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

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

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.

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.

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.

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.

Participants will receive RO7247669 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.

Participants will receive RO7247669 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.

Participants will receive RO7247669 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.

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.

RO7247669 will be administered at a dose of 2100 mg by IV infusion on Days 1 and 15 of each 28 day cycle.

Bevacizumab will be administered at a dose of 10 mg/kg by IV infusion on Days 1 and 15 of each 28 day cycle.

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).

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 5-7 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.

Randomization to first occurrence of disease progression or death from any cause in Stage 1 (up to approximately 5-7 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.

First occurrence of a documented objective response to disease progression or death (up to approximately 5-7 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.

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) Exclusion Criteria: Stage 1 Prior treatment with CD137 agonists or immune checkpoint inhibitors 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 asprin (>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 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 Patients entering Stage 2: immunotherapy-related adverse events that have not resolved to Grade 1 or better or to baseline at time of consent

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).