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

Phase 1

Recruiting

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

• Registration Number: NCT04524871
• Lead Sponsor: Hoffmann-La Roche

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-08-21
• Study First Submitted QC: 2020-08-21
• Study First Posted: 2020-08-24
• Study Start: 2020-11-02
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-12
• Last Update Posted: 2024-12-13
• Primary Completion: 2026-12-31
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 518

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)

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Stage 1: Atezolizumab + Bevacizumab + ADG126	Bevacizumab 15 mg/kg	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.
Stage 1: Atezolizumab + Bevacizumab	Atezolizumab	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.
Stage 1: Atezolizumab + Bevacizumab	Bevacizumab 15 mg/kg	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.
Stage 1: Atezolizumab + Bevacizumab + Tiragolumab	Bevacizumab 15 mg/kg	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.
Stage 1: Atezolizumab + Bevacizumab + Tiragolumab	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.
Stage 1: Atezolizumab + Bevacizumab + Tocilizumab	Atezolizumab	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.
Stage 1: Atezolizumab + Bevacizumab + Tocilizumab	Bevacizumab 15 mg/kg	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.
Stage 1: Atezolizumab + Bevacizumab + Tocilizumab	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.
Stage 1: Atezolizumab + Bevacizumab + TPST-1120	Atezolizumab	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.
Stage 1: Atezolizumab + Bevacizumab + TPST-1120	Bevacizumab 15 mg/kg	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.
Stage 1: Atezolizumab + Bevacizumab + TPST-1120	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.
Stage 1: Tobemstomig 2100 mg Q2W + Bevacizumab	Bevacizumab 15 mg/kg	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.
Stage 1: Tobemstomig 2100 mg Q2W + Bevacizumab	Tobemstomig 2100 mg	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.
Stage 1: Tobemstomig 2100 mg Q2W + Bevacizumab	Bevacizumab 10 mg/kg	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.
Stage 1: Tobemstomig 600 mg Q3W + Bevacizumab	Bevacizumab 15 mg/kg	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.
Stage 1: Tobemstomig 600 mg Q3W + Bevacizumab	Tobemstomig 600 mg	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.
Stage 1: Tobemstomig 1200 mg Q3W + Bevacizumab	Bevacizumab 15 mg/kg	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.
Stage 1: Atezolizumab + Bevacizumab + ADG126	Atezolizumab	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.
Stage 1: Atezolizumab + Bevacizumab + ADG126	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.
Stage 1: Atezolizumab + Bevacizumab + IO-108 1200 mg Q3W	Bevacizumab 15 mg/kg	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.
Stage 1: Atezolizumab + Bevacizumab + IO-108 1200 mg Q3W	IO-108 1200 mg	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.
Stage 1: Atezolizumab + Bevacizumab + NKT2152	Atezolizumab	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.
Stage 1: Atezolizumab + Bevacizumab + NKT2152	Bevacizumab 15 mg/kg	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.
Stage 1: Atezolizumab + Bevacizumab + NKT2152	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.
Stage 1: Atezolizumab + Bevacizumab+ IO-108 1800 mg Q3W	IO-108 1800 mg	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
Stage 1: Tobemstomig 1200 mg Q3W + Bevacizumab	Tobemstomig 1200 mg	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.
Stage 1: Atezolizumab + Bevacizumab + Tiragolumab	Atezolizumab	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.
Stage 1: Atezolizumab + Bevacizumab + IO-108 1200 mg Q3W	Atezolizumab	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.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	From randomization until disease progression or loss of clinical benefit (up to approximately 7-9 years)	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.

Secondary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	Randomization to first occurrence of disease progression or death from any cause in Stage 1 (up to approximately 7-9 years)	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.
Overall Survival (OS)	Randomization to death from any cause (up to approximately 7-9 years)	OS after randomization, defined as the time from randomization to death from any cause.
OS at Specific Timepoints	Randomization to a specific timepoint, such as Month 6	OS at a specific timepoint, such as Month 6
Disease Control	Randomization to end of study (approximately 7-9 years)	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.
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)
Duration of Response (DOR)	First occurrence of a documented objective response to disease progression or death (up to approximately 7-9 years)	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.

Trial Locations

Locations (25)

UC Irvine Medical Center; 🇺🇸 Orange, California, United States

City of Hope; 🇺🇸 Duarte, California, United States

UCLA Center for East; West Medicine; 🇺🇸 Santa Monica, California, United States

Georgetown University Medical Center; 🇺🇸 Washington, District of Columbia, United States

Sarah Cannon Research Institute / Tennessee Oncology; 🇺🇸 Nashville, Tennessee, United States

Centre Georges Francois Leclerc; Oncologie 3; 🇫🇷 Dijon, France

Centre Eugène Marquis; 🇫🇷 Rennes, France

Gustave Roussy; 🇫🇷 Villejuif, France

Hadassah University Medical Center; 🇮🇱 Jerusalem, Israel

Rabin Medical Center-Beilinson Campus; Davidof Institute; 🇮🇱 Petach Tikva, Israel

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of

University of California San Diego; 🇺🇸 La Jolla, California, United States

Smilow Cancer Hospital at Yale New Haven; 🇺🇸 New Haven, Connecticut, United States

University of California San Francisco Cancer Center; Pharmacy; 🇺🇸 San Francisco, California, United States

The University of Texas Southwestern Medical Center at Dallas; 🇺🇸 Dallas, Texas, United States

Beijing Cancer Hospital; Pharmacy room; 🇨🇳 Beijing, China

Zhongshan Hospital Fudan University; 🇨🇳 Shanghai, China

Sourasky Medical Centre; 🇮🇱 Tel-Aviv, Israel

National Taiwan University Hospital; 🇨🇳 Taipei, Taiwan

CHU Hôpitaux de Marseille; 🇫🇷 Marseille CEDEX 05, France

Rambam Medical Center; 🇮🇱 Haifa, Israel

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of

Auckland City Hospital; 🇳🇿 Auckland, New Zealand

National Cheng Kung University Hospital; 🇨🇳 Tainan, Taiwan