This is a Phase 2 trial composed of an open label Lead-In followed by a Randomized Phase designed to evaluate the efficacy and safety of SRF388 in combination with atezolizumab plus bevacizumab compared to placebo (inactive substance) in combination with atezolizumab plus bevacizumab in patients with first-line advanced or metastatic HCC.

This is a Phase 2 trial designed to evaluate the efficacy and safety of SRF388 in combination with atezolizumab plus bevacizumab (Arm A) compared to placebo in combination with atezolizumab plus bevacizumab (Arm B) in patients with first-line advanced or metastatic HCC.

After a Lead-In Phase of up to 30 patients who will receive open-label SRF388 + atezolizumab + bevacizumab, the blinded Randomized Phase will randomize approximately 104 patients with a 1:1 allocation to Arm A or Arm B and stratified by geographic region (Asia excluding Japan vs. rest of world) and Barcelona Clinic Liver Cancer (BCLC) stage (B or C).

Abbreviated Inclusion Criteria:

• ≥ 18 years of age on day of signing informed consent
• Unresectable locally advanced or metastatic HCC
• No prior systemic treatment for unresectable locally advanced or metastatic HCC
• BCLC Stage B or Stage C disease
• Child-Pugh Class A disease
• ≥ 1 measurable lesion per RECIST v1.1
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Laboratory values indicative of adequate organ function as defined in the protocol
• Women of childbearing potential must have a negative pregnancy test within 1 week prior to first dose of study drug
• Women of childbearing potential or men with a heterosexual partner of childbearing potential or pregnant must agree to refrain from sexual intercourse or be willing to use effective methods of contraception as defined in the protocol while receiving study drug and for 6 months after the last dose of any study drug

Abbreviated Exclusion Criteria:

• Currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
• Previously received an anti-interleukin (IL)-27 antibody (Ab) or anti-IL-27-targeted therapy.
• Received prior systemic therapy for unresectable or metastatic disease. (Note: Prior systemic therapies administered for neoadjuvant, adjuvant, or curative intent (localized disease) are permitted if they were given > 1 year prior to the development of recurrent or metastatic disease)
• Known fibrolamellar HCC histology, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• Moderate or severe ascites
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
• History of or current hepatic encephalopathy
• Unable to undergo disease evaluation with a triphasic CT or MRI because of contrast allergy or other contraindication
• Untreated or incompletely treated varices with bleeding or high risk for bleeding.
• Symptomatic or untreated brain metastases or leptomeningeal carcinomatosis.
• Active or history of autoimmune disease or immune deficiency with some exceptions such as controlled thyroid disease, Type 1 diabetes, eczema and other minor skin disorders.
• Medical conditions requiring chronic steroid therapy (ie, > 10 mg/day of prednisone or its equivalent) or anticipates the need for systemic immunosuppressive medications during treatment with study drug
• Known active infection with HIV
• Known infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), except for controlled active HBV or fully treated HCV infection as defined by the protocol
• Inadequately controlled arterial hypertension