Hepatocellular Carcinoma
Conditions
Brief summary
The purpose of this study is to assess the efficacy and safety of tiragolumab, an anti-TIGIT monoclonal antibody, when administered in combination with atezolizumab and bevacizumab as first-line treatment, in participants with unresectable, locally advanced or metastatic HCC. Per amendment version 5, following a memo issued by the Sponsor, participants receiving treatment in the atezolizumab plus bevacizumab plus tiragolumab arm are recommended to discontinue tiragolumab treatment unless the investigator decides the benefit outweighs the risk. Participants receiving treatment in atezolizumab plus bevacizumab plus placebo arm must discontinue placebo treatment. Participants may continue receiving active treatment(s) per protocol until loss of clinical benefit or unacceptable toxicity, whichever occurs first.
Interventions
DRUGAtezolizumab
Atezolizumab will be administered by intravenous (IV) infusion at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle.
DRUGBevacizumab
Bevacizumab will be administered by IV infusion at a dose of 15 milligrams per kilogram (mg/kg) on Day 1 of each 21-day cycle.
DRUGTiragolumab
Tiragolumab will be administered by IV infusion at a fixed dose of 600 mg on Day 1 of each 21-day cycle.
OTHERPlacebo
Placebo matching tiragolumab will be administered by IV infusion on Day 1 of each 21-day cycle.
Sponsors
Chugai Pharmaceutical
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The study has been unblinded as of amendment version 5.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 participants * Disease that is not amenable to curative surgical and/or locoregional therapies * No prior systemic treatment for locally advanced or metastatic and/or unresectable HCC-measurable disease according to RECIST v1.1 * Eastern cooperative oncology group (ECOG) performance status of 0 or 1 within 7 days prior to randomization * Child-pugh Class A within 7 days prior to randomization * Adequate hematologic and end-organ function * Female participants of childbearing potential must be willing to avoid pregnancy within 5 months after the final dose of atezolizumab, within 6 months after the final dose of bevacizumab, and within 90 days after the final dose of tiragolumab/placebo * Male participants with a female partner of childbearing potential or pregnant female partner must remain abstinent or use a condom during the treatment period and for 6 months after the final dose of bevacizumab and for 90 days after the final dose of tiragolumab/placebo to avoid exposing the embryo.
Exclusion criteria
* Pregnancy or breastfeeding within 5 months after the final dose of atezolizumab, within 6 months after the final dose of bevacizumab, and within 90 days after the final dose of tiragolumab/placebo * Prior treatment with cluster of differentiation 137 (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 * 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 * 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 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death * Mixed histology or other subtypes/variants of HCC, including, but not limited to, known liver adenocarcinoma, fibrolamellar HCC, sarcomatoid HCC, other rare HCC variant, or mixed cholangiocarcinoma and HCC * Co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) * Acute epstein-barr virus (EBV) infection or known or suspected chronic active EBV infection * Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Investigator-assessed Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | From randomization to the first occurrence of disease progression (PD) or death from any cause, whichever occurs first (up to approximately 21 months) |
| Overall Survival (OS) | From randomization to death from any cause (up to approximately 36 months) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-assessed PFS Rate According to RECIST v1.1 at 6 and 12 Months | Month 6, Month 12 | — |
| OS Rate at 1 and 2 Years | Year 1, Year 2 | — |
| Investigator-assessed PFS According to HCC mRECIST | From randomization to the first occurrence of PD or death from any cause, whichever occurs first (up to approximately 21 months) | — |
| Investigator-assessed Confirmed ORR According to HCC mRECIST | From randomization up to approximately 21 months | — |
| Investigator-assessed DOR According to HCC mRECIST | From the first occurrence of a documented confirmed objective response to the first occurrence of PD or death from any cause, whichever occurs first (up to approximately 21 months) | — |
| Time to Confirmed Deterioration (TTCD) Assessed Using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer 30 (EORTC QLQ-C30) Subscales | Up to approximately 21 months | The following subscales of the EORTC QLQ-C30 will be used for the assessment: global health status/quality-of-life (GHS/QoL), physical functioning and role functioning. GHS and QoL are scored on a 7-point scale: 1=Very poor to 7=Excellent. Functioning items are scored on a 4-point scale: 1=Not at all to 4=Very much, with a higher score indicating a worse outcome. Scores will be linearly transformed with a minimum score of 0 and maximum score of 100. A higher score indicates a better outcome. |
| Investigator-assessed Confirmed Objective Response Rate (ORR) According to RECIST v1.1 | From randomization up to approximately 21 months | — |
| Percentage of Participants With Adverse Events (AEs) | Up to approximately 36 months | — |
| Serum Concentrations of Atezolizumab | Prior to the first infusion and 30 minutes after atezolizumab infusion on Day 1 of Cycle 1 (cycle = 21 days), prior to infusion on Day 1 of Cycles 2, 3, 4, 8, 12, 16 and at treatment discontinuation visit (up to approximately 21 months) | — |
| Serum Concentrations of Tiragolumab | Prior to the first infusion and 30 minutes after tiragolumab infusion on Day 1 of Cycle 1 (cycle = 21 days), prior to infusion on Day 1 of Cycles 2, 3, 4, 8, 12, 16 and at treatment discontinuation visit (up to approximately 21 months) | — |
| Percentage of Participants With Anti-drug Antibodies (ADAs) to Tiragolumab | Prior to the first infusion on Day 1 of Cycles (cycle = 21 days) 1, 2, 3, 4, 8, 12, 16 and at treatment discontinuation visit (up to approximately 21 months) | — |
| Percentage of Participants With ADAs to Atezolizumab | Prior to the first infusion on Day 1 of Cycles (cycle = 21 days) 1, 2, 3, 4, 8, 12, 16 and at treatment discontinuation visit (up to approximately 21 months) | — |
| Change from Baseline in GHS/QoL, Physical Functioning, and Role Functioning Assessed Using the EORTC QLQ-C30 | Up to approximately 21 months | GHS and QoL are scored on a 7-point scale: 1=Very poor to 7=Excellent. Functioning items are scored on a 4-point scale: 1=Not at all to 4=Very much, with a higher score indicating a worse outcome. Scores will be linearly transformed with a minimum score of 0 and maximum score of 100. A higher score indicates a better outcome. |
| Investigator-assessed Duration of Response (DOR) According to RECIST v1.1 | From the first occurrence of a documented confirmed objective response to the first occurrence of PD or death from any cause, whichever occurs first (up to approximately 21 months) | — |
Countries
Belgium, Brazil, Canada, China, Côte d’Ivoire, France, Germany, Ghana, Hong Kong, Italy, Japan, Kenya, Mexico, New Zealand, Nigeria, Poland, Puerto Rico, Singapore, South Africa, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), Uganda, United Kingdom, United States
Outcome results
None listed