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

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

• Paclitaxel (Drug), also known as Taxane: standard weekly paclitaxel in 28-day cycles
• CB-839 (Drug), also known as telaglenastat: CB-839 administered as oral tablets twice daily (BID)

Primary outcomes

• Overall Response Rate (ORR) [Maximum duration of follow-up for ORR was 14.8 months.]: 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.

Secondary outcomes

• Progression Free Survival (PFS) as Assessed by Investigator [Maximum duration of follow-up for PFS was 17.0 months.]: 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.
• Overall Survival (OS) [Maximum duration of follow-up for OS was 24.1 months.]: 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.
• Duration of Response (DOR) [Maximum duration of follow-up for DOR was 14.8 months.]: 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.
• Clinical Benefit Rate (CBR) [Maximum duration of follow-up for CBR was 14.8 months.]: 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.

Sex: Female, ages: 18 Years to any

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

Participant flow

Outcome results

• Overall Response Rate (ORR) (Primary), Number, percentage of participants: Cohort 1 - African Ancestry, 3rd Line+ 22.2 (2.8 to 60.0); Cohort 2 - African Ancestry, 1st Line 10.0 (0.3 to 44.5); Cohort 3 - Non-African Ancestry, 3rd Line+ 10.5 (1.3 to 33.1); Cohort 4 - Non-African Ancestry, 1st Line 53.8 (25.1 to 80.8) (p 0.2252)
• Progression Free Survival (PFS) as Assessed by Investigator (Secondary), Median, months: Cohort 1 - African Ancestry, 3rd Line+ 2.30 (1.74 to 3.48); Cohort 2 - African Ancestry, 1st Line 5.49 (1.84 to 5.72); Cohort 3 - Non-African Ancestry, 3rd Line+ 2.00 (1.64 to 3.38); Cohort 4 - Non-African Ancestry, 1st Line 7.33 (3.71 to 16.46)
• Overall Survival (OS) (Secondary), Median, months: Cohort 1 - African Ancestry, 3rd Line+ 7.26 (5.09 to 16.95); Cohort 2 - African Ancestry, 1st Line 13.47 (6.97 to 14.69); Cohort 3 - Non-African Ancestry, 3rd Line+ 6.44 (2.73 to 8.84); Cohort 4 - Non-African Ancestry, 1st Line 16.76 (12.88 to NA)
• Duration of Response (DOR) (Secondary), Median, months: Cohort 1 - African Ancestry, 3rd Line+ NA (3.68 to NA); Cohort 2 - African Ancestry, 1st Line 6.47 (NA to NA); Cohort 3 - Non-African Ancestry, 3rd Line+ 7.61 (4.07 to 11.14); Cohort 4 - Non-African Ancestry, 1st Line 11.04 (5.55 to 14.75)
• Clinical Benefit Rate (CBR) (Secondary), Number, percentage of participants: Cohort 1 - African Ancestry, 3rd Line+ 22.2 (2.8 to 60.0); Cohort 2 - African Ancestry, 1st Line 20.0 (2.5 to 55.6); Cohort 3 - Non-African Ancestry, 3rd Line+ 10.5 (1.3 to 33.1); Cohort 4 - Non-African Ancestry, 1st Line 61.5 (31.6 to 86.1)

Adverse events

Time frame: All Cause Mortality: from enrollment through study follow-up. Maximum duration of follow-up was 24.1 months. Adverse Events: from first dose of study drug through end of treatment (EOT) + 28 days post treatment discontinuation. Median duration of treatment was 84 days for COhort 1, 118 days for Cohort 2, 51.0 days for Cohort 3, and 224.0 days for Cohort 4.

Serious adverse events by term

Other adverse events by term

112 more terms not shown.

• Study Protocol (PDF, 2017-01-06)
• Statistical Analysis Plan (PDF, 2019-10-08)

• Sam Whiting, MD, PhD, Study director, Calithera Biosciences, Inc