Safety and Efficacy of Folic Acid Combined With Atezolizumab and Bevacizumab as First-Line Therapy for Unresectable Hepatocellular Carcinoma: A Prospective, Open-Label, Single-Arm, Phase Ib/II Clinical Trial
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 78
- 主要终点
- Incidence of Dose-Limiting Toxicities (DLTs) During Phase Ib
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •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.
排除标准
- •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.
研究组 & 干预措施
Folic Acid Plus Atezolizumab and Bevacizumab
All participants will receive folic acid in combination with atezolizumab and bevacizumab. During the phase Ib dose-finding portion, sequential cohorts will receive folic acid 1 mg once daily or 5 mg once daily, starting 7 days before the first administration of atezolizumab and bevacizumab, 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 intravenously on Day 1 of each 3-week cycle.
干预措施: Folic Acid (Drug)
Folic Acid Plus Atezolizumab and Bevacizumab
All participants will receive folic acid in combination with atezolizumab and bevacizumab. During the phase Ib dose-finding portion, sequential cohorts will receive folic acid 1 mg once daily or 5 mg once daily, starting 7 days before the first administration of atezolizumab and bevacizumab, 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 intravenously on Day 1 of each 3-week cycle.
干预措施: Atezolizumab & Bevacizumab (Drug)
结局指标
主要结局
Incidence of Dose-Limiting Toxicities (DLTs) During Phase Ib
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- Objective Response Rate per mRECIST(Up to 24 months)
- Investigator-Assessed Objective Response Rate per RECIST 1.1(Up to 24 months)
- Disease Control Rate (DCR)(Up to 24 months)
- Duration of Response (DOR)(Up to approximately 36 months)
- Time to Response (TTR)(Up to 24 months)
- Progression-Free Survival (PFS)(Up to approximately 36 months)
- Progression-Free Survival Rates at 6 and 12 Months(6 months and 12 months)
- Overall Survival (OS)(Up to approximately 36 months)
- Overall Survival Rates at 12 and 24 Months(12 months and 24 months)
- AFP Response Rate(Up to 24 months)
- Conversion to Curative Surgical Resection(Up to 24 months)
- 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)