Phase III Study of Rilvegostomig in Combination With Bevacizumab With or Without Tremelimumab as First-line Treatment of Hepatocellular Carcinoma

The purpose of this study is to assess the efficacy and tolerability of rilvegostomig in combination with bevacizumab with or without tremelimumab as first-line treatment in participants with advanced HCC. The study comprises 2 parts - a safety lead-in and a randomised period. Prior to the start of the randomised period of the study, a single-arm safety lead-in period will be applied to evaluate the safety and tolerability of rilvegostomig in combination with bevacizumab and tremelimumab.

• Tremelimumab (Drug): IV therapy
• Rilvegostomig (Drug): IV therapy
• Bevacizumab (Drug): IV therapy
• Atezolizumab (Drug): IV therapy

Primary outcomes

• To demonstrate the efficacy of Arm A relative to Arm C by assessment of OS in participants with advanced HCC [Up to approximately 6 years]: OS is defined as the time from randomisation until the date of death due to any cause.

Secondary outcomes

• To demonstrate the efficacy of Arm B relative to Arm C by assessment of OS in participants with advanced HCC [Up to approximately 6 years]: OS is defined as the time from randomisation until the date of death due to any cause.
• To further demonstrate the efficacy of Arm A relative to Arm C and Arm B relative to Arm C in participants with advanced HCC [Up to approximately 6 years]: PFS according to RECIST 1.1
• To further demonstrate the efficacy of Arm A relative to Arm C and Arm B relative to Arm C in participants with advanced HCC [Up to approximately 6 years]: ORR according to RECIST 1.1
• To further demonstrate the efficacy of Arm A relative to Arm C and Arm B relative to Arm C in participants with advanced HCC [Up to approximately 6 years]: DoR according to RECIST 1.1
• To demonstrate the efficacy of Arm A relative to Arm B in participants with advanced HCC [Up to approximately 6 years]: OS
• To demonstrate the efficacy of Arm A relative to Arm B in participants with advanced HCC [Up to approximately 6 years]: PFS
• To demonstrate the efficacy of Arm A relative to Arm B in participants with advanced HCC [Up to approximately 6 years]: ORR
• To demonstrate the efficacy of Arm A relative to Arm B in participants with advanced HCC [Up to approximately 6 years]: DoR
• To demonstrate the efficacy of Arm A relative to Arm C in the population defined by PD-L1 expression subgroups [Up to approximately 6 years]: Association of PD-L1 expression level with: • OS
• To demonstrate the efficacy of Arm A relative to Arm C in the population defined by PD-L1 expression subgroups [Up to approximately 6 years]: Association of PD-L1 expression level with: • PFS per RECIST 1.1
• To demonstrate the efficacy of Arm A relative to Arm C in the population defined by PD-L1 expression subgroups [Up to approximately 6 years]: Association of PD-L1 expression level with: • ORR per RECIST 1.1
• To demonstrate the efficacy of Arm B relative to Arm C in the population defined by PD-L1 expression subgroups [Up to approximately 6 years]: Association of PD-L1 expression level with: OS
• To demonstrate the efficacy of Arm B relative to Arm C in the population defined by PD-L1 expression subgroups [Up to approximately 6 years]: Association of PD-L1 expression level with: PFS per RECIST 1.1
• To demonstrate the efficacy of Arm B relative to Arm C in the population defined by PD-L1 expression subgroups [Up to approximately 6 years]: Association of PD-L1 expression level with: ORR per RECIST 1.1
• To investigate the immunogenicity of Arm A and Arm B [Up to approximately 6 years]: Presence of ADAs for tremelimumab and rilvegostomig
• Occurrence of adverse events (AEs) and serious adverse events (SAEs) [Up to approximately 6 years]: Occurrence of AEs and SAEs will be graded according to the revised NCI CTCAE v5.0.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Locally advanced or metastatic and/or unresectable HCC
* WHO/ECOG performance status of 0 or 1
* BCLC stage B (that is not eligible for locoregional therapy) or stage C.
* Child-Pugh Score class A
* At least one measurable target lesion
* Participants with active HBV infection must receive antiviral therapy for a minimum of 14 days prior to randomization to show evidence of HBV stabilization or signs of viral response.
* Participants with active HCV infection must be well controlled. Participants co-infected with HBV and HCV are not eligible.
* Adequate organ and bone marrow function measured during the screening period.
* Adequate organ and bone marrow function measured during the screening period
* Must not have received prior systemic therapy for intermediate, advanced, or metastatic HCC.
* Disease that is not amenable to curative surgical and/or locoregional therapies. For participants who received locoregional therapy for HCC, locoregional therapy must have been completed ≥ 28 days prior to the baseline scan for the current study.

Exclusion Criteria:

Medical condition

* Any evidence of uncontrolled intercurrent diseases
* Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment
* History of another primary malignancy
* Persistent toxicities caused by previous anti-cancer therapy excluding alopecia, not yet improved to Grade ≤ 1 or baseline.
* Clinically meaningful ascites, pleural effusion, or pericardial effusion requiring non-pharmacologic intervention to maintain symptomatic control within 6 months prior to the first scheduled dose.
* History of active primary immunodeficiency or active infection
* History of hepatic encephalopathy
* Current or recent (within 10 days of first dose of study treatment) use of aspirin (≥ 325 mg/day) or treatment with dipyridamole, ticlopidine, clopidogrel, and cilostazol
* Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purposes is ineligible
* History of significant bleeding disorders, vasculitis, or a significant bleeding episode from the GI tract within 6 months prior to study randomization.
* Participants with untreated or incompletely treated varices with bleeding or high-risk (red wale signs or other high-risk factors) for bleeding.

HCC related

* Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
* Central nervous system metastases or spinal cord compression (including asymptomatic and adequately treated disease)
* Prior treatment with anti-CTLA-4 and/or anti-TIGIT.
* Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior to initiation of study treatment, except palliative radiotherapy to bone lesions within 7 days prior to initiation of study treatment

126 more sites not listed.