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

Inclusion Criteria:

Stage 1

1. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 7 days prior to randomization
2. 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
3. Liver Diseases criteria in cirrhotic patients
4. Child-Pugh class A within 7 days prior to randomization
5. Disease that is not amenable to curative surgical and/or locoregional therapies
6. No prior systemic treatment for HCC
7. Life expectancy >= 3 months
8. 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

1. Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1
2. Adequate hematologic and end-organ function within 7 days prior to initiation of study treatment
3. Documented virology status of hepatitis, as confirmed by screening tests for hepatitis B virus - (HBV) and hepatitis C virus (HCV)
4. Negative HIV test at screening
5. 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

1. ECOG Performance Status of 0, 1, or 2
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
3. Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage 1 (if deemed clinically feasible)

Exclusion Criteria:

Stage 1

1. Prior treatment with CD137 agonists or immune checkpoint inhibitors
2. Treatment with investigational therapy within 28 days prior to initiation of study
3. Treatment with locoregional therapy to liver within 28 days prior to initiation of study, or non-recovery from side effects of any such procedure
4. Untreated or incompletely treated esophageal and/or gastric varices with bleeding or at high risk for bleeding
5. Prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study
6. AEs from prior anti-cancer therapy that have not resolved to Grade <= 1 or better, with the exception of alopecia of any grade
7. Inadequately controlled hypertension
8. History of hypertensive crisis or hypertensive encephalopathy
9. Significant vascular disease
10. History of hemoptysis within 1 month prior to initiation of study
11. Evidence of bleeding diathesis or significant coagulopathy
12. Current or recent use of asprin (>325 mg/day) or treatment with clopidogrel, dipyramidole, ticlopidine, or cilostazol
13. Current or recent use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose
14. Core biopsy or other minor surgical procedure within 3 days prior to initiation of study
15. History of abdominal or tracheoesophageal fistula, GI perforation, or intra-abdominal abscess, intestinal obstruction and/or clinical signs/symptoms of GI obstruction
16. Evidence of abdominal free air not explained by paracentesis or recent surgery
17. Serious, non-healing/dehiscing wound, active ulcer, or untreated bone fracture
18. Grade >=2 proteinuria
19. Metastatic disease involving major airways/blood vessels, or centrally located mediastinal tumor masses of large volume
20. History of intra-abdominal inflammatory process
21. 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
22. 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
23. Chronic daily treatment with NSAID
24. Eligible only for control arm

Stage 1 and 2

1. Fibrolamellar or sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
2. History of hepatic encephalopathy
3. Moderate or severe ascites
4. HBV and HCV coinfection
5. Symptomatic, untreated, or actively progressing CNS metastases
6. History of leptomeningeal disease
7. Uncontrolled tumor-related pain
8. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
9. Uncontrolled or symptomatic hypercalcemia
10. Active or history of autoimmune disease or immune deficiency
11. History of IPF, organizing pneumonia, drug-induced or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
12. Active TB
13. Significant CV disease within 3 months prior to initiation of study, unstable arrhythmia, or unstable angina
14. Major surgery, other than for diagnosis, within 4 weeks prior to initiation of study, or anticipated major surgery during study
15. History of malignancy other than HCC within 5 years prior to screening
16. Severe infection within 4 weeks prior to initiation of study
17. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study
18. Prior allogeneic stem cell or solid organ transplantation
19. 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
20. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
21. 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
22. Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study
23. Patients entering Stage 2: immunotherapy-related adverse events that have not resolved to Grade 1 or better or to baseline at time of consent