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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Cabozantinib
* Drug: Cabozantinib
* Drug: Sorafenib
* Drug: Atezolizumab


Participation Criteria
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Eligibility Criteria
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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 must be completed ≥ 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Approximately 740 eligible subjects with advanced HCC will be randomized in a 2:1:1 ratio. Experimental arm (approximately 370 subjects) will receive cabozantinib plus atezolizumab. Control arm (approximately 185 subjects) will receive sorafenib. Single-agent cabozantinib arm (approximately 185 subjects) will receive single-agent cabozantinib
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental arm<br>Subjects with advanced HCC will receive cabozantinib 40 mg oral, qd + atezolizumab 1200 mg infusion, q3w | Drug: Cabozantinib<br>* Supplied as 20-mg tablets; administered orally daily at 40 mg<br>* Other names: Cabometyx®;Drug: Atezolizumab<br>* Supplied as 1200-mg vials; administered as an IV infusion once every 3 weeks (q3w).<br>* Other names: Tecentriq®;|
| Active Comparator: Control arm<br>Subjects with advanced HCC will receive sorafenib 400 mg bid (twice a day) | Drug: Sorafenib<br>* Supplied as 200-mg tablets; administered orally twice daily at 400 mg<br>* Other names: Nexavar®;|
| Other: Single-Agent Cabozantinib arm<br>Subjects with advanced HCC will receive cabozantinib 60 mg qd | Drug: Cabozantinib<br>* Supplied as 60-mg tablets; administered orally once daily at 60 mg<br>* Other names: Cabometyx®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Progression Free Survival (PFS) for the experimental arm vs. the control arm | Duration of PFS per Response Evaluable Criteria in Solid Tumors version 1.1 (RECIST 1.1) | Up to 25 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 Overall Survival (OS) for the experimental arm vs. the control arm |  | Up to 38 months after the first subject is randomized. Defined as time from randomization to date of death from any cause. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Progression Free Survival (PFS) for the single-agent arm vs. the control arm | Duration of PFS per RECIST 1.1 by BIRC | Up to 20 months after the first subject is randomized. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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liver, cancer, hepatocellular, carcinoma