A Study Evaluating The Efficacy and Safety of Neoadjuvant Immunotherapy Combinations in Patients With Surgically Resectable Hepatocellular Carcinoma

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)

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.

Study Overview

• Status: Recruiting
• Conditions: Carcinoma, Hepatocellular
• Intervention / Treatment: Drug: Atezolizumab; Drug: Bevacizumab; Drug: Tiragolumab; Drug: Tobemstomig

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Reference Study ID Number: GO44457 https://forpatients.roche.com/; Phone Number: 888-662-6728 (U.S. and Canada); Email: global.rochegenentechtrials@roche.com

Study Locations

• France
  • Dijon, France, 21079
    • Recruiting
    • Centre Georges Francois Leclerc (CGFL)
  • Rennes, France, 35042
    • Recruiting
    • Centre Eugene Marquis (CEM)
  • Villejuif, France, 94805
    • Recruiting
    • Gustave Roussy
  • Villejuif, France, 94800
    • Recruiting
    • Assistance Publique-Hopitaux de Paris
• Korea, Republic of
  • Gyeonggi-do, Korea, Republic of, 13496
    • Recruiting
    • CHA Bundang Medical Center
  • Seoul, Korea, Republic of, 05505
    • Recruiting
    • Asan Medical Center
  • Seoul, Korea, Republic of, 06351
    • Recruiting
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 03722
    • Recruiting
    • Severance Hospital, Yonsei University Health System
• New Zealand
  • Auckland, New Zealand, 1023
    • Recruiting
    • Auckland District Health Board (ADHB); Auckland City Hospital (ACH)
• Spain
  • Madrid, Spain, 28040
    • Recruiting
    • Hospital Universitario Fundacion Jimenez Diaz.
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Recruiting
      • Hospital Universitario Marques de Valdecilla
  • Navarra
    • Pamplona, Navarra, Spain, 31620
      • Recruiting
      • Clinica Universidad de Navarra
• Taiwan
  • Tainan, Taiwan, 70457
    • Recruiting
    • National Cheng Kung University Hospital
  • Taipei City, Taiwan, 112
    • Recruiting
    • Taipei Veterans General Hospital
  • Zhongzheng Dist., Taiwan, 10002
    • Recruiting
    • National Taiwan University Hospital (NTUH) - Cancer Research Center
• United Kingdom
  • London, United Kingdom
    • Recruiting
    • Imperial College London - Imperial Centre for Translational and Experimental Medicine (ICTEM)
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Recruiting
      • University of Southern California (USC); Norris Comprehensive Cancer Center
    • Santa Monica, California, United States, 90404-2023
      • Recruiting
      • University of California Los Angeles (UCLA) - Cancer Care - Santa Monica
  • Colorado
    • New Haven, Colorado, United States, 06519-1110
      • Recruiting
      • Yale School of Medicine - Smilow Cancer Hospital - Yale-New Haven Hospital Location
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Recruiting
      • Georgetown University Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201-2013
      • Recruiting
      • Barbara Ann Karmanos Cancer Institute - Karmanos Cancer Center - Main Campus
  • New York
    • Bronx, New York, United States, 10461
      • Recruiting
      • Montefiore Einstein Cancer Center
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Medical Center; Herbert Irving Pavilion Location
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-4206
      • Recruiting
      • University of Pennsylvania - Abramson Cancer Center
  • Texas
    • Dallas, Texas, United States, 75390-8813
      • Recruiting
      • UT Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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 Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Atezolizumab; Atezolizumab will be administered at a dose of 1200 mg by IV infusion on Day 1.; Other Names: Tecentriq; Drug: Bevacizumab; Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1.; Other Names: Avastin
Experimental: 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.	Drug: Atezolizumab; Atezolizumab will be administered at a dose of 1200 mg by IV infusion on Day 1.; Other Names: Tecentriq; Drug: Bevacizumab; Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1.; Other Names: Avastin; Drug: Tiragolumab; Tiragolumab will be administered at a dose of 600 mg by IV infusion on Day 1.
Experimental: Tobe + Bev; Participants in the Tobemstomig + Bev arm will receive up to three cycles of treatment until surgery or unacceptable toxicity, whichever occurs first.	Drug: Bevacizumab; Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1.; Other Names: Avastin; Drug: Tobemstomig; Tobemstomig will be administered at a dose of 600 mg by IV infusion on Day 1; Other Names: RO7247669

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Pathologic Response (MPR) Rate	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.	At the time of surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse-Free Survival (RFS)	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.	Surgery to the first documented recurrence of disease (up to approximately 2 years)
Overall Survival (OS)	OS is defined as the time from randomization to death from any cause.	Randomization to death from any cause (up to approximately 3 years)
Proportion of Participants Downstaged to Within Milan Criteria	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.	Prior to surgery
R0 Resection Rate	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.	At the time of surgery
Percentage of Participants With Adverse Events		Up to approximately 3 years after first participant enrolled
Proportion of Participants With Delayed or Canceled Surgery Due to Treatment-Related Adverse Events	Proportion of participants with delayed or canceled surgery due to treatment-related adverse events (defined as > 28 days from surgical restaging visit).	>28 days from surgical restaging visit, anticipated up to 56 days
Post-Operative Surgical Complication Rates According to The Clavien-Dindo Surgical Classification	Post-operative surgical complication rates according to the Clavien-Dindo surgical classification. Clinically relevant complications are defined as Clavien-Dindo Grade >= IIIa.	Surgery to treatment completion/discontinuation (up to approximately 2 years)
Pathologic Complete Response (pCR) Rate	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.	At the time of surgery
Event-Free Survival (EFS)	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.	Randomization up to approximately 3 years
OS Rate at 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.	Randomization up to 24 months
OS Rate at 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.	Randomization up to 36 months
Objective Response Rate (ORR)	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.	Prior to surgery
Post-Operative Mortality	Post-operative mortality is defined as death within 90 days after surgery	Within 90 days after surgery

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2023
• Primary Completion (Estimated): September 30, 2025
• Study Completion (Estimated): September 30, 2028

Study Registration Dates

• First Submitted: June 7, 2023
• First Submitted That Met QC Criteria: June 15, 2023
• First Posted (Actual): June 18, 2023

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Immune Checkpoint Inhibitors; Bevacizumab; Atezolizumab
• Other Study ID Numbers: GO44457

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here ( https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No