A Multicenter, Non-randomized, Open-label Dose Escalation Phase Ib Study of Regorafenib in Combination With Pembrolizumab in Patients With Advanced Hepatocellular Carcinoma (HCC) With no Prior Systemic Therapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Bayer
- 入组人数
- 58
- 试验地点
- 7
- 主要终点
- Severity of TEAEs
研究概览
简要总结
This study will determine if the combination of regorafenib and pembrolizumab is safe and tolerated in patients with advanced liver cancer. In addition, the study will explore the anti-tumor activity of this combination as well as potentially identifying blood and tissue biomarkers associated with disease activity, status or response. The study will also investigate how the drugs behave in your body
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female patients ≥ 18 years of age on day of signing informed consent.
- •Histological or cytological confirmation of HCC (hepatocellular carcinoma) or non-invasive diagnosis of HCC as per American Association for the Study of Liver Diseases (AASLD) criteria in patients with a confirmed diagnosis of cirrhosis.
- •Barcelona Clinic Liver Cancer (BCLC) stage B or C that cannot benefit from treatments of established efficacy such as resection, local ablation, chemoembolization.
- •Liver function status Child-Pugh (CP) Class A. CP status should be calculated based on clinical findings and laboratory results during the screening period.
- •Any local or loco-regional therapy of intrahepatic tumor lesions (e.g. surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) must have been completed ≥ 4 weeks before first dose of study medication. Note: patients who received sole intrahepatic intra-arterial chemotherapy, without lipiodol or embolizing agents are not eligible.
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or
- •At least one uni-dimensional measurable lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to RECIST (RECIST version 1.1) and no older than 28 days before start of the study treatment. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, may be considered measurable if there has been demonstrated progression in the lesion.
- •Life expectancy of at least 3 months.
- •Adequate bone marrow and organ function as assessed by the laboratory tests performed within 7 days before of treatment initiation.
- •For patients recruited in the expansion cohort only, provision of archival (block) or fresh tumor tissue samples at baseline is mandatory. If archival tumor tissue is not available, patients should be willing to undergo a biopsy for provision of fresh tumor samples
排除标准
- •Prior systemic therapy for HCC; prior exposure to regorafenib.
- •Previous treatment with a programmed death 1 (PD1), programmed death-ligand (PD-L1), or cytotoxicT-lymphocyte-associated protein 4 (CTLA-4) inhibitors, or any form of immunotherapy for HCC.
- •Previous treatment with live vaccine within 30 days of planned start of study drugs (seasonal flu vaccines that do not contain a live virus are permitted).
- •Active autoimmune disease (active defined as having autoimmune disease related symptoms and detectable autoantibodies) that has required systemic treatment in the past 2 years (i.e., with use of diseasemodifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drugs. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
- •Known history of human immunodeficiency virus (HIV) infection (HIV 1/2 antibodies).
- •Dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab(+) and detectable HCV RNA) at study entry.
- •Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE Grade 2 dyspnea).
- •Known history of metastatic brain or meningeal tumors.
- •Significant acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease,malabsorption, or CTCAE Grade ≥ 2 diarrhea of any etiology.
研究组 & 干预措施
Dose escalation
The regorafenib starting dose will be 120 mg q.d.(once daily) 3 weeks on / 1 week off in combination with the recommended dose of pembrolizumab (200 mg Q3W). Pembrolizumab dose will not be escalated or de-escalated.
干预措施: Regorafenib(Stivarga, BAY73-4506) (Drug)
Dose escalation
The regorafenib starting dose will be 120 mg q.d.(once daily) 3 weeks on / 1 week off in combination with the recommended dose of pembrolizumab (200 mg Q3W). Pembrolizumab dose will not be escalated or de-escalated.
干预措施: Pembrolizumab (Drug)
Dose expansion
Dose expansion cohorts will continue to be expanded until the sample size of 30-35 patients per cohort is reached.
干预措施: Regorafenib(Stivarga, BAY73-4506) (Drug)
Dose expansion
Dose expansion cohorts will continue to be expanded until the sample size of 30-35 patients per cohort is reached.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Severity of TEAEs
时间窗: Up to 30 days after last dose of study drug
Incidence of treatment-emergent adverse event(TEAEs)
时间窗: Up to 30 days after last dose of study drug
The incidence of treatment-emergent adverse events and treatment-emergent drug-related adverse events summarized in frequency tables using worst CTCAE v4.03 grade.
Dose Limiting Toxicities(DLTs)
时间窗: Up to 42 days after first treatment administration
次要结局
- Time to progression (TTP)(After approximately 36 months)
- Overall survival (OS)(After approximately 36 months)
- Overall response rate (ORR)(After approximately 36 months)
- Disease control rate (DCR)(After approximately 36 months)
- Duration of response (DOR)(After approximately 36 months)
- Duration of stable disease(After approximately 36 months)
- Maximum Tolerated Dose (MTD)(After approximately 18 months)
- Progression-free survival (PFS)(After approximately 36 months)