A Phase 1/2, Dose-escalation, Open-label, Non-comparative Study of Nivolumab or Nivolumab in Combination With Ipilimumab in Advanced Hepatocellular Carcinoma Subjects With or Without Chronic Viral Hepatitis; and a Randomized, Open-label Study of Nivolumab vs Sorafenib in Advanced Hepatocellular Carcinoma Subjects Who Are Naive to Systemic Therapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 657
- 试验地点
- 60
- 主要终点
- Number of Participants With Adverse Events (AEs)
研究概览
简要总结
The first part of the study is the Dose Escalation Phase designed to establish the safety of nivolumab at different dose levels for each of the three cohorts (uninfected hepatocellular carcinoma (HCC) subjects, hepatitis C virus (HCV)-infected HCC subjects, and hepatitis B virus (HBV)-infected subjects).
The second part of the study is the Expansion Phase designed to generate additional clinical data at specified doses for each of the 3 cohorts. A third cohort has been added in this study to compare the efficacy of nivolumab and sorafenib in the treatment of Advanced HCC. A fourth cohort will generate data on the safety and efficacy of the combination nivolumab plus ipilimumab in the treatment of Advanced HCC. In the fifth cohort, additional clinical data will be generated for Child-Pugh B subjects. A Cabozantinib Combination Cohort has been added to evaluate the safety and tolerability of nivolumab in combination with cabozantinib and nivolumab with ipilimumab in combination with cabozantinib.
详细描述
Study Classification: Pharmacokinetics/Pharmacodynamics
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Subjects of 18 years or older (men and women) with histologically confirmed advanced hepatocellular carcinoma, not eligible for surgical and/or locoregional therapies; or progressive disease after surgical and /or locoregional therapies
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1
- •Dose Escalation Phase: Child-Pugh score of 7 points or less. Cohort 5: Child-Pugh Class B (B7-B8). For all other cohorts Child-Pugh score of 6 points or less
排除标准
- •History of autoimmune disease
- •Any prior or current clinically significant ascites
- •Any history of hepatic encephalopathy
研究组 & 干预措施
Non-infected: Nivolumab
Nivolumab intravenous solution on specific days
干预措施: Nivolumab (Biological)
HCV-infected: Nivolumab
Nivolumab intravenous solution on specific days
干预措施: Nivolumab (Biological)
HBV-infected: Nivolumab
Nivolumab intravenous solution on specific days
干预措施: Nivolumab (Biological)
Nivolumab
Nivolumab intravenous solution on specific days
干预措施: Nivolumab (Biological)
Sorafenib
Sorafenib tablets on specific days
干预措施: Sorafenib (Drug)
Nivolumab plus Ipilimumab Combination
Nivolumab intravenous solution + Ipilimumab intravenous solution on specific days
干预措施: Nivolumab (Biological)
Nivolumab plus Ipilimumab Combination
Nivolumab intravenous solution + Ipilimumab intravenous solution on specific days
干预措施: Ipilimumab (Drug)
Child-Pugh B
Nivolumab intravenous solution on specific days
干预措施: Nivolumab (Biological)
Nivolumab plus Cabozantinib Combination
Nivolumab intravenous solution + cabozantinib oral tablets on specific days
干预措施: Cabozantinib (Drug)
Nivolumab plus Ipilimumab plus Cabozantinib
Nivolumab intravenous solution + Ipilimumab intravenous solution + cabozantinib oral tablets on specific days
干预措施: Cabozantinib (Drug)
结局指标
主要结局
Number of Participants With Adverse Events (AEs)
时间窗: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Number of Participants With Serious Adverse Events (SAEs)
时间窗: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, and requires inpatient hospitalization or causes prolongation of existing hospitalization.
Number of Participants With Adverse Events Leading to Discontinuation
时间窗: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Number of Participants Who Died
时间窗: From first dose of study medication until study closure (Up to approximately 144 months)
Number of participants who died during the study.
Number of Participants With Laboratory Abnormalities in Specific Liver Tests
时间窗: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Participants with abnormalities in liver function tests related to potential drug-induced liver injury. Blood samples were collected and analyzed for liver function parameters, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Abnormalities were assessed relative to the upper limit of normal (ULN) for each parameter. Abbreviations: ALT = Alanine Aminotransferase; AST = Aspartate Aminotransferase; ULN = Upper Limit of Normal.
Number of Participants With Laboratory Abnormalities in Specific Thyroid Tests
时间窗: From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months)
Number of participants with thyroid-related laboratory abnormalities during the study. Blood samples were collected and analyzed for thyroid function markers (FT3, FT4). Abnormalities were assessed against LLN and ULN for each parameter. Abbreviations: FT3 = Free T3; FT4 = Free T4; LLN = Lower Limit of Normal; ULN = Upper Limit of Normal; TSH = Thyroid Stimulating Hormone
Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR) for Cohort 2
时间窗: From the start of the study treatment until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by BICR per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
Objective Response Rate (ORR) by Investigator for Cohorts 3, 4, 5, and 6
时间窗: From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 5) until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months)
Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by Investigator per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: The appearance of 1or more new lesions is also considered progression).
次要结局
- Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR) for Cohort 1(From the start of the study treatment until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months))
- Number of Participants With Complete Response (CR) Assessed by Blinded Independent Central Review (BICR)(From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to approximately 144 months after first dose)
- Disease Control Rate (DCR) Assessed by Blinded Independent Central Review (BICR)(From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) until disease progression, or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months))
- Duration of Response (DOR) Assessed by Blinded Independent Central Review (BICR)(From first documented response to first documented progression or death, whichever occurs first (Up to approximately 144 months))
- Time to Response (TTR) Assessed by Blinded Independent Central Review (BICR)(From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) to the date of attainment of complete response (CR) or partial response (PR) (up to approximately 144 months))
- Time to Progression (TTP) Assessed by Blinded Independent Central Review (BICR)(From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 144 months))
- Time to Progression (TTP) Rate Assessed by Blinded Independent Central Review (BICR)(At 6 and 12 months)
- Progression Free Survival (PFS) Assessed by Blinded Independent Central Review (BICR)(From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to documented disease progression or death, whichever occurs first (up to approximately 144 months))
- Overall Survival (OS)(From the date of randomization (Cohort 3, 4, 6) or the date of first dose (Cohort 1, 2, 5) up to the date of death or date last known alive (up to approximately 144 months))
- Overall Survival (OS) Rate(At 6, 12, 24, 48 and 60 months)
- Maximum Observed Serum Concentration (Cmax)(At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks))
- Time of Maximum Observed Serum Concentration (Tmax)(At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks))
- Area Under the Serum Concentration Time Curve in the Dosing Interval [AUC(TAU)](At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks))
- Serum Concentration Achieved at the End of Dosing Interval (Trough Concentration) (Ctrough)(At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks))
- Serum Concentration Achieved at the End of the Infusion (Ceoinf)(At Cycle 1 Day 1 and Cycle 3 Day 1 (Each Cycle = 2 Weeks))
- Ratio of an Exposure Measure at Steady State to That After the First Dose (Exposure Measure Includes Cmax) (AI_Cmax)(At Cycle 3 Day 1 (Each Cycle = 2 Weeks))
- Accumulation Index Ratio of AUC at Steady State to That After the First Dose (AI_AUC)(At Cycle 3 Day 1 (Each Cycle = 2 Weeks))
- Effective T-Half (T-HALF)(At Cycle 3 Day 1 (Each Cycle = 2 Weeks))
- Number of Participants With Anti-drug Antibodies (ADA)(From first dose of study medication through 100 days following last dose of study treatment (Assessed approximately 04 months up to a max of approximately 106 months))