A Multicenter, Phase II Study to Evaluate the Safety and Efficacy of Atezolizumab, Bevacizumab, and Tocilizumab in Patients With Advanced Hepatocellular Carcinoma
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 51
- 试验地点
- 1
- 主要终点
- Incidence of grade ≥3 immune-related adverse events (irAEs) within 24 weeks after treatment initiation
研究概览
简要总结
This is a Phase 2, open-label, single-arm, multicenter study designed to evaluate the safety and efficacy of atezolizumab, bevacizumab, and tocilizumab in patients with locally advanced, metastatic, and/or unresectable hepatocellular carcinoma (HCC). Approximately 51 patients will be enrolled at 6 study sites and will receive combination therapy consisting of atezolizumab, bevacizumab, and tocilizumab. Patients assigned to the study will receive atezolizumab 1,200 mg intravenously and bevacizumab 15 mg/kg intravenously on Day 1 of each 21-day cycle, alongside tocilizumab 4 mg/kg intravenously on Day 1 of each 42-day cycle for up to 5 doses. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined discontinuation criteria are met. The study population includes adult patients with locally advanced, metastatic, and/or unresectable HCC who have received no prior systemic therapy for hepatocellular carcinoma. Eligible patients must have histologically, cytologically, or radiologically confirmed diagnosis, at least one measurable lesion according to RECIST version 1.1, Child-Pugh class A liver function, ECOG performance status 0 or 1, and adequate organ function. The primary objective is to assess the incidence of Grade 3 or higher immune-related adverse events (irAEs) occurring within 24 weeks after treatment initiation according to NCI CTCAE version 5.0. Secondary objectives include evaluation of objective response rate (ORR) and disease control rate (DCR) according to RECIST v1.1, progression-free survival, overall survival, and the rate of treatment discontinuation due to adverse events. Safety evaluations will include assessment of adverse events, serious adverse events, laboratory parameters, vital signs, and other clinical assessments. Exploratory objectives include evaluation of the correlation between treatment response and serum inflammatory markers (such as IL-6 and CRP) and immune cell profiles using blood samples collected at protocol-defined intervals. Tumor assessments will be performed at protocol-defined intervals using radiologic imaging every 6 weeks from Cycle 1 Day 1 up to Week 54, and every 9 weeks thereafter. The primary efficacy analysis will be based on the Full Analysis Set according to RECIST v1.1. This study is intended to evaluate the clinical activity and safety profile of prophylactic tocilizumab in combination with atezolizumab and bevacizumab in this patient population and to generate data to inform future clinical development.
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
- 19 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically, cytologically, or radiologically confirmed diagnosis of locally advanced, metastatic, and/or unresectable hepatocellular carcinoma (HCC).
- •Age ≥19 years at the time of signing the informed consent form (ICF).
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days prior to the first dose of study drug.
- •Child-Pugh class A (score 5-6) within 7 days prior to the first dose of study drug.
- •Disease not amenable to curative surgical and/or locoregional therapy.
- •- Patients who have experienced disease progression after prior surgical and/or locoregional therapy are eligible.
- •Ability to provide written informed consent prior to initiation of any study-specific procedures, including agreement to comply with the requirements and restrictions listed in this protocol.
- •No prior systemic therapy for hepatocellular carcinoma, including investigational agents.
- •- Prior use of herbal or traditional medicines with known or potential anticancer activity is permitted only if discontinued prior to initiation of study treatment.
- •Estimated life expectancy of at least 3 months.
- •At least one measurable lesion according to RECIST version 1.
- •- Patients who have received prior locoregional therapy (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, or transarterial embolization) are eligible if the target lesion has not been previously treated or if the lesion has demonstrated progression within the treated area per RECIST v1.
- •Adequate hematologic and organ function, as defined by the following laboratory values obtained within 7 days prior to the first dose of study drug (no blood transfusion or albumin administration within 2 weeks prior to or during screening to meet eligibility criteria).
- •Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (≥1500/μL)
- •Lymphocyte count ≥ 0.5 x 109/L (≥500/μL)
- •Platelet count ≥ 100 x 109/L (≥100,000/μL)
- •Hemoglobin ≥ 90 g/L (≥9.0 g/dL)
- •AST, ALT, and ALP ≤ 5 x ULN
- •Total bilirubin ≤ 3 x ULN
- •Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥50 mL/min (calculated using the Cockcroft-Gault formula)
- •Albumin ≥ 28 g/L (≥2.8 g/dL)
- •For patients not receiving anticoagulants: INR or aPTT ≤1.5 x ULN, patients receiving low-molecular-weight heparin are eligible.
- •Documented hepatitis virus status based on screening tests for HBV and HCV.
- •For patients with active HBV infection: HBV DNA <500 IU/mL during screening, initiation of antiviral therapy at least 14 days prior to the first dose of study drug, and willingness to continue antiviral therapy throughout the study.
- •For patients with active or prior HCV infection: negative HCV RNA (PCR).
- •Patients with co-infection of HBV and HCV are not eligible.
- •Reproductive status:
- •Female patients must not be pregnant or breastfeeding.
- •Negative serum pregnancy test within 72 hours prior to the first dose of study drug.
- •Female patients must agree not to breastfeed from the time of consent until at least 6 months after the last dose of study drug.
- •Females of childbearing potential and non-sterilized males must agree to use two effective methods of contraception during the study and for at least 6 months after the last dose.
- •Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram or MUGA scan, with no severe valvular disease or clinically significant arrhythmia.
- •Corrected QT interval using Fridericia's formula (QTcF) ≤470 msec.
- •Willingness to provide blood samples.
排除标准
- •Prior systemic therapy for locally advanced, metastatic, and/or unresectable hepatocellular carcinoma, including chemotherapy, biologic therapy, immunotherapy, hormonal therapy, or investigational agents.
- •- Prior adjuvant therapy is permitted if disease recurrence occurred at least 6 months after completion of the last treatment, including adjuvant therapy and radiotherapy.
- •Presence of multiple primary malignancies.
- •- Exceptions include completely resected basal cell carcinoma, stage I squamous cell carcinoma, carcinoma in situ, intramucosal carcinoma, superficial bladder cancer, or other malignancies with no recurrence for ≥5 years.
- •Known fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, or mixed hepatocellular-cholangiocarcinoma.
- •Untreated or incompletely treated esophageal or gastric varices with bleeding or high risk of bleeding: Patients must undergo esophagogastroduodenoscopy (EGD) prior to enrollment, and all varices must be evaluated and treated according to institutional standard of care. If evaluation has been performed within 6 months prior to the first dose of study drug, repeat evaluation is not required.
- •Residual toxicities from prior therapy that, in the investigator's opinion, may interfere with safety evaluation of the study drug, or patients for whom the possibility of surgical resection cannot be completely excluded at the time of enrollment.
- •History of severe hypersensitivity reactions to other monoclonal antibody products.
- •Prior exposure to or hypersensitivity to anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 antibodies, or other agents targeting T-cell regulation.
- •Known hypersensitivity or allergy to atezolizumab, bevacizumab, or tocilizumab.
- •Active autoimmune disease or a history of chronic or recurrent autoimmune disease, or use of systemic immunosuppressive medications within 2 weeks prior to the first dose of study drug.
- •Patients with hypothyroidism requiring only hormone replacement therapy, vitiligo, psoriasis not requiring systemic treatment, or other conditions deemed stable and safe by the investigator may be eligible.
- •Patients with primary or secondary immunodeficiency or active immunodeficiency are excluded.
- •Current or prior history of interstitial lung disease or pulmonary fibrosis diagnosed based on imaging or clinical findings.
- •- Patients with radiation pneumonitis may be eligible if clinically stable (beyond the acute phase) without concern for recurrence.
- •Known central nervous system (CNS) metastases.
- •Presence of clinically significant pericardial effusion, pleural effusion, or ascites requiring treatment.
- •Uncontrolled tumor-related pain: patients requiring chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) for pain control during study treatment are excluded.
- •History of transient ischemic attack or cerebrovascular accident within 180 days prior to enrollment.
- •History of significant cardiovascular disease, including any of the following:
- •Myocardial infarction within 180 days prior to enrollment.
- •Uncontrolled angina within 180 days prior to enrollment
- •Congestive heart failure classified as New York Heart Association (NYHA) Class III or IV.
- •Uncontrolled hypertension despite appropriate medical management (e.g., systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥90 mmHg persisting for ≥24 hours).
- •Arrhythmia requiring treatment.
- •Significant vascular disease, including recent peripheral arterial thrombosis or aneurysm requiring surgical intervention.
- •Uncontrolled diabetes mellitus.
- •Systemic infection requiring treatment within 14 days prior to the first dose of study drug and treated with intravenous antibiotics (prophylactic use of oral antibiotics is permitted).
- •Use of systemic corticosteroids (>10 mg/day of prednisolone or equivalent) or other immunosuppressive medications within 28 days prior to the first dose of study drug (excluding short-term use for diagnostic, prophylactic, or similar purposes).
- •Patients who received anticancer therapy (e.g., cytotoxic chemotherapy, targeted therapy, immunotherapy) within 28 days prior to the first dose of study drug.
- •- Adjuvant therapy completed more than 6 months prior is permitted.
- •Pleurodesis or pericardiodesis within 28 days prior to the first dose of study drug.
- •Current or recent (within 2 weeks) use of aspirin (>325 mg/day) or antiplatelet agents such as clopidogrel, dipyridamole, ticlopidine, or cilostazol for therapeutic purposes: prophylactic anticoagulation is permitted if INR <1.5 × ULN and aPTT is within normal limits.
- •Major surgery under general anesthesia within 28 days prior to the first dose of study drug.
- •Surgery under local anesthesia within 14 days prior to the first dose of study drug.
- •Palliative radiotherapy within 28 days prior to the first dose of study drug, or radiotherapy to bone metastases within 14 days prior to the first dose.
- •Positive test for any of the following:
- •- HIV-1 antibody, HIV-2 antibody.
- •Pregnant or breastfeeding patients, or those with a possibility of pregnancy or plans to become pregnant.
- •Patients who received unapproved or investigational agents (e.g., investigational drugs, unapproved drug combinations, or unapproved formulations) within 28 days prior to enrollment.
- •Patients deemed unable to provide informed consent due to comorbid conditions such as dementia.
- •Patients unable or unwilling to sign the informed consent form.
- •Known pre-existing central nervous system demyelinating disorders or seizure disorders.
- •Known active diverticulitis, chronic ulcerative lower gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis), or other symptomatic lower gastrointestinal conditions that may predispose patients to gastrointestinal perforation.
- •Current active infection or history of recurrent infections, including but not limited to tuberculosis, atypical mycobacterial infection, herpes zoster, or other bacterial, viral, fungal, or mycobacterial infections (excluding fungal nail bed infections).
结局指标
主要结局
Incidence of grade ≥3 immune-related adverse events (irAEs) within 24 weeks after treatment initiation
时间窗: Within 24 weeks after treatment initiation.
Incidence of Grade 3 or higher immune-related adverse events (irAEs) occurring after treatment initiation, evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
次要结局
- Objective Response Rate (ORR) by Investigator According to RECIST v1.1(From baseline (Cycle 1 Day 1) until disease progression or end of treatment, assessed every 6 weeks through Week 54 and every 9 weeks thereafter, up to 2 years.)
- Disease Control Rate (DCR) by Investigator According to RECIST v1.1(From baseline (Cycle 1 Day 1) until disease progression or end of treatment, assessed every 6 weeks through Week 54 and every 9 weeks thereafter, up to 2 years)
- Progression-Free Survival (PFS)(From the first dose of study treatment until first documented disease progression or death from any cause, up to approximately 36 months)
- Overall Survival (OS)(From the first dose of study treatment up to the end of study follow-up (up to approximately 36 months))
- Rate of Treatment Discontinuation Due to Adverse Events(From the first dose until 28 days after the last dose of study treatment (up to approximately 2 years))
研究者
Hong Jae Chon
Principal Investigator
CHA University