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

Official title

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)

Overview

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.

Interventions

• Drug Atezolizumab
  Atezolizumab will be administered at a dose of 1200 mg by IV 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.
• Drug Tiragolumab
  Tiragolumab will be administered at a dose of 600 mg by IV infusion on Day 1 of each 21 day cycle.
• Drug Tocilizumab
  Tocilizumab will be administered at a dose of 8 mg/kg by IV infusion on Day 1 of each 21 day cycle.
• 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 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.
• 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.
• Drug Tobemstomig 1200 mg
  Tobemstomig will be administered at a dose of 1200 mg every 3 weeks.
• 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).

Primary outcome measures

• Objective Response Rate (ORR) [Time frame: From randomization until disease progression or loss of clinical benefit (up to approximately 7-9 years)]

Secondary outcome measures (7)

• Progression Free Survival (PFS) [Time frame: Randomization to first occurrence of disease progression or death from any cause in Stage 1 (up to approximately 7-9 years)]
• Overall Survival (OS) [Time frame: Randomization to death from any cause (up to approximately 7-9 years)]
• OS at Specific Timepoints [Time frame: Randomization to a specific timepoint, such as Month 6]
• Duration of Response (DOR) [Time frame: First occurrence of a documented objective response to disease progression or death (up to approximately 7-9 years)]
• Disease Control [Time frame: Randomization to end of study (approximately 7-9 years)]
• Percentage of Participants With Adverse Events During Stage 1 [Time frame: Baseline through the end of the study (approximately 7-9 years)]
• Percentage of Participants With Adverse Events During Stage 2 [Time frame: Baseline through the end of the study (approximately 7-9 years)]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 16 centers

• UC Irvine Medical Center — Costa Mesa
• City of Hope — Duarte
• UC Irvine Medical Center — Orange
• University of California San Diego Medical Center — San Diego
• University of California San Francisco Cancer Center — San Francisco
• UCLA Center for East — Santa Monica
• Cherry Creek Medical Center — Aurora
• University of Colorado Hospital - Anschutz Cancer Pavilion — Aurora
• … and 8 more centers

France · 4 centers

• Centre Georges Francois Leclerc — Dijon
• CHU Hôpitaux de Marseille — Marseille
• Centre Eugène Marquis — Rennes
• Gustave Roussy — Villejuif

Israel · 4 centers

• Rambam Medical Center — Haifa
• Hadassah University Medical Center — Jerusalem
• Davidof Center - Rabin Medical Center — Petah Tikva
• Sourasky Medical Centre — Tel Aviv

South Korea · 4 centers

• CHA Bundang Medical Center — Gyeonggi-do
• Seoul National University Hospital — Seoul
• Samsung Medical Center — Seoul
• Asan Medical Center — Seoul

China · 2 centers

• Beijing Cancer Hospital — Beijing
• Zhongshan Hospital Fudan University — Shanghai

Taiwan · 2 centers

• National Cheng Kung University Hospital — Tainan
• National Taiwan University Hospital — Taipei

New Zealand · 1 center

• Auckland City Hospital — Auckland

Publications

• Finn RS, Ryoo BY, Hsu CH, Li D, Burgoyne AM, Cotter C, Badhrinarayanan S, Wang Y, Yin A, Edubilli TR, Mahrus S, Secrest MH, Shemesh CS, Yu N, Hack SP, Cha E, Gane E. Tiragolumab in combination with atezolizumab and bevacizumab in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (MORPHEUS-Liver): a randomised, open-label, phase 1b-2, study. Lancet Oncol. 2025 Feb; PMID 39855251

Identifiers

NCT: NCT04524871 · GO42216

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗