Study of Cabozantinib in Combination With Nivolumab and Ipilimumab in Patients With Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (COSMIC-313)

• ClinicalTrials.gov Identifier: NCT03937219
• Recruitment Status: Active, not recruiting
• First Posted: May 3, 2019
• Last Update Posted: April 13, 2023
• Sponsor: Exelixis
• Information provided by (Responsible Party): Exelixis

Tracking Information

• First Submitted Date: May 2, 2019
• First Posted Date: May 3, 2019
• Last Update Posted Date: April 13, 2023
• Actual Study Start Date: June 25, 2019
• Actual Primary Completion Date: January 31, 2022 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: May 2, 2019): Duration of Progression-Free Survival (PFS) per RECIST 1.1 as determined by blinded independent radiology committee (BIRC) [ Time Frame: Up to 23 months after first subject randomized ]
• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures (submitted: December 19, 2020): Duration of Overall Survival (OS) [ Time Frame: Up to 69 months after first subject randomized ]
• Original Secondary Outcome Measures (submitted: May 2, 2019): Duration of Overall Survival (OS) [ Time Frame: Up to 58 months after first subject randomized ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Cabozantinib in Combination With Nivolumab and Ipilimumab in Patients With Previously Untreated Advanced or Metastatic Renal Cell Carcinoma
• Official Title: A Randomized, Double-Blind, Controlled Phase 3 Study of Cabozantinib in Combination With Nivolumab and Ipilimumab Versus Nivolumab and Ipilimumab in Subjects With Previously Untreated Advanced or Metastatic Renal Cell Carcinoma of Intermediate or Poor Risk
• 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).
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
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.

Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

• Condition: Renal Cell Carcinoma

Intervention

• Drug: Cabozantinib
  Specified dose on specified days.
  Other Names:

  • Cabometyx
  • XL184
• Biological: Nivolumab
  Specified dose on specified days.
  Other Names:

  • Opdivo
  • BMS-936558
• Biological: Ipilimumab
  Specified dose on specified days.
  Other Names:

  • Yervoy
  • BMS-734016
• Drug: Cabozantinib-matched placebo
  Specified dose on specified days.

Study Arms

• Experimental: Experimental Arm
  Cabozantinib + nivolumab + ipilimumab (4 doses) followed by cabozantinib + nivolumab
  Interventions:

  • Drug: Cabozantinib
  • Biological: Nivolumab
  • Biological: Ipilimumab
• Active Comparator: Control Arm
  Cabozantinib-matched placebo + nivolumab + ipilimumab (4 doses) followed by cabozantinib-matched placebo + nivolumab
  Interventions:

  • Biological: Nivolumab
  • Biological: Ipilimumab
  • Drug: Cabozantinib-matched placebo

Publications *

• Labriola MK, George DJ. Setting a new standard for long-term survival in metastatic kidney cancer. Cancer. 2022 Jun 1;128(11):2058-2060. doi: 10.1002/cncr.34177. Epub 2022 Apr 5. No abstract available.
• Mar N, Kaakour D, Rezazadeh Kalebasty A. Renal Cell Carcinoma-Lessons in Diversity, Breakthroughs, and Challenges. JCO Oncol Pract. 2022 Mar;18(3):197-199. doi: 10.1200/OP.21.00446. Epub 2021 Sep 22. No abstract available.
• Hofmann F, Hwang EC, Lam TB, Bex A, Yuan Y, Marconi LS, Ljungberg B. Targeted therapy for metastatic renal cell carcinoma. Cochrane Database Syst Rev. 2020 Oct 14;10(10):CD012796. doi: 10.1002/14651858.CD012796.pub2.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: December 19, 2020): 840
• Original Estimated Enrollment (submitted: May 2, 2019): 676
• Estimated Study Completion Date: March 2025
• Actual Primary Completion Date: January 31, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Czechia, Finland, France, Germany, Hong Kong, Hungary, Israel, Italy, Korea, Republic of, Mexico, Netherlands, New Zealand, Poland, Singapore, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT03937219
• Other Study ID Numbers: XL184-313
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Exelixis
• Original Responsible Party: Same as current
• Current Study Sponsor: Exelixis
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Exelixis
• Verification Date: April 2023