A Study Evaluating The Efficacy and Safety of Neoadjuvant Immunotherapy Combinations in Patients With Surgically Resectable Hepatocellular Carcinoma
- Conditions
- Carcinoma, Hepatocellular
- Interventions
- Registration Number
- NCT05908786
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 62
- 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
General
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Atezo + Bev Atezolizumab 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. Atezo + Bev Bevacizumab 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. Atezo + Bev +Tira Atezolizumab 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. Atezo + Bev +Tira Bevacizumab 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. Atezo + Bev +Tira Tiragolumab 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. Tobe + Bev Bevacizumab 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. Tobe + Bev Tobemstomig 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.
- Primary Outcome Measures
Name Time Method Major Pathologic Response (MPR) Rate 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.
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) Randomization to death from any cause (up to approximately 3 years) OS is defined as the time from randomization to death from any cause.
Pathologic Complete Response (pCR) Rate At the time of surgery pCR rate is defined as the proportion of participants with an absence of residual tumor at the time of surgery, as assessed by central pathological review.
Proportion of Participants Downstaged to Within Milan Criteria Prior to surgery Proportion of participants downstaged to within Milan criteria (for participants beyond criteria at randomization). Within Milan criteria is defined as single tumor \<= 5 cm or 2 - 3 nodules all \<= 3 cm.
Post-Operative Mortality Within 90 days after surgery Post-operative mortality is defined as death within 90 days after surgery
Relapse-Free Survival (RFS) Surgery to the first documented recurrence of disease (up to approximately 2 years) RFS is defined as the time from surgery to the first documented recurrence of disease (intrahepatic or extrahepatic) according to EASL and/or RECIST v1.1, or death from any cause.
OS Rate at 24 Months Randomization up to 24 months OS rate at 24 months is defined as the proportion of participants who have not experience death from any cause at 24 months after randomization.
Percentage of Participants With Adverse Events Up to approximately 3 years after first participant enrolled R0 Resection Rate At the time of surgery R0 resection rate (proportion of resected participants obtaining an R0 resection). R0 resection is defined as a microscopically margin-negative resection, in which no tumor (gross or microscopic) remains in the primary tumor bed.
Post-Operative Surgical Complication Rates According to The Clavien-Dindo Surgical Classification Surgery to treatment completion/discontinuation (up to approximately 2 years) Post-operative surgical complication rates according to the Clavien-Dindo surgical classification. Clinically relevant complications are defined as Clavien-Dindo Grade \>= IIIa.
Event-Free Survival (EFS) Randomization up to approximately 3 years EFS is defined as the time from randomization to any of the following events (whichever occurs first): disease progression that precludes surgery, as assessed by the investigator according RECIST v1.1; local regional, or distant disease recurrence as measured by EASL and/or RECIST v1.1; or death from any cause.
Objective Response Rate (ORR) Prior to surgery ORR is defined as the proportion of participants with a radiographic Complete Response (CR) or Partial Response (PR) prior to surgery, as determined by the investigator according to RECIST v1.1 and HCC mRECIST. Responses will be assessed and determined according to RECIST v1.1 and HCC mRECIST but are not required to be confirmed by subsequent imaging assessments.
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 Proportion of participants with delayed or canceled surgery due to treatment-related adverse events (defined as \> 28 days from surgical restaging visit).
OS Rate at 36 Months Randomization up to 36 months OS rate at 36 months is defined as the proportion of participants who have not experience death from any cause at 36 months after randomization.
Trial Locations
- Locations (35)
Centre Eugene Marquis (CEM)
🇫🇷Rennes, France
Gustave Roussy
🇫🇷Villejuif CEDEX, France
University Essen
🇩🇪Essen, Germany
Montefiore Einstein Cancer Center
🇺🇸Bronx, New York, United States
University of Southern California (USC)
🇺🇸Los Angeles, California, United States
University of California Los Angeles (UCLA) - Cancer Care - Santa Monica
🇺🇸Santa Monica, California, United States
Yale School of Medicine - Smilow Cancer Hospital - Yale-New Haven Hospital Location
🇺🇸New Haven, Colorado, United States
Georgetown University Medical Center
🇺🇸Washington, District of Columbia, United States
Barbara Ann Karmanos Cancer Institute - Karmanos Cancer Center - Main Campus
🇺🇸Detroit, Michigan, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
UT Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Fred Hutchinson/University of Washington Cancer Consortium
🇺🇸Seattle, Washington, United States
Klinikum Klagenfurt am Wörthersee
🇦🇹Klagenfurt am Worthersee, Austria
Wiener Gesundheitsverbund, Klinik Favoriten
🇦🇹Vienna, Austria
Department of Internal Medicine III AKH and Medical University of Vienna
🇦🇹Vienna, Austria
Centre Georges Francois Leclerc (CGFL)
🇫🇷Dijon, France
Assistance Publique-Hopitaux de Paris
🇫🇷Villejuif, France
Universitaets Klinikum Frankfurt - Zentrum der Inneren Medizin
🇩🇪Frankfurt, Germany
Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz
🇩🇪Mainz, Germany
CHA Bundang Medical Center
🇰🇷Gyeonggi-do, Korea, Republic of
Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Auckland District Health Board (ADHB)
🇳🇿Auckland, New Zealand
Hospital Universitario Marques de Valdecilla
🇪🇸Santander, Cantabria, Spain
ClÃnica Universidad de Navarra
🇪🇸Pamplona, Navarra, Spain
Hospital Clinic de Barcelona (Hospital Clinic i Provincial)
🇪🇸Barcelona, Spain
Hospital Universitario Fundacion Jimenez Diaz.
🇪🇸Madrid, Spain
Taichung Veterans General Hospital
🇨🇳Taichung, Taiwan
National Cheng Kung University Hospital
🇨🇳Tainan, Taiwan
Chang Gung Medical Foundation, Kaohsiung Chang Gung Memorial Hospital
🇨🇳Tainan, Taiwan
Taipei Veterans General Hospital
🇨🇳Taipei City, Taiwan
National Taiwan University Hospital (NTUH) - Cancer Research Center
🇨🇳Zhongzheng Dist., Taiwan
Belfast Health and Social Care Trust - Belfast City Hospital
🇬🇧Belfast, United Kingdom
Imperial College London - Imperial Centre for Translational and Experimental Medicine (ICTEM)
🇬🇧London, United Kingdom