A Study Evaluating Atezolizumab, With or Without Bevacizumab, in Patients With Unresectable Hepatocellular Carcinoma and Child-Pugh B7 and B8 Cirrhosis

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and efficacy of atezolizumab and bevacizumab, or atezolizumab alone, as first-line treatment in participants with unresectable, locally advanced or metastatic hepatocellular carcinoma (HCC) with Child-Pugh B7 or B8 cirrhosis.

Detailed Description
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This is a Phase II, open-label, multicohort, multicenter study in participants with unresectable, locally advanced, or metastatic hepatocellular carcinoma (HCC) who have Child-Pugh B7 or B8 liver cirrhosis and have received no prior systemic therapy in this treatment setting. The study is designed to non-comparatively evaluate the safety and efficacy of atezolizumab plus bevacizumab (Cohort A) or atezolizumab monotherapy (Cohort B) in this population.

Official Title
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A Phase II, Open-Label, Multi-Cohort, Multicenter Study in Patients With Unresectable Hepatocellular Carcinoma and Child-Pugh B7 and B8 Cirrhosis

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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General Inclusion Criteria: Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology/cytology or clinically by American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic patients Disease that is not amenable to curative surgical and/or locoregional therapies No prior systemic treatment (including systemic investigational agents) for locally advanced or metastatic and/or unresectable HCC Measurable disease (at least one untreated target lesion) according to RECIST v1.1 ECOG Performance Status of 0-2 within 7 days prior to initiation of study treatment Child-Pugh B7 or B8 cirrhosis at screening and within 7 days prior to study treatment Adequate hematologic and end-organ function Life expectancy of at least 12 weeks Female participants of childbearing potential must be willing to avoid pregnancy and egg donation General Exclusion Criteria: Pregnancy or breastfeeding Prior treatment with CD137 agonists or immune checkpoint blockade therapies Treatment with investigational therapy within 28 days prior to initiation of study treatment Treatment with locoregional therapy to liver within 28 days prior to initiation of study treatment, or non-recovery from side effects of any such procedure Treatment with systemic immunostimulatory agents Treatment with systemic immunosuppressive medication Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment Inadequately controlled hypertension Active or history of autoimmune disease or immune deficiency History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan History of malignancy other than HCC within 3 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death Known fibrolamellar HCC, sarcomatoid HCC, other rare HCC variant, or mixed cholangiocarcinoma and HCC Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases Prior allogeneic stem cell or solid organ transplantation Listed for liver transplantation Co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) Untreated or incompletely treated esophageal and/or gastric varices with bleeding or that are at high risk for bleeding A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment Grade ≥3 hemorrhage or bleeding event within 6 months prior to initiation of study treatment History of hepatic encephalopathy requiring hospitalization or treatment escalation within 6 months prior to study treatment, or any continued symptoms of encephalopathy despite medical management History, planned, or recommended placement of transjugular intrahepatic portosystemic shunt (TIPS) History of ascites requiring therapeutic paracentesis over the last 3 months History of spontaneous bacterial peritonitis within last 12 months

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Atezolizumab+Bevacizumab<br>Participants will receive Atezolizumab plus Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator. | Drug: Atezolizumab<br>* Atezolizumab will be administered at a dose of 1200 mg by IV infusion on Day 1 of each 21-day cycle.<br>* Other names: Tecentriq;Drug: Bevacizumab<br>* Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21-day cycle.<br>* Other names: Avastin;|
| Experimental: Cohort B: Atezolizumab<br>Participants will receive Atezolizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator. | Drug: Atezolizumab<br>* Atezolizumab will be administered at a dose of 1200 mg by IV infusion on Day 1 of each 21-day cycle.<br>* Other names: Tecentriq;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Adverse Events |  | Baseline through the end of the study (up to approximately 36 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Investigator-assessed confirmed ORR is defined as proportion of participants with a CR/PR on two consecutive occasions ≥ 4 weeks apart with the use of RECIST v1.1 and HCC mRECIST in Cohorts A and B. | Randomization up to approximately 36 months | 
| Duration of Response (DOR) | Investigator-assessed DOR is defined as the time from the first occurrence of a confirmed objective response to the time of disease progression, or death from any cause, whichever occurs first, with the use of RECIST v1.1 and HCC mRECIST in Cohorts A and B | Randomization up to approximately 36 months | 
| Progression Free Survival (PFS) | Investigator-assessed PFS is defined as the time from treatment initiation to the first occurrence of disease progression with the use of RECIST v1.1 and HCC mRECIST, or death from any cause, whichever occurs first, in Cohorts A and B. | Randomization up to approximately 36 months | 
| Overall Survival (OS) | OS is defined as the time from treatment initiation to the date of death due to any cause in Cohorts A and B. | Randomization up to approximately 36 months | 
| Change From Baseline in EORTC QLQ-C30 Scores | The QLQ-C30 is a validated, reliable self-reported measure. It consists of 30 questions that assess five aspects of participant functioning, three symptom scales, global health status and quality of life (QoL), and six single items with a recall period of the previous week. Scale scores can be obtained for the multi-item scales. The functioning and symptoms items are scored on a 4-point scale that ranges from not at all to very much, and the global health status and QoL items are scored on a 7-point scale that ranges from very poor to excellent. | Baseline up to approximately 36 months | 
| Change From Baseline in QLQ-HCC18 Scores | The EORTC QLQ-HCC18 is a disease-specific measure designed for use along with the EORTC QLQ-C30 in patients with HCC. It contains six multi-item symptom scales, and two single-item scales for a total of 18 questions with a recall period the past week. | Baseline up to approximately 36 months | 
| Change from baseline in PRO-CTCAE Scores | The PRO-CTCAE is a validated item bank that is used to characterize the presence, frequency of occurrence, severity, and/or degree of interference with daily function of 78 patient-reportable symptomatic treatment toxicities. | Baseline up to approximately 36 months | 
| Change From Baseline in IL46 Scores | The EORTC IL46 is a single question that assesses bother (burden) of treatment. It is rated on a scale from 1 to 4, ranging from not at all to very much. | Baseline up to approximately 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cirrhosis, liver cancer, liver tumor, Child-Pugh B, hepatocellular carcinoma, atezolizumab, bevacizumab, Immune Checkpoint Inhibitor, Digestive System Neoplasms