Advanced Renal Cell Carcinoma, Metastatic Renal Cell Carcinoma
Conditions
Keywords
Tumor Metabolism, RCC, Glutaminase Inhibitor, CB-839, CANTATA, TKI, Tyrosine Kinase Inhibitor, cabozantinib, Cabometyx, Cometriq, glutaminase, glutamine, renal cell, clear cell, kidney cancer, cMET, MET, HGFR, telaglenastat
Brief summary
Tthe primary objective of this study is to compare blinded Independent Radiology Committee (IRC)-adjudicated progression free survival (PFS) of patients treated with CB-839 + cabozantinib (CB-Cabo) versus placebo + cabozantinib (Pbo-Cabo) for advanced or metastatic clear-cell RCC (ccRCC).
Interventions
DRUGCB-839
Oral glutaminase inhibitor
DRUGCabozantinib
Oral receptor tyrosine kinase inhibitor
DRUGPlacebo
Placebo tablets
Sponsors
Calithera Biosciences, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Participants, care providers, investigators and outcomes assessors are blinded to treatment. Progression free survival (PFS) will be assessed by a blinded Independent Radiology Committee for the primary endpoint of the study.
Intervention model description
This is a double blinded placebo-controlled study where patients will be randomized 1:1 to either CB-839 (telaglenastat) plus cabozantinib or placebo plus cabozantinib
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Documented histological or cytological diagnosis of renal cell carcinoma with a clear-cell component 2. Adult patients 3. Karnofsky Performance Score (KPS) ≥ 70% 4. Measurable Disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) 5. 1-2 lines of prior therapy for advanced or metastatic renal cell carcinoma (RCC) including one anti-angiogenic therapy (any vascular endothelial growth factor \[VEGF\] pathway-targeted agent used either as monotherapy or as a component of a combination regimen) OR the combination regimen of nivolumab + ipilimumab 6. Adequate hepatic, renal, cardiac and hematologic function
Exclusion criteria
1. Prior treatment with cabozantinib (or other mesenchymal-epithelial transition \[MET\] inhibitor) or CB-839 2. Receipt of other anticancer therapy within 2-6 weeks, depending on the treatment 3. Untreated or active brain metastases or central nervous system cancer, as defined per protocol 4. Prior gastric surgery, small bowel resection, or other conditions that may impede adequate absorption of oral study drug 5. Known active infection with human immunodeficiency virus (HIV), Hepatitis B or C virus 6. Inability to discontinue proton-pump-inhibitor use before randomization 7. Patients who are pregnant or lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) as Assessed by the Independent Radiology Committee (IRC) | Up to the primary analysis data cut-off date of 31 Aug 2020. Maximum duration of follow-up for PFS was 22.14 months. | PFS is defined as the time from randomization to the occurrence of disease progression as assessed by the IRC using RECIST v1.1 or death from any cause, whichever occurs first. Subjects not experiencing disease progression or death at the time of analysis of PFS will be censored at the date of the last evaluable radiographic disease assessment. 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. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to the primary analysis data cut-off date of 31 Aug 2020. Maximum duration of follow-up for OS was 25.86 months. | OS is defined as the time from randomization to death due to any cause. Estimated from Kaplan-Meier methodology. 95% confidence interval (CI) based on Brookmeyer-Crowley methodology. |
| PFS as Assessed by the Investigator | Up to the primary analysis data cut-off date of 31 Aug 2020. Maximum duration of follow-up for PFS was 22.64 months. | PFS is defined as the time from randomization to the occurrence of disease progression as assessed by the IRC using RECIST v1.1 or death from any cause, whichever occurs first. Subjects not experiencing disease progression or death at the time of analysis of PFS will be censored at the date of the last evaluable radiographic disease assessment. 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. 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
Australia, France, Germany, Italy, New Zealand, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Eligible participants were randomized in a 1:1 ratio to either the Pbo-Cabo arm or the CB-Cabo arm. Randomization was stratified by prior treatment with PD-1/PD-L1 inhibitor therapy (yes vs. no) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Prognostic Risk Group (favorable vs. intermediate vs. poor).
Participants by arm
| Arm | Count |
|---|---|
| Pbo-Cabo Placebo twice daily (BID) + cabozantinib (60 mg once daily \[QD\]) administered orally on Days 1 through 28 of each 28-day cycle until disease progression per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) or unacceptable toxicity, whichever occurred first. | 223 |
| CB-Cabo CB-839 800 mg BID + cabozantinib (60 mg once daily \[QD\]) administered orally on Days 1 through 28 of each 28-day cycle until disease progression per RECIST v1.1 or unacceptable toxicity, whichever occurred first. | 221 |
| Total | 444 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 89 | 93 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Other, Not Specified | 1 | 0 |
| Overall Study | Study terminated by sponsor | 124 | 118 |
| Overall Study | Withdrawal by Subject | 8 | 7 |
Baseline characteristics
| Characteristic | Pbo-Cabo | Total | CB-Cabo |
|---|---|---|---|
| Age, Continuous | 61.7 years STANDARD_DEVIATION 10.33 | 61.2 years STANDARD_DEVIATION 10.36 | 60.6 years STANDARD_DEVIATION 10.37 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 25 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 173 Participants | 349 Participants | 176 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 36 Participants | 70 Participants | 34 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants | 8 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 6 Participants | 9 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 31 Participants | 63 Participants | 32 Participants |
| Race/Ethnicity, Customized Other, Not Specified | 3 Participants | 12 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 176 Participants | 350 Participants | 174 Participants |
| Sex: Female, Male Female | 68 Participants | 115 Participants | 47 Participants |
| Sex: Female, Male Male | 155 Participants | 329 Participants | 174 Participants |
| Stratification Factor: IMDC Category Favorable | 39 Participants | 78 Participants | 39 Participants |
| Stratification Factor: IMDC Category Intermediate | 149 Participants | 296 Participants | 147 Participants |
| Stratification Factor: IMDC Category Poor | 35 Participants | 70 Participants | 35 Participants |
| Stratification Factor: Prior PD-1/PD-L1 Inhibitor Therapy No | 84 Participants | 168 Participants | 84 Participants |
| Stratification Factor: Prior PD-1/PD-L1 Inhibitor Therapy Yes | 139 Participants | 276 Participants | 137 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 89 / 223 | 93 / 221 |
| other Total, other adverse events | 213 / 217 | 222 / 225 |
| serious Total, serious adverse events | 74 / 217 | 90 / 225 |
Outcome results
Primary
Progression-Free Survival (PFS) as Assessed by the Independent Radiology Committee (IRC)
PFS is defined as the time from randomization to the occurrence of disease progression as assessed by the IRC using RECIST v1.1 or death from any cause, whichever occurs first. Subjects not experiencing disease progression or death at the time of analysis of PFS will be censored at the date of the last evaluable radiographic disease assessment. 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. 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: Up to the primary analysis data cut-off date of 31 Aug 2020. Maximum duration of follow-up for PFS was 22.14 months.
Population: Intent-to-Treat (ITT) Analysis Set: All randomized participants, analyzed according to the treatment group to which they are randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pbo-Cabo | Progression-Free Survival (PFS) as Assessed by the Independent Radiology Committee (IRC) | 9.33 months |
| CB-Cabo | Progression-Free Survival (PFS) as Assessed by the Independent Radiology Committee (IRC) | 9.17 months |
Comparison: Stratified Analysis 1: Stratified by prior programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PDL1) inhibitor therapy (yes vs no) and International Metastatic Renal Cell Carcinoma Database (IMDC) prognostic risk group (favorable vs intermediate vs poor).p-value: 0.652895% CI: [0.74, 1.21]Log Rank
Comparison: Stratified Analysis 2: Stratified by prior PD-1/PD-L1 inhibitor therapy \[yes vs. no\] and IMDC prognostic risk group \[favorable vs. intermediate/poor\].p-value: 0.819395% CI: [0.76, 1.24]Log Rank
Comparison: Stratified Analysis 3: Stratified by the number of prior anti-angio cancer therapy \[0 vs. \>=1\].p-value: 0.834595% CI: [0.76, 1.25]Log Rank
Comparison: Unstratified Analysisp-value: 0.947995% CI: [0.78, 1.27]Log Rank
Secondary
Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause. Estimated from Kaplan-Meier methodology. 95% confidence interval (CI) based on Brookmeyer-Crowley methodology.
Time frame: Up to the primary analysis data cut-off date of 31 Aug 2020. Maximum duration of follow-up for OS was 25.86 months.
Population: ITT Analysis Set: All randomized participants, analyzed according to the treatment group to which they are randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pbo-Cabo | Overall Survival (OS) | 24.84 months |
| CB-Cabo | Overall Survival (OS) | 22.24 months |
Comparison: Stratified Analysis 1: Stratified by prior PD-1/PD-L1 inhibitor therapy \[yes vs. no\] and IMDC prognostic risk group \[favorable vs. intermediate vs. poor\].p-value: 0.386795% CI: [0.83, 1.6]Log Rank
Comparison: Stratified Analysis 2: Stratified by prior PD-1/PD-L1 inhibitor therapy \[yes vs. no\] and IMDC prognostic risk group \[favorable vs. intermediate/poor\].p-value: 0.336795% CI: [0.85, 1.62]Log Rank
Comparison: Stratified Analysis 3: Stratified by prior PD-1/PD-L1 inhibitor therapy \[yes vs. no\] and IMDC prognostic risk group \[favorable vs. intermediate/poor\].p-value: 0.241695% CI: [0.88, 1.69]Log Rank
Comparison: Unstratified Analysisp-value: 0.304395% CI: [0.86, 1.64]Log Rank
Secondary
PFS as Assessed by the Investigator
PFS is defined as the time from randomization to the occurrence of disease progression as assessed by the IRC using RECIST v1.1 or death from any cause, whichever occurs first. Subjects not experiencing disease progression or death at the time of analysis of PFS will be censored at the date of the last evaluable radiographic disease assessment. 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. 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: Up to the primary analysis data cut-off date of 31 Aug 2020. Maximum duration of follow-up for PFS was 22.64 months.
Population: ITT Analysis Set: All randomized participants, analyzed according to the treatment group to which they are randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pbo-Cabo | PFS as Assessed by the Investigator | 8.38 months |
| CB-Cabo | PFS as Assessed by the Investigator | 9.17 months |
Comparison: Stratified Analysis 1: Stratified by prior PD-1/PD-L1 inhibitor therapy \[yes vs. no\] and IMDC prognostic risk group \[favorable vs. intermediate vs. poor\].p-value: 0.969295% CI: [0.79, 1.25]Log Rank
Comparison: Stratified Analysis 2: Stratified by prior PD-1/PD-L1 inhibitor therapy \[yes vs. no\] and IMDC prognostic risk group \[favorable vs. intermediate/poor\].p-value: 0.923595% CI: [0.8, 1.27]Log Rank
Comparison: Stratified Analysis 3: Stratified by the number of prior anti-angio cancer therapy \[0 vs. \>=1\].p-value: 0.954995% CI: [0.8, 1.26]Log Rank
Comparison: Unstratified Analysisp-value: 0.819395% CI: [0.82, 1.29]Log Rank