A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Liver) (MORPHEUS-LIVER)

A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Liver)

This is a Phase Ib/II, open-label, multicenter, randomized umbrella study in participants with advanced liver cancers. The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, modify the participant population, or introduce additional cohorts of participants with other types of advanced primary liver cancer.

Cohort 1 will enroll participants with locally advanced or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy for their disease. Eligible participants will initially be randomly assigned to one of several treatment arms (Stage 1). Participants who experience loss of clinical benefit or unacceptable toxicity during Stage 1 may be eligible to receive treatment with a different treatment combination (Stage 2). When a Stage 2 treatment combination is available, this will be introduced by amending the protocol.

Study Overview

• Status: Recruiting
• Conditions: Advanced Liver Cancers
• Intervention / Treatment: Drug: Atezolizumab; Drug: Tiragolumab; Drug: Tocilizumab; Drug: TPST-1120; Drug: ADG126; Drug: Bevacizumab 15 mg/kg; Drug: Tobemstomig 2100 mg; Drug: Bevacizumab 10 mg/kg; Drug: Tobemstomig 600 mg; Drug: Tobemstomig 1200 mg; Drug: IO-108 1200 mg; Drug: NKT2152; Drug: IO-108 1800 mg

• Study Type: Interventional
• Enrollment (Estimated): 518
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Reference Study ID Number: GO42216 https://forpatients.roche.com/; Phone Number: 888-662-6728 (U.S. and Canada); Email: global.rochegenentechtrials@roche.com

Study Locations

• China
  • Beijing, China, 100142
    • Recruiting
    • Beijing Cancer Hospital; Pharmacy room
  • Shanghai, China, 200032
    • Recruiting
    • Zhongshan Hospital Fudan University
• France
  • Dijon, France, 21079
    • Recruiting
    • Centre Georges Francois Leclerc; Oncologie 3
  • Marseille CEDEX 05, France
    • Recruiting
    • CHU Hôpitaux de Marseille
  • Rennes, France, 35000
    • Recruiting
    • Centre Eugène Marquis
  • Villejuif, France, 94805
    • Recruiting
    • Gustave Roussy
• Israel
  • Haifa, Israel, 3109601
    • Recruiting
    • Rambam Medical Center
  • Jerusalem, Israel
    • Recruiting
    • Hadassah University Medical Center
  • Petach Tikva, Israel, 4941492
    • Recruiting
    • Rabin Medical Center-Beilinson Campus; Davidof Institute
  • Tel-Aviv, Israel, 6423906
    • Recruiting
    • Sourasky Medical Centre
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Recruiting
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 05505
    • Recruiting
    • Asan Medical Center
  • Seoul, Korea, Republic of, 06351
    • Recruiting
    • Samsung Medical Center
• New Zealand
  • Auckland, New Zealand, 1023
    • Recruiting
    • Auckland City Hospital
• Taiwan
  • Tainan, Taiwan, 70457
    • Recruiting
    • National Cheng Kung University Hospital
  • Taipei, Taiwan, 10002
    • Recruiting
    • National Taiwan University Hospital
• United States
  • California
    • Costa Mesa, California, United States, 92627
      • Recruiting
      • UC Irvine Medical Center
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope
    • La Jolla, California, United States, 92037-1337
      • Recruiting
      • University of California San Diego
    • Orange, California, United States, 92868
      • Recruiting
      • UC Irvine Medical Center
    • San Francisco, California, United States, 94115
      • Recruiting
      • University of California San Francisco Cancer Center; Pharmacy
    • Santa Monica, California, United States, 90404
      • Recruiting
      • UCLA Center for East; West Medicine
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Smilow Cancer Hospital at Yale New Haven
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Recruiting
      • Georgetown University Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • Sarah Cannon Research Institute / Tennessee Oncology
  • Texas
    • Dallas, Texas, United States, 75390
      • Recruiting
      • The University of Texas Southwestern Medical Center at Dallas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Stage 1

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 7 days prior to randomization
• Locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC) with diagnosis confirmed by histology/cytology or clinically by American Association for the Study of
• Liver Diseases criteria in cirrhotic patients
• Child-Pugh class A within 7 days prior to randomization
• Disease that is not amenable to curative surgical and/or locoregional therapies
• No prior systemic treatment for HCC
• Life expectancy >= 3 months
• Availability of a representative tumor specimen that is suitable for determination of PD-L1 and/or additional biomarker status via central testing

Stage 1 and Stage 2

• Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1
• Adequate hematologic and end-organ function within 7 days prior to initiation of study treatment
• Documented virology status of hepatitis, as confirmed by screening tests for hepatitis B virus - (HBV) and hepatitis C virus (HCV)
• Negative HIV test at screening
• For women of childbearing potential: agreement to remain abstinent or use contraception and for men: agreement to remain abstinent or use contraception, and agreement to refrain from donating sperm

Stage 2

• ECOG Performance Status of 0, 1, or 2
• Ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity not related to atezolizumab or RO7247669 or loss of clinical benefit as determined by the investigator while receiving Stage 1 treatment
• Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage 1 (if deemed clinically feasible)

NKT2152-Containing Arm:

• Total bilirubin ≤ 1.5 X ULN in the absence of Gilbert's disease (≤ 3.0 X ULN if Gilbert's disease)
• AST/ALT ≤ 2.5 X ULN (≤ 5 X ULN if liver metastases present)

Exclusion Criteria:

Stage 1

• Prior treatment with CD137 agonists or immune checkpoint blockade therapies or inhibitors targeting HIF2a
• Treatment with investigational therapy within 28 days prior to initiation of study
• Treatment with locoregional therapy to liver within 28 days prior to initiation of study, or non-recovery from side effects of any such procedure
• Untreated or incompletely treated esophageal and/or gastric varices with bleeding or at high risk for bleeding
• Prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study
• AEs from prior anti-cancer therapy that have not resolved to Grade <= 1 or better, with the exception of alopecia of any grade
• Inadequately controlled hypertension
• History of hypertensive crisis or hypertensive encephalopathy
• Significant vascular disease
• History of hemoptysis within 1 month prior to initiation of study
• Evidence of bleeding diathesis or significant coagulopathy
• Current or recent use of aspirin (>325 mg/day) or treatment with clopidogrel, dipyramidole, ticlopidine, or cilostazol
• Current or recent use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose
• Core biopsy or other minor surgical procedure within 3 days prior to initiation of study
• History of abdominal or tracheoesophageal fistula, GI perforation, or intra-abdominal abscess, intestinal obstruction and/or clinical signs/symptoms of GI obstruction
• Evidence of abdominal free air not explained by paracentesis or recent surgery
• Serious, non-healing/dehiscing wound, active ulcer, or untreated bone fracture
• Grade >=2 proteinuria
• Metastatic disease involving major airways/blood vessels, or centrally located mediastinal tumor masses of large volume
• History of clinically significant intra-abdominal inflammatory process
• Radiotherapy within 28 days or abdominal/pelvic radiotherapy within 60 days prior to initiation of study with the exception of palliative radiotherapy to bone lesions within 7 days prior to initiation of study
• Major surgery, open biopsy, or significant traumatic injury within 28 days prior to initiation of study; or abdominal surgery, abdominal interventions or significant abdominal traumatic injury within 60 days prior to initiation of study; or anticipation of need for major surgery during study or non-recovery from side effects of any such procedure
• Chronic daily treatment with NSAID
• Eligible only for control arm

Stage 1 and 2

• Fibrolamellar or sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
• History of hepatic encephalopathy
• Moderate or severe ascites
• HBV and HCV coinfection
• Symptomatic, untreated, or actively progressing CNS metastases
• History of leptomeningeal disease
• Uncontrolled tumor-related pain
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
• Uncontrolled or symptomatic hypercalcemia
• Active or history of autoimmune disease or immune deficiency
• History of IPF, organizing pneumonia, drug-induced or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
• Active TB
• Significant CV disease within 3 months prior to initiation of study, unstable arrhythmia, or unstable angina
• Major surgery, other than for diagnosis, within 4 weeks prior to initiation of study, or anticipated major surgery during study
• History of malignancy other than HCC within 5 years prior to screening
• Severe infection within 4 weeks prior to initiation of study
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study
• Prior allogeneic stem cell or solid organ transplantation
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known allergy or hypersensitivity to any of the study drugs or any of their excipients
• Treatment with systemic immunostimulatory, immunosuppressive agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study
• Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study
• Grade >= 3 hemorrhage or bleeding event within 8 weeks prior to initiation of study treatment
• Patients entering Stage 2: immunotherapy-related adverse events that have not resolved to Grade 1 or better or to baseline at time of consent

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

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Stage 1: Atezolizumab + Bevacizumab; Participants will receive atezolizumab plus bevacizumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.	Drug: Atezolizumab; Atezolizumab will be administered at a dose of 1200 mg by IV on Day 1 of each 21 day cycle.; Other Names: Tecentriq; Drug: Bevacizumab 15 mg/kg; Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.; Other Names: Avastin
Experimental: Stage 1: Atezolizumab + Bevacizumab + Tiragolumab; Participants will receive atezolizumab plus bevacizumab plus tiragolumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.	Drug: Atezolizumab; Atezolizumab will be administered at a dose of 1200 mg by IV on Day 1 of each 21 day cycle.; Other Names: Tecentriq; Drug: Tiragolumab; Tiragolumab will be administered at a dose of 600 mg by IV infusion on Day 1 of each 21 day cycle.; Drug: Bevacizumab 15 mg/kg; Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.; Other Names: Avastin
Experimental: Stage 1: Atezolizumab + Bevacizumab + Tocilizumab; Participants will receive atezolizumab plus bevacizumab plus tocilizumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.	Drug: Atezolizumab; Atezolizumab will be administered at a dose of 1200 mg by IV on Day 1 of each 21 day cycle.; Other Names: Tecentriq; Drug: Tocilizumab; Tocilizumab will be administered at a dose of 8 mg/kg by IV infusion on Day 1 of each 21 day cycle.; Other Names: Actemra; Drug: Bevacizumab 15 mg/kg; Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.; Other Names: Avastin
Experimental: Stage 1: Atezolizumab + Bevacizumab + TPST-1120; Participants will receive atezolizumab plus bevacizumab plus TPST-1120 until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.	Drug: Atezolizumab; Atezolizumab will be administered at a dose of 1200 mg by IV on Day 1 of each 21 day cycle.; Other Names: Tecentriq; Drug: TPST-1120; TPST-1120 will be administered at a dose of 1200 mg by mouth on Days 1-21 of each 21 day cycle.; Drug: Bevacizumab 15 mg/kg; Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.; Other Names: Avastin
Experimental: Stage 1: Atezolizumab + Bevacizumab + ADG126; Participants will receive atezolizumab plus bevacizumab plus ADG126 until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.	Drug: Atezolizumab; Atezolizumab will be administered at a dose of 1200 mg by IV on Day 1 of each 21 day cycle.; Other Names: Tecentriq; Drug: ADG126; ADG126 will be administered at a dose of 6 mg/kg by IV infusion on Day 1 of every other cycle (cycle length = 21 days).; Drug: Bevacizumab 15 mg/kg; Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.; Other Names: Avastin
Experimental: Stage 1: Tobemstomig 2100 mg Q2W + Bevacizumab; Participants will receive Tobemstomig plus bevacizumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.	Drug: Bevacizumab 15 mg/kg; Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.; Other Names: Avastin; Drug: Tobemstomig 2100 mg; Tobemstomig will be administered at a dose of 2100 mg by IV infusion on Days 1 and 15 of each 28 day cycle.; Drug: Bevacizumab 10 mg/kg; Bevacizumab will be administered at a dose of 10 mg/kg by IV infusion on Days 1 and 15 of each 28 day cycle.; Other Names: Avastin
Experimental: Stage 1: Tobemstomig 600 mg Q3W + Bevacizumab; Participants will receive Tobemstomig plus bevacizumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.	Drug: Bevacizumab 15 mg/kg; Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.; Other Names: Avastin; Drug: Tobemstomig 600 mg; Tobemstomig will be administered at a dose of 600 mg by IV infusion on Day 1 of each 21 day cycle.
Experimental: Stage 1: Tobemstomig 1200 mg Q3W + Bevacizumab; Participants will receive Tobemstomig plus bevacizumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.	Drug: Bevacizumab 15 mg/kg; Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.; Other Names: Avastin; Drug: Tobemstomig 1200 mg; Tobemstomig will be administered at a dose of 1200 mg every 3 weeks.
Experimental: Stage 1: Atezolizumab + Bevacizumab + NKT2152; Participants will receive atezolizumab plus bevacizumab plus NKT2152 until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.	Drug: Atezolizumab; Atezolizumab will be administered at a dose of 1200 mg by IV on Day 1 of each 21 day cycle.; Other Names: Tecentriq; Drug: Bevacizumab 15 mg/kg; Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.; Other Names: Avastin; Drug: NKT2152; NKT2152 will be administered by mouth.
Experimental: Stage 1: Atezolizumab + Bevacizumab + IO-108 1200 mg Q3W; Participants will receive atezolizumab plus bevacizumab plus IO-108 until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.	Drug: Atezolizumab; Atezolizumab will be administered at a dose of 1200 mg by IV on Day 1 of each 21 day cycle.; Other Names: Tecentriq; Drug: Bevacizumab 15 mg/kg; Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.; Other Names: Avastin; Drug: IO-108 1200 mg; IO-108 will be administered at a dose 1200 mg by IV infusion on Day 1 of each 21 day cycle.
Experimental: Stage 1: Atezolizumab + Bevacizumab+ IO-108 1800 mg Q3W; Participants will receive atezolizumab plus bevacizumab plus IO-108 until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic andbiochemical data, local biopsy results (if available), and clinical status	Drug: IO-108 1800 mg; IO-108 will be administered at a dose 1800 mg by IV infusion on Day 1 of each 21 day cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR, defined as the proportion of participants with a complete response or partial response on two consecutive occasions >=4 weeks apart during Stage 1, as determined by the investigator according to RECIST v1.1.	From randomization until disease progression or loss of clinical benefit (up to approximately 7-9 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS at Specific Timepoints	OS at a specific timepoint, such as Month 6	Randomization to a specific timepoint, such as Month 6
Progression Free Survival (PFS)	PFS after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first) in Stage 1, as determined by the investigator according to RECIST v1.1.	Randomization to first occurrence of disease progression or death from any cause in Stage 1 (up to approximately 7-9 years)
Overall Survival (OS)	OS after randomization, defined as the time from randomization to death from any cause.	Randomization to death from any cause (up to approximately 7-9 years)
Duration of Response (DOR)	DOR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first) in Stage 1, as determined by the investigator according to RECIST v1.1.	First occurrence of a documented objective response to disease progression or death (up to approximately 7-9 years)
Disease Control	Disease control, defined as stable disease for >=12 weeks or a complete or partial response, as determined by the investigator according to RECIST v1.1.	Randomization to end of study (approximately 7-9 years)
Percentage of Participants With Adverse Events During Stage 1		Baseline through the end of the study (approximately 7-9 years)
Percentage of Participants With Adverse Events During Stage 2		Baseline through the end of the study (approximately 7-9 years)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Collaborators: Tempest Therapeutics; Adagene Inc; Immune-Onc Therapeutics; NiKang Therapeutics, Inc.
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): November 2, 2020
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): August 31, 2026

Study Registration Dates

• First Submitted: August 21, 2020
• First Submitted That Met QC Criteria: August 21, 2020
• First Posted (Actual): August 24, 2020

Study Record Updates

• Last Update Posted (Estimated): November 13, 2024
• Last Update Submitted That Met QC Criteria: November 12, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Liver Neoplasms; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab; Atezolizumab
• Other Study ID Numbers: GO42216

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
• product manufactured in and exported from the U.S.: No