Clear Cell Renal Cell Carcinoma
Conditions
Keywords
advanced, metastatic RCC, RCC, CB-839, Everolimus, CBE, Glutaminase Inhibitor, Glutaminase, Tumor Metabolism, Glutamine
Brief summary
The primary objective of this study is to compare the progression-free survival (PFS) of participants treated with telaglenastat and everolimus versus placebo and everolimus for advanced or metastatic clear cell renal cell carcinoma (ccRCC) previously treated with the following: * At least 2 lines of therapy, including at least 1 vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI) * Radiographic progression of metastatic RCC must have occurred (per investigator assessment) on or after the most recent systemic therapy and within 6 months prior to cycle 1 day 1
Interventions
Sponsors
Calithera Biosciences, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blinded, placebo-controlled
Intervention model description
This is a double blinded placebo-controlled study where participants will be randomized 2:1 to either CB-839 plus everolimus (CBE) or placebo plus everolimus (PboE)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Karnofsky Performance Score (KPS) ≥ 70% * Estimated Life Expectancy of at least 3 months * Documented histological or cytological diagnosis of renal cell carcinoma with a clear-cell component. * Measurable Disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the Investigator * Must have received at least two prior lines of systemic therapy, including at least one VEGF TKI (e.g., sunitinib, sorafenib, pazopanib, cabozantinib) a) Radiographic progression of mRCC must have occurred (per investigator assessment) on or after the most recent systemic therapy and within 6 months prior to Cycle 1 Day 1 (C1D1). * Prior treatment with other anti-cancer therapies including cytokines, monoclonal antibodies, immunotherapies, and cytotoxic chemotherapy is allowed
Exclusion criteria
* Prior treatment with mammalian target of rapamycin (mTOR) inhibitors (everolimus or temsirolimus) or CB-839 * Receipt of any anticancer therapy within the following windows before randomization: * TKI therapy within 2 weeks or 5 half-lives, whichever is longer * Any type of anti-cancer antibody within 4 weeks * Cytotoxic chemotherapy within 4 weeks * Investigational therapy within 4 weeks or 5 half-lives, whichever is longer * Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before randomization. Patients with clinically relevant ongoing complications from prior radiation therapy are not eligible. * Unable to receive medications orally (PO) or any condition that may prevent adequate absorption of oral study medication * Major surgery within 28 days prior to randomization * Patients with active and/or untreated central nervous system (CNS) cancer are not eligible. Patients with treated brain metastasis must have 1) documented radiographic stability of at least 4 weeks duration demonstrated on baseline contrast-enhanced CNS imaging (eg contrast-enhanced magnetic resonance imaging \[MRI\] of the brain) prior to randomization and 2) must be symptomatically stable and off steroids for at least 2 weeks before randomization. * Requirement for continued proton pump inhibitor after randomization * Chronic treatment with corticosteroids or other immunosuppressive agents except (i) inhaled or topical steroids or replacement dose corticosteroids equivalent to ≤ 10 mg prednisone and (ii) patients receiving physiological doses of hydrocortisone for adrenal insufficiency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | As of the primary data cutoff date of 26 Apr 2019; maximum duration of follow-up for PFS was 11.2 months. | PFS was defined as the time from randomization to the date of documented disease progression (assessed by Investigator per Response Evaluation Criteria in Solid Tumors \[RECIST\] v1.1) within 2 scheduled scan intervals following previous evaluable radiologic tumor assessment or death for any cause, whichever occurred first. Participants with no documentation of disease progression or death on-study were censored at the date of last available tumor assessment. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | As of the data cutoff date of 30 Sep 2020; maximum duration of follow-up for OS was 30.4 months. | Overall survival is defined as the time from randomization to the date of death from any cause. Participants with no documentation of death on-study were censored at the date at which they were last known to be alive. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Everolimus Placebo oral tablets BID in combination with standard QD everolimus in 28 day cycles. | 23 |
| CB-839 + Everolimus CB-839 oral tablets BID in combination with standard QD everolimus in 28 day cycles. | 46 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 15 | 27 |
| Overall Study | Study terminated by sponsor (after primary endpoint was met) | 8 | 19 |
Baseline characteristics
| Characteristic | CB-839 + Everolimus | Total | Placebo + Everolimus |
|---|---|---|---|
| Age, Continuous | 65.8 years STANDARD_DEVIATION 9.18 | 64.6 years STANDARD_DEVIATION 9.69 | 62.1 years STANDARD_DEVIATION 10.38 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants | 62 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) White | 41 Participants | 62 Participants | 21 Participants |
| Sex: Female, Male Female | 9 Participants | 12 Participants | 3 Participants |
| Sex: Female, Male Male | 37 Participants | 57 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 15 / 23 | 27 / 46 |
| other Total, other adverse events | 23 / 23 | 45 / 46 |
| serious Total, serious adverse events | 8 / 23 | 21 / 46 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS was defined as the time from randomization to the date of documented disease progression (assessed by Investigator per Response Evaluation Criteria in Solid Tumors \[RECIST\] v1.1) within 2 scheduled scan intervals following previous evaluable radiologic tumor assessment or death for any cause, whichever occurred first. Participants with no documentation of disease progression or death on-study were censored at the date of last available tumor assessment. 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: As of the primary data cutoff date of 26 Apr 2019; maximum duration of follow-up for PFS was 11.2 months.
Population: Intent to Treat Population: all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Everolimus | Progression Free Survival (PFS) | 1.91 months |
| CB-839 + Everolimus | Progression Free Survival (PFS) | 3.81 months |
Comparison: Stratified analysis. Stratification factors were Memorial Sloan Kettering Cancer Center (MSKCC) Prognostic Risk (favorable versus intermediate/poor risk) and number of prior therapies with a tyrosine kinase inhibitor (TKI; 1 versus \> 1). Due to stratification cells having \< 10 events, TKI stratification factor was removed for analysis.p-value: 0.0790595% CI: [0.34, 1.2]Log Rank
Comparison: Unstratified analysisp-value: 0.118495% CI: [0.37, 1.28]Log Rank
Secondary
Overall Survival (OS)
Overall survival is defined as the time from randomization to the date of death from any cause. Participants with no documentation of death on-study were censored at the date at which they were last known to be alive.
Time frame: As of the data cutoff date of 30 Sep 2020; maximum duration of follow-up for OS was 30.4 months.
Population: ITT Population: all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Everolimus | Overall Survival (OS) | 9.72 months |
| CB-839 + Everolimus | Overall Survival (OS) | 14.37 months |
Comparison: Stratified analysis: Stratification factors are MSKCC Prognostic Risk (favorable vs intermediate/poor risk) and number of prior therapies with a TKI (1 vs \> 1). Due to stratification cells having \< 10 events, TKI stratification factor was removed for analysis.p-value: 0.480195% CI: [0.42, 1.5]Log Rank
Comparison: Unstratified analysisp-value: 0.560395% CI: [0.44, 1.56]Log Rank