TNBC - Triple-Negative Breast Cancer, Triple Negative Breast Cancer
Conditions
Keywords
African ancestry, African American, CB-839, Glutaminase Inhibitor, Glutaminase, TNBC, Tumor Metabolism, Glutamine
Brief summary
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
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
Interventions
DRUGPaclitaxel
standard weekly paclitaxel in 28-day cycles
DRUGCB-839
CB-839 administered as oral tablets twice daily (BID)
Sponsors
Calithera Biosciences, Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - African Ancestry, 3rd Line+ Participants self-identifying as African ancestry (includes African American) with at least 2 prior lines of systemic therapy for advanced/metastatic disease including a taxane, received 800 mg CB-839 tablets orally (PO) twice daily (BID) on Days 1 through 28 of each 28-day cycle along with 80 mg/m\^2 of paclitaxel intravenous (IV) infusion on Days 1, 8, and 15 of each 28-day cycle until disease progression, unacceptable toxicity, initiation of another systemic anticancer treatment, death, or withdrawal of consent. | 9 |
| Cohort 2 - African Ancestry, 1st Line Participants self-identifying as African ancestry (includes African American) with no prior systemic therapy for advanced or metastatic disease received 800 mg CB-839 tablets PO BID on Days 1 through 28 of each 28-day cycle along with 80 mg/m\^2 of paclitaxel IV infusion on Days 1, 8, and 15 of each 28-day cycle until disease progression, unacceptable toxicity, initiation of another systemic anticancer treatment, death, or withdrawal of consent. | 10 |
| Cohort 3 - Non-African Ancestry, 3rd Line+ Participants not self-identifying as African ancestry (includes African American) with at least 2 prior lines of systemic therapy for advanced/metastatic disease including a taxane, received 800 mg CB-839 tablets PO BID on Days 1 through 28 of each 28-day cycle along with 80 mg/m\^2 of paclitaxel IV infusion on Days 1, 8, and 15 of each 28-day cycle until disease progression, unacceptable toxicity, initiation of another systemic anticancer treatment, death, or withdrawal of consent. | 20 |
| Cohort 4 - Non-African Ancestry, 1st Line Participants not self-identifying as African ancestry (includes African American) with no prior systemic therapy for advanced or metastatic disease received 800 mg CB-839 tablets PO BID on Days 1 through 28 of each 28-day cycle along with 80 mg/m\^2 of paclitaxel IV infusion on Days 1, 8, and 15 of each 28-day cycle until disease progression, unacceptable toxicity, initiation of another systemic anticancer treatment, death, or withdrawal of consent. | 13 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 4 | 0 |
| Overall Study | Investigator Decision | 0 | 0 | 1 | 0 |
| Overall Study | Other, Not Specified | 1 | 1 | 1 | 1 |
| Overall Study | Radiologic Disease Progression | 8 | 7 | 13 | 10 |
| Overall Study | Study Termination by Sponsor | 0 | 0 | 0 | 2 |
| Overall Study | Symptomatic Deterioration | 0 | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 - African Ancestry, 3rd Line+ | Total | Cohort 4 - Non-African Ancestry, 1st Line | Cohort 3 - Non-African Ancestry, 3rd Line+ | Cohort 2 - African Ancestry, 1st Line |
|---|---|---|---|---|---|
| Age, Continuous | 50.4 years STANDARD_DEVIATION 9.4 | 57.3 years STANDARD_DEVIATION 11.78 | 59.5 years STANDARD_DEVIATION 11.13 | 55.8 years STANDARD_DEVIATION 13.02 | 64.0 years STANDARD_DEVIATION 8.68 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 0 Participants | 3 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 49 Participants | 13 Participants | 17 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 9 Participants | 19 Participants | 0 Participants | 0 Participants | 10 Participants |
| Race/Ethnicity, Customized Other, Not Specified | 0 Participants | 3 Participants | 0 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 0 Participants | 30 Participants | 13 Participants | 17 Participants | 0 Participants |
| Sex: Female, Male Female | 9 Participants | 52 Participants | 13 Participants | 20 Participants | 10 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 9 | 7 / 10 | 14 / 20 | 7 / 13 |
| other Total, other adverse events | 9 / 9 | 10 / 10 | 19 / 20 | 13 / 13 |
| serious Total, serious adverse events | 2 / 9 | 2 / 10 | 5 / 20 | 2 / 13 |
Outcome results
Primary
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.
Time frame: Maximum duration of follow-up for ORR was 14.8 months.
Population: Response Evaluable Analysis Set: all participants who had measurable disease at baseline, received at least 1 dose of study drug (telaglenastat or paclitaxel) and completed at least 1 post baseline tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - African Ancestry, 3rd Line+ | Overall Response Rate (ORR) | 22.2 percentage of participants |
| Cohort 2 - African Ancestry, 1st Line | Overall Response Rate (ORR) | 10.0 percentage of participants |
| Cohort 3 - Non-African Ancestry, 3rd Line+ | Overall Response Rate (ORR) | 10.5 percentage of participants |
| Cohort 4 - Non-African Ancestry, 1st Line | Overall Response Rate (ORR) | 53.8 percentage of participants |
p-value: 0.2252exact one-sample binomial tests
p-value: 0.9437exact one-sample binomial tests
p-value: 0.5797exact one-sample binomial tests
p-value: 0.0243exact one-sample binomial tests
Secondary
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.
Time frame: Maximum duration of follow-up for CBR was 14.8 months.
Population: Response Evaluable Analysis Set: all participants who had measurable disease at baseline, received at least 1 dose of study drug (telaglenastat or paclitaxel) and completed at least 1 post baseline tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - African Ancestry, 3rd Line+ | Clinical Benefit Rate (CBR) | 22.2 percentage of participants |
| Cohort 2 - African Ancestry, 1st Line | Clinical Benefit Rate (CBR) | 20.0 percentage of participants |
| Cohort 3 - Non-African Ancestry, 3rd Line+ | Clinical Benefit Rate (CBR) | 10.5 percentage of participants |
| Cohort 4 - Non-African Ancestry, 1st Line | Clinical Benefit Rate (CBR) | 61.5 percentage of participants |
Secondary
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.
Time frame: Maximum duration of follow-up for DOR was 14.8 months.
Population: Response Evaluable Analysis Set: all participants who had measurable disease at baseline, received at least 1 dose of study drug (telaglenastat or paclitaxel) and completed at least 1 post baseline tumor assessment. Participants defined as responders.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - African Ancestry, 3rd Line+ | Duration of Response (DOR) | NA months |
| Cohort 2 - African Ancestry, 1st Line | Duration of Response (DOR) | 6.47 months |
| Cohort 3 - Non-African Ancestry, 3rd Line+ | Duration of Response (DOR) | 7.61 months |
| Cohort 4 - Non-African Ancestry, 1st Line | Duration of Response (DOR) | 11.04 months |
Secondary
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.
Time frame: Maximum duration of follow-up for OS was 24.1 months.
Population: PFS Evaluable Analysis Set: all participants who received at least 1 dose of any study-specific treatment (telaglenastat or paclitaxel).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - African Ancestry, 3rd Line+ | Overall Survival (OS) | 7.26 months |
| Cohort 2 - African Ancestry, 1st Line | Overall Survival (OS) | 13.47 months |
| Cohort 3 - Non-African Ancestry, 3rd Line+ | Overall Survival (OS) | 6.44 months |
| Cohort 4 - Non-African Ancestry, 1st Line | Overall Survival (OS) | 16.76 months |
Secondary
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.
Time frame: Maximum duration of follow-up for PFS was 17.0 months.
Population: PFS Evaluable Analysis Set: all participants who received at least 1 dose of any study-specific treatment (telaglenastat or paclitaxel).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - African Ancestry, 3rd Line+ | Progression Free Survival (PFS) as Assessed by Investigator | 2.30 months |
| Cohort 2 - African Ancestry, 1st Line | Progression Free Survival (PFS) as Assessed by Investigator | 5.49 months |
| Cohort 3 - Non-African Ancestry, 3rd Line+ | Progression Free Survival (PFS) as Assessed by Investigator | 2.00 months |
| Cohort 4 - Non-African Ancestry, 1st Line | Progression Free Survival (PFS) as Assessed by Investigator | 7.33 months |