patient is last known to be alive.Kaplan-Meier product-limit estimates. Brookmeyer-Crowley methodology for a non-parametric 95% CI is used. Median is defined to be the smallest observed survival time for which the value of the estimated survival function is less than or equal to 0.5. | Maximum duration of follow-up for OS was 24.1 months. | 
| Duration of Response (DOR) | Duration of response is defined as the time between the first documentation of a confirmed PR or a CR to the first documentation of PD or death, whichever occurs first. The duration of response will be censored at the date of last radiographic disease if the patient is alive and progression free at the time of database lock, disease progression or death occurs after missing data for two consecutive radiographic disease assessments, or patient receives non-protocol TNBC treatment prior to documentation of disease progression. RECIST v1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition, the sum must also demonstrate an absolute increase of at least 5 mm. | Maximum duration of follow-up for DOR was 14.8 months. | 
| Clinical Benefit Rate (CBR) | Clinical Benefit Rate is defined as the percentage of patients with best response of CR, PR, or SD per RECIST v1.1 criteria lasting ≥ 16 weeks for 3rd line + patients and ≥ 24 weeks for 1st line patients. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | Maximum duration of follow-up for CBR was 14.8 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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African ancestry, African American, CB-839, Glutaminase Inhibitor, Glutaminase, TNBC, Tumor Metabolism, Glutamine