Renal Cell Carcinoma
Conditions
Keywords
renal, cancer, carcinoma
Brief summary
This is a multicenter, randomized, double-blinded, controlled Phase 3 trial of cabozantinib in combination with nivolumab and ipilimumab versus nivolumab and ipilimumab in combination with matched placebo. Approximately 840 eligible subjects with intermediate- or poor-risk advanced or metastatic RCC by IMDC criteria will be randomized in a 1:1 ratio at approximately 180 sites.
Detailed description
This is a multicenter, randomized, double-blinded, controlled Phase 3 trial of cabozantinib in combination with nivolumab and ipilimumab versus nivolumab and ipilimumab in combination with matched placebo. The primary objective of this study is to evaluate the effect of cabozantinib in combination with nivolumab and ipilimumab (triplet) on the duration of progression-free survival (PFS) versus nivolumab and ipilimumab. A secondary objective is to evaluate the effect of triplet combination on the duration of overall survival (OS).
Interventions
DRUGCabozantinib
Specified dose on specified days.
BIOLOGICALNivolumab
Specified dose on specified days.
BIOLOGICALIpilimumab
Specified dose on specified days.
DRUGCabozantinib-matched placebo
Specified dose on specified days.
Sponsors
Exelixis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention model description
Approximately 840 eligible subjects with intermediate- or poor-risk advanced or metastatic RCC by IMDC criteria will be randomized in a 1:1 ratio.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) renal cell carcinoma with a clear-cell component. * Intermediate- or poor-risk RCC as defined by International Metastatic RCC Database Consortium (IMDC) criteria. * Measurable disease per RECIST 1.1 as determined by the Investigator. Measurable disease must be outside the radiation field if radiation therapy was previously administered. * Karnofsky Performance Status (KPS) ≥ 70%. * Adequate organ and marrow function.
Exclusion criteria
* Prior systemic anticancer therapy for unresectable locally advanced or metastatic RCC including investigational agents. * Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks prior to randomization. * Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and stable for at least 4 weeks prior to randomization. * Concomitant anticoagulation with oral anticoagulants or platelet inhibitors. * Administration of a live, attenuated vaccine within 30 days prior to randomization. * Uncontrolled, significant intercurrent or recent illness including, but not limited to serious cardiovascular disorders (including uncontrolled hypertension defined as sustained blood pressure (BP) \> 150 mm Hg systolic or \> 90 mm Hg diastolic despite optimal antihypertensive treatment), GI disorders associated with high risk for perforation or fistula formation, tumors invading GI tract, bowel obstruction, intra-abdominal abscess, clinically significant bleeding events, cavitating pulmonary lesions, or lesions invading major pulmonary blood vessels. * Other clinically significant disorders such as: * Autoimmune disease that has been symptomatic or required treatment within the past two years from the date of randomization. * Any condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. * Active infection requiring systemic treatment. Acute or chronic hepatitis B or C infection, known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or known positive test for tuberculosis infection where there is clinical or radiographic evidence of active myobacterial infection. * Known history of COVID-19 unless the subject has clinically recovered from the disease at least 30 days prior to randomization. * Major surgery (eg, nephrectomy, GI surgery, removal or biopsy of brain metastasis) within 4 weeks prior to randomization. Minor surgeries within 10 days prior to randomization. Subjects must have complete wound healing from major or minor surgery before randomization. * Any other active malignancy at time of randomization or diagnosis of another malignancy within 3 years prior to randomization that requires active treatment, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Progression-Free Survival (PFS) by Blinded Independent Radiology Committee (BIRC) | Up to 32 months | Duration of PFS was defined as the time from randomization to the earlier of either the date of radiographic progression per BIRC or the date of death due to any cause. PFS (months) = (earliest date of progression, death, censoring - date of randomization + 1)/30.4375. PFS was determined as per Response Evaluation Criteria in Solid Tumors version (RECIST) v1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Overall Survival (OS) | Up to 58 months | Duration of OS (months) = (earliest date of death or censoring - date of randomization + 1)/30.4375. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Czechia, Finland, France, Germany, Hong Kong, Hungary, Israel, Italy, Mexico, Netherlands, New Zealand, Poland, Singapore, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
The results reported in this study are based upon the data cutoff date of 09 May 2024.
Participants by arm
| Arm | Count |
|---|---|
| Cabozantinib + Nivolumab + Ipilimumab Participants received cabozantinib 40 mg orally qd + 4 doses of nivolumab 3 mg/kg infusion q3w + 4 doses of ipilimumab 1 mg/kg infusion q3w followed by cabozantinib 40 mg orally qd + nivolumab 480 mg infusion q4w. | 428 |
| Placebo + Nivolumab + Ipilimumab Participants received cabozantinib matched placebo orally qd + 4 doses of nivolumab 3 mg/kg infusion q3w + 4 doses of ipilimumab 1 mg/kg infusion q3w followed by cabozantinib matched placebo orally qd + nivolumab 480 mg infusion q4w. | 427 |
| Total | 855 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 223 | 211 |
| Overall Study | Lost to Follow-up | 3 | 4 |
| Overall Study | Withdrawal by Subject | 17 | 25 |
Baseline characteristics
| Characteristic | Cabozantinib + Nivolumab + Ipilimumab | Placebo + Nivolumab + Ipilimumab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 151 Participants | 151 Participants | 302 Participants |
| Age, Categorical Between 18 and 65 years | 277 Participants | 276 Participants | 553 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 130 Participants | 127 Participants | 257 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 263 Participants | 273 Participants | 536 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 35 Participants | 27 Participants | 62 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 10 Participants | 14 Participants |
| Race (NIH/OMB) Asian | 29 Participants | 33 Participants | 62 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 6 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 51 Participants | 43 Participants | 94 Participants |
| Race (NIH/OMB) White | 339 Participants | 331 Participants | 670 Participants |
| Sex: Female, Male Female | 102 Participants | 115 Participants | 217 Participants |
| Sex: Female, Male Male | 326 Participants | 312 Participants | 638 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 224 / 426 | 217 / 423 |
| other Total, other adverse events | 421 / 426 | 416 / 423 |
| serious Total, serious adverse events | 272 / 426 | 257 / 423 |
Outcome results
Primary
Duration of Progression-Free Survival (PFS) by Blinded Independent Radiology Committee (BIRC)
Duration of PFS was defined as the time from randomization to the earlier of either the date of radiographic progression per BIRC or the date of death due to any cause. PFS (months) = (earliest date of progression, death, censoring - date of randomization + 1)/30.4375. PFS was determined as per Response Evaluation Criteria in Solid Tumors version (RECIST) v1.1.
Time frame: Up to 32 months
Population: PFS Intent-to-Treat (PITT) population was defined as the first 550 randomized participants regardless of whether any study treatment or the correct study treatment was received. Here, overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabozantinib + Nivolumab + Ipilimumab | Duration of Progression-Free Survival (PFS) by Blinded Independent Radiology Committee (BIRC) | NA months |
| Placebo + Nivolumab + Ipilimumab | Duration of Progression-Free Survival (PFS) by Blinded Independent Radiology Committee (BIRC) | 11.30 months |
p-value: 0.013195% CI: [0.57, 0.94]Log Rank
Secondary
Duration of Overall Survival (OS)
Duration of OS (months) = (earliest date of death or censoring - date of randomization + 1)/30.4375.
Time frame: Up to 58 months
Population: The ITT population was defined as all randomized participants regardless of whether any study treatment or the correct study treatment was received. Here, overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabozantinib + Nivolumab + Ipilimumab | Duration of Overall Survival (OS) | 41.86 months |
| Placebo + Nivolumab + Ipilimumab | Duration of Overall Survival (OS) | 41.99 months |