Phase 1b/2 Study of Oprozomib in Combination With Sorafenib in Subjects With Advanced Hepatocellular Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 发起方
- Amgen
- 试验地点
- 6
- 主要终点
- Maximum Tolerated Dose (MTD) - Phase 1b
研究概览
简要总结
The purpose of Phase 1b of the study is to determine the maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PDn) and assess the safety, tolerability and activity of oprozomib in combination with sorafenib in subjects with advanced hepatocellular carcinoma (HCC).
The purpose of Phase 2 of the study is to evaluate the efficacy of oprozomib in combination with sorafenib versus sorafenib alone and to compare the key outcome measures for subjects with advanced HCC.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Patients with advanced HCC
- •For the Phase 2 portion of the study, at least 1 measurable tumor lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, which has not been previously treated with local therapy
- •Cirrhotic status of Child-Pugh Class A only
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- •The following laboratory parameters:
- •Albumin ≥ 2.8 g/dL
- •Platelet count ≥ 60,000/mm3
- •Absolute neutrophil count (ANC) ≥ 1500/mm3
- •Hemoglobin ≥ 8.5 g/dL
- •Total bilirubin ≤ 3 mg/dL
- •Alanine aminotransaminase (ALT) and aspartate aminotransferase (AST) ≤ 3 times upper limit of normal (ULN)
- •Amylase and lipase ≤ 1.5 times ULN
- •Calculated or measured creatinine clearance (CrCl) ≥ 30 mL/min
- •Prothrombin time (PT)-international normalized ratio (INR) ≤ 2.3 or PT ≤ 6 seconds above control
排除标准
- •Previous or concurrent cancer that is distinct in primary site or histology from HCC, EXCEPT cervical and breast carcinoma in situ, adequately treated basal cell or squamous cell carcinoma of the skin, or superficial bladder tumors (Ta, Tis & T1)
- •Renal failure requiring hemo- or peritoneal dialysis
- •History of cardiac disease
- •Active clinically serious infections. Hepatitis B is allowed if no active replication is present. Hepatitis C is allowed if no antiviral treatment is required
- •Known history of human immunodeficiency virus (HIV) infection
- •Known history or symptomatic metastatic brain or meningeal tumors
- •Clinically significant gastrointestinal (GI) bleeding, serious nonhealing wound and ulcer within 3 months prior to study entry, or bone fracture within 30 days prior to study entry
- •History of organ allograft
- •Known or suspected allergy to the investigational agent or any agent given in association with this trial
- •Inability to swallow medication, inability or unwillingness to comply with the drug administration requirements, or GI condition that could interfere with the oral absorption or tolerance of treatment
- •Uncontrolled diabetes
- •Any contraindication to oral hydration (e.g., preexisting cardiac impairment or fluid restriction)
- •Uncontrolled ascites
- •Pleural effusion or ascites that causes respiratory compromise (NCI-CTCAE ≥ Grade 2 dyspnea).
- •Women who are pregnant and/or breastfeeding
- •Prior use of any systemic anticancer chemotherapy for HCC
- •Prior use of systemic investigational agents for HCC
- •Concomitant treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors
- •Known hypersensitivity or intolerance to dexamethasone or 5-HT3 antagonist
研究组 & 干预措施
Oprozomib with Sorafenib
Phase 1b:
Oprozomib doses will be escalated in sequential groups of at least 2 subjects. Study subjects will receive oprozomib at dose levels of 90, 120, 150, 180, 210, or 240 mg + sorafenib to reach the dose levels of 600 or 800 mg total daily dose until the maximum tolerated dose (MTD) is reached.
Phase 2:
Study subjects who meet the entry criteria will receive oprozomib + sorafenib at the RP2D (recommended Phase 2 dose) established in the Phase 1b portion of the study.
干预措施: Oprozomib (Drug)
Oprozomib with Sorafenib
Phase 1b:
Oprozomib doses will be escalated in sequential groups of at least 2 subjects. Study subjects will receive oprozomib at dose levels of 90, 120, 150, 180, 210, or 240 mg + sorafenib to reach the dose levels of 600 or 800 mg total daily dose until the maximum tolerated dose (MTD) is reached.
Phase 2:
Study subjects who meet the entry criteria will receive oprozomib + sorafenib at the RP2D (recommended Phase 2 dose) established in the Phase 1b portion of the study.
干预措施: Sorafenib (Drug)
Sorafenib
Phase 2:
Study subjects who meet the entry criteria will receive sorafenib 400 mg twice a day (800 mg total daily dose).
干预措施: Sorafenib (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) - Phase 1b
时间窗: 16 months
To determine the maximum tolerated dose (MTD) and identify the recommended Phase 2 dose (RP2D) of oprozomib in combination with sorafenib in subjects with advanced hepatocellular carcinoma (HCC).
Time To Progression (TTP) - Phase 2
时间窗: 16 months
To evaluate the efficacy of oprozomib in combination with sorafenib versus sorafenib alone in subjects with advanced HCC, as measured by time to progression (TTP), defined as time from randomization to disease progression.
次要结局
- Progression-free Survival (PFS) - Phase 2(16 months)
- Pharmacodynamic (PDn) parameter - Phase 1b(16 months)
- Overall Survival (OS) - Phase 2(16 months)
- Adverse Events (AEs) and Serious Adverse Events (SAEs) - Phase 1b & Phase 2(Until 30 days after the end of study (32 months))
- Pharmacokinetics (PK) parameters - Phase 1b(16 months)
- Overall Response Rate (ORR) - Phase 2(16 months)