This study is evaluating the safety and potential effectiveness of adding folic acid to atezolizumab plus bevacizumab as first-line treatment for adults with unresectable hepatocellular carcinoma (HCC).
The main questions this study aims to answer are:
Is daily folic acid safe and well tolerated when given together with atezolizumab and bevacizumab? What dose of folic acid should be recommended for further study? Does the combination show sufficient antitumor activity to support further clinical testing?
This is an open-label, single-arm phase Ib/II study. All participants will receive folic acid together with atezolizumab and bevacizumab. There is no placebo or separate control group.
Participants will:
Take folic acid by mouth once daily, starting 7 days before the first dose of atezolizumab and bevacizumab.
Receive atezolizumab and bevacizumab by intravenous infusion every 3 weeks. Attend regular clinic visits for physical examinations, blood tests, safety assessments, and tumor imaging.
Have tumor imaging every 6 weeks during the first 24 weeks and every 9 weeks thereafter.
Provide blood samples for exploratory biomarker studies. An additional tumor biopsy during treatment may be offered but is optional.
Treatment will continue until disease progression, unacceptable side effects, withdrawal of consent, or another protocol-defined reason for stopping treatment. Immunotherapy may be continued for up to 24 months.
Age 18 to 75 years, male or female, and willing to provide written informed consent.
Hepatocellular carcinoma (HCC) confirmed by histologic/cytologic examination or diagnosed according to accepted guideline-based clinical criteria.
Unresectable HCC as determined by multidisciplinary evaluation; BCLC stage B disease that is unsuitable for, declined, or has progressed after locoregional treatment, or BCLC stage C disease; candidate for first-line systemic therapy.
No prior systemic anticancer therapy for unresectable HCC. Prior locoregional treatment must have been completed at least 4 weeks before the first study treatment, with treatment-related toxicities recovered to Grade ≤1 or baseline.
Prior treatment with PD-1, PD-L1, CTLA-4, or other immune checkpoint inhibitors, or prior bevacizumab treatment for HCC.
Eligible for curative resection, ablation, or liver transplantation and willing to undergo such treatment.
Active or recent clinically significant bleeding, including gastrointestinal bleeding, hemoptysis, or other Grade ≥2 bleeding within 6 months before the first study treatment, or untreated high-risk varices.
Arterial thromboembolism, myocardial infarction, unstable angina, stroke/transient ischemic attack, severe arrhythmia, or NYHA class >II heart failure within 6 months before the first study treatment.
Single group
Folic Acid
DrugFolic acid will be administered orally once daily, beginning 7 days before the first administration of atezolizumab and bevacizumab. During phase Ib, sequential dose levels of 1 mg once daily and 5 mg once daily will be evaluated to determine the recommended phase II dose (RP2D). In the phase II expansion, participants will receive folic acid at the selected RP2D.
Atezolizumab & Bevacizumab
DrugAtezolizumab 1200 mg and bevacizumab 15 mg/kg will be administered by intravenous infusion on Day 1 of each 3-week treatment cycle.
Incidence of Dose-Limiting Toxicities (DLTs) During Phase Ib
The number and proportion of participants experiencing a protocol-defined dose-limiting toxicity (DLT). DLTs will be graded according to NCI CTCAE version 6.0 and adjudicated according to protocol-defined attribution criteria.
Recommended Phase II Dose (RP2D) of Folic Acid
The recommended phase II dose of folic acid will be selected based on the integrated assessment of dose-limiting toxicities, overall safety and tolerability, treatment adherence, serum folate exposure, and pharmacodynamic findings during the phase Ib dose-finding portion.
Objective Response Rate (ORR) by Blinded Independent Central Review per RECIST Version 1.1
The proportion of participants treated at the recommended phase II dose whose best overall response is a confirmed complete response (CR) or partial response (PR), as assessed by blinded independent central review (BICR) according to RECIST version 1.1. A response must be confirmed by a subsequent assessment at least 4 weeks later.
Objective Response Rate per mRECIST
Proportion of participants with a confirmed complete response (CR) or partial response (PR) according to modified RECIST criteria for hepatocellular carcinoma.
Investigator-Assessed Objective Response Rate per RECIST 1.1
Proportion of participants with a confirmed CR or PR according to investigator assessment using RECIST version 1.1.
Disease Control Rate (DCR)
Proportion of participants achieving CR, PR, or stable disease according to RECIST version 1.1.
Duration of Response (DOR)
Time from the first documented CR or PR to disease progression or death from any cause.
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