Study of Cabozantinib in Combination With Atezolizumab Versus Sorafenib in Subjects With Advanced HCC Who Have Not Received Previous Systemic Anticancer Therapy (COSMIC-312)

• ClinicalTrials.gov Identifier: NCT03755791
• Recruitment Status: Active, not recruiting
• First Posted: November 28, 2018
• Last Update Posted: March 22, 2024
• Sponsor: Exelixis
• Information provided by (Responsible Party): Exelixis

Tracking Information

• First Submitted Date: November 26, 2018
• First Posted Date: November 28, 2018
• Last Update Posted Date: March 22, 2024
• Actual Study Start Date: June 10, 2018
• Actual Primary Completion Date: March 8, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 20, 2024)

• Duration of Progression Free Survival (PFS) for the experimental arm vs. the control arm [ Time Frame: Up to 27 months after the first subject is randomized. Defined as time from randomization to the earlier of progressive disease (PD) per RECIST 1.1 as determined by the Blinded Independent Radiology Committee (BIRC) or death from any cause. ]
  Duration of PFS per Response Evaluable Criteria in Solid Tumors version 1.1 (RECIST 1.1)
• Duration of Overall Survival (OS) for the experimental arm vs. the control arm [ Time Frame: Up to 36 months after the first subject is randomized. Defined as time from randomization to date of death from any cause. ]

Original Primary Outcome Measures (submitted: November 26, 2018)

• Duration of Progression Free Survival (PFS) [ Time Frame: Up to 20 months after the first subject is randomized. Defined as time from randomization to the earlier of progressive disease (PD) per RECIST 1.1 as determined by the Blinded Independent Radiology Committee (BIRC) or death from any cause. ]
  Duration of PFS per Response Evaluable Criteria in Solid Tumors version 1.1 (RECIST 1.1)
• Duration of Overall Survival (OS) [ Time Frame: Up to 36 months after the first subject is randomized. Defined as time from randomization to date of death from any cause. ]

Current Secondary Outcome Measures (submitted: June 4, 2019)

Duration of Progression Free Survival (PFS) for the single-agent arm vs. the control arm [ Time Frame: Up to 20 months after the first subject is randomized. ]

Duration of PFS per RECIST 1.1 by BIRC

Original Secondary Outcome Measures (submitted: November 26, 2018)

Objective response rate (ORR) [ Time Frame: Up to 20 months after the first subject is randomized. ]

ORR per RECIST 1.1 by BIRC

• 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 Atezolizumab Versus Sorafenib in Subjects With Advanced HCC Who Have Not Received Previous Systemic Anticancer Therapy
• Official Title: A Randomized, Controlled Phase 3 Study of Cabozantinib (XL184) in Combination With Atezolizumab Versus Sorafenib in Subjects With Advanced Hepatocellular Carcinoma Who Have Not Received Previous Systemic Anticancer Therapy
• Brief Summary: This Phase 3 study evaluates the safety and efficacy of cabozantinib in combination with atezolizumab versus the standard of care sorafenib in adults with advanced hepatocellular carcinoma (HCC) who have not received previous systemic anticancer therapy. A single-agent cabozantinib arm will be enrolled in which subjects receive single agent cabozantinib in order to determine its contribution to the overall safety and efficacy of the combination with atezolizumab.
• Detailed Description: This is a multicenter, randomized, open-label, controlled Phase 3 trial of cabozantinib in combination with atezolizumab versus sorafenib in adults with advanced HCC who have not received previous systemic anticancer therapy in the advanced HCC setting. The primary objective of this study is to evaluate the effect of cabozantinib in combination with atezolizumab on the duration of progression-free survival (PFS) and duration of overall survival (OS) versus sorafenib. The secondary objective is to evaluate the activity of single-agent cabozantinib compared with sorafenib in this patient population.
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

At least 740 eligible subjects with advanced HCC will be randomized in a 2:1:1 ratio. Experimental arm (at least 370 subjects) will receive cabozantinib plus atezolizumab. Control arm (at least 185 subjects) will receive sorafenib. Single-agent cabozantinib arm (at least185 subjects) will receive single-agent cabozantinib

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Hepatocellular Carcinoma

Intervention

• Drug: Cabozantinib
  Supplied as 20-mg tablets; administered orally daily at 40 mg
  Other Names:

  • XL184
  • Cabometyx®
• Drug: Cabozantinib
  Supplied as 60-mg tablets; administered orally once daily at 60 mg
  Other Names:

  • XL184
  • Cabometyx®
• Drug: Sorafenib
  Supplied as 200-mg tablets; administered orally twice daily at 400 mg
  Other Name: Nexavar®
• Drug: Atezolizumab
  Supplied as 1200 mg/20 mL (60 mg/mL) in sing-dose vials; administered as an IV infusion once every 3 weeks (q3w).
  Other Name: Tecentriq®

Study Arms

• Experimental: Experimental arm
  Subjects with advanced HCC will receive cabozantinib 40 mg oral, qd + atezolizumab 1200 mg infusion, q3w
  Interventions:

  • Drug: Cabozantinib
  • Drug: Atezolizumab
• Active Comparator: Control arm
  Subjects with advanced HCC will receive sorafenib 400 mg bid (twice a day)
  Intervention: Drug: Sorafenib
• Single-Agent Cabozantinib arm
  Subjects with advanced HCC will receive cabozantinib 60 mg qd
  Intervention: Drug: Cabozantinib

Publications *

• Kelley RK, Rimassa L, Cheng AL, Kaseb A, Qin S, Zhu AX, Chan SL, Melkadze T, Sukeepaisarnjaroen W, Breder V, Verset G, Gane E, Borbath I, Rangel JDG, Ryoo BY, Makharadze T, Merle P, Benzaghou F, Banerjee K, Hazra S, Fawcett J, Yau T. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):995-1008. doi: 10.1016/S1470-2045(22)00326-6. Epub 2022 Jul 4.
• Kelley RK, W Oliver J, Hazra S, Benzaghou F, Yau T, Cheng AL, Rimassa L. Cabozantinib in combination with atezolizumab versus sorafenib in treatment-naive advanced hepatocellular carcinoma: COSMIC-312 Phase III study design. Future Oncol. 2020 Jul;16(21):1525-1536. doi: 10.2217/fon-2020-0283. Epub 2020 Jun 3.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 7, 2023): 837
• Original Estimated Enrollment (submitted: November 26, 2018): 640
• Estimated Study Completion Date: December 1, 2024
• Actual Primary Completion Date: March 8, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histological or cytological diagnosis of HCC or clinical diagnosis of HCC in cirrhotic patients by CT or MRI per the AASLD 2018 or EASL 2018 guidelines.
• The subject has disease that is not amenable to a curative treatment approach (eg, transplant, surgery, ablation therapy) or locoregional therapy (eg, TACE).
• Measurable disease per RECIST 1.1 as determined by the Investigator.
• Barcelona Clinic Liver Cancer (BCLC) stage Category B or C.
• Child-Pugh Score of A.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Exclusion Criteria:

• Known fibrolamellar carcinoma, sarcomatoid HCC or mixed hepatocellular cholangiocarcinoma.
• Prior systemic anticancer therapy for advanced HCC including but not limited to chemotherapy, small molecule kinase inhibitors, and immune checkpoint inhibitors (ICIs). Subjects who have received local intratumoral or arterial chemotherapy are eligible; local anticancer therapy within ≥ 28 days before randomization
• Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 8 weeks prior to randomization.
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 8 weeks prior to randomization.
• Concomitant anticoagulation with oral anticoagulants

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, China, Colombia, Czechia, France, Georgia, Germany, Hong Kong, Hungary, Ireland, Israel, Italy, Korea, Republic of, Mexico, Netherlands, New Zealand, Philippines, Poland, Romania, Russian Federation, Singapore, Spain, Switzerland, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT03755791
• Other Study ID Numbers: XL184-312
• 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: March 2024