A Phase Ib/II, Open-Label, Multicenter, Randomized Platform Study Evaluating The Efficacy and Safety of Neoadjuvant Immunotherapy Combinations in Patients With Surgically Resectable Hepatocellular Carcinoma (MORPHEUS-NEO HCC)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 62
- 试验地点
- 43
- 主要终点
- Major Pathologic Response (MPR) Rate
研究概览
简要总结
This is a Phase Ib/II, open-label, multicenter, randomized platform study to evaluate neoadjuvant immunotherapy combinations in participants with resectable HCC. The study is designed with the flexibility to open new treatment arms as new agents become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, or modify the participant population.
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
- •Diagnosis of HCC confirmed either histologically or clinically according to AASLD criteria for patients with cirrhosis. For participants without cirrhosis, histological confirmation is mandatory.
- •HCC that is amenable to R0 surgical resection with curative intent in the opinion of the surgeons and oncologists or hepatologists involved in the care of the participant. Patients presenting with resectable HCC within or beyond Milan criteria (without extrahepatic spread or macrovascular invasion) are eligible.
- •Measurable disease (at least one target lesion) according to RECIST v1.1 as determined by the investigator
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 7 days prior to randomization
- •Child-Pugh Class A within 7 days prior to randomization
- •Negative HIV test at screening
- •No prior locoregional or systemic treatment for HCC
- •Adequate hematologic and end-organ function
- •Documented virology status of hepatitis
- •For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception
- •For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating sperm
排除标准
- •Presence of extrahepatic disease or macrovascular invasion
- •Known fibrolamellar HCC, sarcomatoid HCC, mixed cholangiocarcinoma and HCC, or other rare variants of HCC
- •History of hepatic encephalopathy if clinically significant within one year prior to initiation of study treatment
- •Moderate or severe ascites
- •Active co-infection with HBV and HCV
- •Known active co-infection with HBV and hepatitis D viral infection
- •Prior treatment with CD137 agonists or immune checkpoint inhibitors, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- •Treatment with investigational therapy within 28 days prior to initiation of study treatment
- •Untreated or incompletely treated esophageal and/or gastric varices with bleeding or that are at high risk for bleeding
- •A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment
- •Inadequately controlled hypertension
- •History of hypertensive crisis or hypertensive encephalopathy
- •Significant vascular disease within 6 months prior to initiation of study treatment
- •History of hemoptysis within 1 month prior to initiation of study treatment
- •Evidence of bleeding diathesis or significant coagulopathy
- •Current or recent (<= 10 days prior to initiation of study treatment) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes
- •History of abdominal or tracheoesophageal fistula, GI perforation or intra-abdominal abscesses within 6 months prior to initiation of study treatment
- •History of intestinal obstruction and/or clinical sign or symptoms of GI obstruction
- •Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
- •Grade >= proteinuria
- •Major surgical procedure, open biopsy, or significant traumatic injury, or abdominal surgery, interventions or traumatic injuries, or anticipation of need of major surgical procedure other than potentially curative liver resection
- •Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID)
- •Serious infection requiring oral or IV antibiotics and/or hospitalization
- •Active tuberculosis
研究组 & 干预措施
Atezo + Bev
Participants in the atezolizumab plus bevacizumab (Atezo + Bev) arm will receive up to three cycles of treatment until surgery or unacceptable toxicity, whichever occurs first.
干预措施: Atezolizumab (Drug)
Atezo + Bev
Participants in the atezolizumab plus bevacizumab (Atezo + Bev) arm will receive up to three cycles of treatment until surgery or unacceptable toxicity, whichever occurs first.
干预措施: Bevacizumab (Drug)
Tobe + Bev
Participants in the Tobemstomig + Bev arm will receive up to three cycles of treatment until surgery or unacceptable toxicity, whichever occurs first.
Enrollment is closed.
干预措施: Tobemstomig (Drug)
Tobe + Bev
Participants in the Tobemstomig + Bev arm will receive up to three cycles of treatment until surgery or unacceptable toxicity, whichever occurs first.
Enrollment is closed.
干预措施: Bevacizumab (Drug)
Atezo + Bev +Tira
Participants in the atezolizumab plus bevacizumab plus tiragolumab (Atezo + Bev +Tira) arm will receive up to three cycles of treatment until surgery or unacceptable toxicity, whichever occurs first.
干预措施: Atezolizumab (Drug)
Atezo + Bev +Tira
Participants in the atezolizumab plus bevacizumab plus tiragolumab (Atezo + Bev +Tira) arm will receive up to three cycles of treatment until surgery or unacceptable toxicity, whichever occurs first.
干预措施: Bevacizumab (Drug)
Atezo + Bev +Tira
Participants in the atezolizumab plus bevacizumab plus tiragolumab (Atezo + Bev +Tira) arm will receive up to three cycles of treatment until surgery or unacceptable toxicity, whichever occurs first.
干预措施: Tiragolumab (Drug)
结局指标
主要结局
Major Pathologic Response (MPR) Rate
时间窗: At the time of surgery
MPR rate is defined as the proportion of participants with =\<10% residual viable tumor in the tumor bed at the time of surgery, as assessed by central pathological review.
Major Pathologic Response (MPR) Rate
时间窗: At the time of surgery (up to 15 weeks)
MPR rate was defined as the percentage of participants who had achieved MPR and was estimated for each treatment cohort in the efficacy-evaluable population. MPR was defined as ≤ 10% residual viable tumor in the tumor bed at the time of surgical resection in the primary tumor, as assessed by the central pathology laboratory. Participants who did not proceed to surgery were considered as non-responders for MPR. Percentages have been rounded off.
次要结局
- Overall Survival (OS)(Randomization to death from any cause (up to approximately 3 years))
- Pathologic Complete Response (pCR) Rate(At the time of surgery)
- Proportion of Participants Downstaged to Within Milan Criteria(Prior to surgery)
- Post-Operative Mortality(Within 90 days after surgery)
- Percentage of Participants With Adverse Events(Up to approximately 3 years after first participant enrolled)
- Relapse-Free Survival (RFS)(Surgery to the first documented recurrence of disease (up to approximately 2 years))
- OS Rate at 24 Months(Randomization up to 24 months)
- R0 Resection Rate(At the time of surgery)
- Post-Operative Surgical Complication Rates According to The Clavien-Dindo Surgical Classification(Surgery to treatment completion/discontinuation (up to approximately 2 years))
- Event-Free Survival (EFS)(Randomization up to approximately 3 years)
- Objective Response Rate (ORR)(Prior to surgery)
- Proportion of Participants With Delayed or Canceled Surgery Due to Treatment-Related Adverse Events(>28 days from surgical restaging visit, anticipated up to 56 days)
- OS Rate at 36 Months(Randomization up to 36 months)
- Duration of Hospital Stay Post-surgery(From time of surgery (15 weeks) up to 6 weeks (± 2 weeks) post-surgery (up to 23 weeks))
- Pathologic Complete Response (pCR) Rate(At the time of surgery (up to 15 weeks))
- Relapse-free Survival (RFS), as Assessed by the Investigator According to European Association for the Study of the Liver (EASL) and/or Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)(From surgery to the first documented recurrence of disease (up to 20.5 months))
- Event-free Survival (EFS), as Assessed by the Investigator According to EASL and RECIST v1.1(From randomization to PD that precluded surgery or disease recurrence or death from any cause, whichever occurred first (up to 20.5 months))
- Overall Survival (OS)(From randomization to death from any cause (up to 20.5 months))
- OS Rate at 6 Months, 12 Months, and 18 Months(At Months 6, 12, and 18)
- Objective Response Rate (ORR), as Assessed by the Investigator According to RECIST v1.1(Prior to surgery (at approximately Week 11))
- ORR, as Assessed by the Investigator According to Hepatocellular Carcinoma-Specific Modified Response Evaluation Criteria in Solid Tumors (HCC mRECIST)(Prior to surgery (at approximately Week 11))
- Percentage of Participants Downstaged to Within Milan Criteria (for Participants Beyond Criteria at Randomization)(At the time of surgery (up to 15 weeks))
- Negative Surgical Margins (R0) Resection Rate(At the time of surgery (up to 15 weeks))
- Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Immune-related AEs(From initiation of study treatment up to 135 days (Serious AEs and AESI) or 30 days (all other AEs) after the final dose of study treatment or until initiation of new systemic anti-cancer therapy (up to 7.7 moths))
- Percentage of Participants With Delayed or Cancelled Surgery Due to Treatment-related Adverse Events (TRAEs)(Assessed at pre-surgery (scheduled at Week 11))
- Length of Surgical Delays(Assessed at pre-surgery (scheduled at Week 11) up to 20 weeks)
- Duration of Surgery(At the time of surgery (up to 15 weeks))
- Number of Participants With Specific Surgical Approach(At the time of surgery (up to 15 weeks))
- Intraoperative Blood Loss(At the time of surgery (up to 15 weeks))
- Number of Participants Needing Intraoperative Blood Transfusion(At the time of surgery (up to 15 weeks))
- Post-operative Surgical Complication Rates Assessed According to the Clavien-dindo Surgical Classification(From time of surgery (15 weeks) up to neo-adjuvant treatment completion/discontinuation (6 weeks [± 2 weeks]) (up to 23 weeks))
- Number of Participants With Post-operative Mortality(From surgery (15 weeks) up to 90 days post-surgery (up to 27.8 weeks))