A Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma

Hoffmann-La Roche558 enrolled

Overview

This study will evaluate the efficacy and safety of atezolizumab in combination with bevacizumab compared with sorafenib in participants with locally advanced or metastatic Hepatocellular Carcinoma (HCC) who have received no prior systemic treatment.

The participants will be randomized in a 2:1 ratio to one of the two treatment arms: Arm A (experimental arm): Atezolizumab +bevacizumab; Arm B (control arm): Sorafenib

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

558

Conditions

Carcinoma, Hepatocellular

Interventions

AtezolizumabDRUG

Atezolizumab will be administered by IV, 1200 mg on day 1 of each 21 day cycle

BevacizumabDRUG

Bevacizumab will be administered by IV, 15 mg/kg on day 1 of each 21 day cycle

SorafenibDRUG

Sorafenib will be administered by mouth, 400 mg twice per day, on days 1-21 of each 21-day cycle

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Locally advanced or metastatic and/or unresectable Hepatocellular Carcinoma (HCC) * No prior systemic therapy for HCC. Previous use of herbal therapies/traditional Chinese medicines with anti-cancer activity included in the label is allowed, provided that these medications are discontinued prior to randomization. * At least one measurable untreated lesion * ECOG Performance Status of 0 or 1 * Adequate hematologic and end-organ function * For women of childbearing potential: agreement to remain abstinent * For men: agreement to remain abstinent * Child-Pugh class A Exclusion Criteria: * History of leptomeningeal disease * 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 scan * Known active tuberculosis * History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death * Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 5 months after the last dose of atezolizumab, 6 months after the last dose of bevacizumab, or 1 month after the last dose of sorafenib * Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC * Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding * A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment. * Moderate or severe ascites * History of hepatic encephalopathy * Co-infection of HBV and HCV * Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases * Uncontrolled tumor-related pain * Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures * Uncontrolled or symptomatic hypercalcemia * Treatment with systemic immunostimulatory agents * Inadequately controlled arterial hypertension * Prior history of hypertensive crisis or hypertensive encephalopathy * Evidence of bleeding diathesis or significant coagulopathy * History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration * Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture * Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses * Local therapy to liver within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure * Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID)

Locations (119)

Outcomes

Primary Outcomes

Overall Survival (OS) in the Global Population

OS was defined as the time from randomization to death from any cause.

Time frame: From randomization to death from any cause up to the clinical cut off date (CCOD) of 29Aug2019 (up to approximately 18 months) and 31Aug2020 (up to approximately 30 months)

Progression Free Survival by Independent Review Facility-Assessment (PFS-IRF) Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the Global Population

PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause whichever occurs first as determined by an IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

Overall Survival (OS) in the China Population

OS was defined as the time from randomization to death from any cause.

Time frame: From randomization to death from any cause up to the clinical cut off date (CCOD) of 29Aug2019 (up to approximately 18 months) and 31Aug2020 (up to approximately 30 months)

PFS-IRF Per RECIST v1.1 in the China Population

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

Data from ClinicalTrials.gov

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Secondary Outcomes

Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the Global Population

ORR was defined as the percentage of participants with a complete response (CR) or a partial response (PR) as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR

Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)

Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the Global Population

ORR was defined as the percentage of participants with CR or PR as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver measuring only the residual vital tumor mass in the liver. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR

Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)

ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the Global Population

ORR was defined as the percentage of participants with CR or PR as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR

Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)

Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the Global Population

DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm.

Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)

Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the Global Population

DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm.

Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)

Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the Global Population

DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm.

Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)

PFS-IRF Per HCC mRECIST in the Global Population

PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the Global Population

PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the Global Population

Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

TTP-IRF Per HCC mRECIST in the Global Population

Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the Global Population

Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

Overall Survival by Baseline AFP in the Global Population

OS was defined as the time from randomization to death from any cause. Subpopulations with baseline AFP \<400 ng/mL and AFP\>/= 400 ng/mL were analyzed.

Time frame: From randomization to death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

PFS-IRF Per RECIST v1.1 by Baseline AFP in the Global Population

PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm). Subpopulations with baseline AFP \<400 ng/mL and AFP\>/= 400 ng/mL were analyzed.

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

PFS-INV Per RECIST v1.1 by Baseline AFP in the Global Population

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

Time to Deterioration (TTD) in the Global Population

TTD was defined as the time from randomization to the first deterioration (decrease from baseline of \>/= 10 points) in the patient-reported health-related global health status/quality of life (GHS /HRQoL), physical function or role function scales of the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for cancer (EORTC) QLQ-C30, maintained for two consecutive assessments, or one assessment followed by death from any cause within 3 weeks.

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

Number of Participants With Adverse Events (AEs) in the Global Population

An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

Time frame: Up to end of study (up to approximately 56 months)

Maximum Serum Concentration (Cmax) of Atezolizumab at Cycle 1 in the Global Population

Time frame: Post-dose on Day 1 of Cycle 1 (cycle length = 21 days)

Trough Serum Concentration (Cmin) of Atezolizumab in the Global Population

Time frame: Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length = 21 days)

Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the Global Population

Time frame: Baseline and post-baseline on Day 1 (pre-dose) of Cycles 2, 3, 4, 8, 12, 16 (cycle length = 21 days) and treatment discontinuation visit (up to approximately 30 months)

Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the China Population

Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)

Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the China Population

Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)

ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the China Population

Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)

Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the China Population

Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)

Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the China Population

DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm.

Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)

Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the China Population

DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 mm.

Time frame: Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)

PFS-IRF Per HCC mRECIST in the China Population

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the China Population

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the China Population

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

TTP-IRF Per HCC mRECIST in the China Population

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the China Population

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

Time to Deterioration (TTD) in the China Population

Time frame: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)

Number of Participants With Adverse Events (AEs) in the China Population

Time frame: Up to end of study (up to approximately 56 months)

Maximum Serum Concentration (Cmax) of Atezolizumab in the China Population

Time frame: Post-dose on Day 1 of Cycle 1 (cycle length = 21 days)

Trough Serum Concentration (Cmin) of Atezolizumab in the China Population

Time frame: Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length = 21 days)

Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the China Population

Time frame: Baseline and post-baseline on Day 1 (pre-dose) of Cycles 2, 3, 4, 8, 12, 16 (cycle length = 21 days) and treatment discontinuation visit (up to approximately 18 months)