Unresectable Hepatocellular Carcinoma
Conditions
Brief summary
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.
Interventions
DRUGFolic Acid
Folic 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 1200 mg and bevacizumab 15 mg/kg will be administered by intravenous infusion on Day 1 of each 3-week treatment cycle.
Sponsors
West China Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* 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. * At least one measurable lesion according to RECIST version 1.1. The measurable lesion must not have received prior locoregional treatment unless unequivocal radiologic progression has subsequently occurred. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and life expectancy of at least 12 weeks. * Child-Pugh class A (score 5-6), without clinically decompensated ascites or hepatic encephalopathy. * Adequate bone marrow function: absolute neutrophil count ≥1.5 × 10\^9/L, platelet count ≥75 × 10\^9/L, and hemoglobin ≥90 g/L. * Adequate hepatic and renal function: total bilirubin ≤3 × upper limit of normal (ULN); AST and ALT ≤5 × ULN; albumin ≥28 g/L; INR ≤1.5; serum creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min. * Urine protein dipstick ≤1+. If urine protein is ≥2+, 24-hour urinary protein must be \<1 g. Blood pressure must be adequately controlled at ≤150/90 mmHg. * Upper gastrointestinal endoscopic evaluation within 6 months before the first study treatment. Intermediate- or high-risk gastroesophageal varices must have been appropriately managed and considered to have an acceptable bleeding risk by the investigator. * Participants with positive HBsAg or detectable HBV DNA must receive appropriate antiviral therapy and have HBV DNA \<500 IU/mL before the first study treatment. HCV infection must be clinically stable. * Serum vitamin B12 at or above the institutional lower limit of normal, with no uncorrected megaloblastic anemia or progressive unexplained neurologic symptoms. * Participants of reproductive potential must agree to use highly effective contraception according to protocol requirements.
Exclusion criteria
* 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. * Tumor invasion of major blood vessels considered by the investigator to confer a significant near-term risk of fatal bleeding, or clinically significant risk of tumor rupture. * Uncontrolled hypertension, clinically significant proteinuria, active peptic ulcer disease, high risk of gastrointestinal perforation or fistula, unhealed wound, or major surgery within 28 days before the first study treatment. * Active autoimmune disease requiring systemic treatment, or systemic corticosteroid therapy equivalent to prednisone \>10 mg/day or other immunosuppressive therapy within 14 days before the first study treatment, except physiologic replacement therapy. * Prior solid-organ transplantation or allogeneic hematopoietic stem-cell transplantation. * Active severe infection, including uncontrolled HBV or HCV infection, active tuberculosis, or HIV infection associated with clinically significant immunodeficiency. * Symptomatic, untreated, or unstable central nervous system metastases. * Vitamin B12 deficiency, pernicious anemia, folic acid hypersensitivity, or continuous use of folic acid \>0.4 mg/day within 14 days before screening that cannot be discontinued. * Current use of methotrexate or other antifolate drugs, or use of phenytoin, phenobarbital, or primidone that cannot be replaced or appropriately monitored. * Pregnancy or breastfeeding; serious concurrent disease, psychiatric or cognitive disorder, or compliance issue that could interfere with study participation. * Participation in another interventional clinical study within 4 weeks before the first study treatment, or any other condition considered by the investigator to make the participant unsuitable for enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Dose-Limiting Toxicities (DLTs) During Phase Ib | From the first folic acid dose on Day -7 through Cycle 1 Day 21 (28 days) | 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 | At completion of the Phase Ib dose-finding portion, approximately up to 10 months after study initiation | 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 | From the first study treatment until documented disease progression or initiation of new anticancer therapy, up to 24 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate per mRECIST | Up to 24 months | 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 | Up to 24 months | Proportion of participants with a confirmed CR or PR according to investigator assessment using RECIST version 1.1. |
| Disease Control Rate (DCR) | Up to 24 months | Proportion of participants achieving CR, PR, or stable disease according to RECIST version 1.1. |
| Duration of Response (DOR) | Up to approximately 36 months | Time from the first documented CR or PR to disease progression or death from any cause. |
| Time to Response (TTR) | Up to 24 months | Time from the first study treatment to the first documented CR or PR. |
| Progression-Free Survival (PFS) | Up to approximately 36 months | Time from the first study treatment to disease progression according to RECIST version 1.1 or death from any cause, whichever occurs first. |
| Progression-Free Survival Rates at 6 and 12 Months | 6 months and 12 months | Proportion of participants alive without disease progression at 6 months and 12 months after initiation of study treatment. |
| Overall Survival (OS) | Up to approximately 36 months | Time from the first study treatment to death from any cause. |
| Overall Survival Rates at 12 and 24 Months | 12 months and 24 months | Proportion of participants alive at 12 months and 24 months after initiation of study treatment. |
| AFP Response Rate | Up to 24 months | Proportion of evaluable participants with a decrease in serum alpha-fetoprotein (AFP) of at least 20% from baseline. |
| Conversion to Curative Surgical Resection | Up to 24 months | Proportion of participants who become eligible for and undergo protocol-defined R0 surgical resection after multidisciplinary evaluation. |
| Incidence of Adverse Events | From informed consent through protocol-defined safety follow-up; immune-related adverse events monitored for at least 90 days after the last dose of atezolizumab | Incidence and severity of adverse events, serious adverse events, treatment-related adverse events, immune-related adverse events, and adverse events leading to treatment interruption or discontinuation, graded according to NCI CTCAE version 6.0. |
Outcome results
None listed