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

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 7 daysprior to randomization

• Locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC)with diagnosis confirmed by histology/cytology or clinically by American Associationfor 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 determinationof 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 ofstudy treatment

• Documented virology status of hepatitis, as confirmed by screening tests forhepatitis B virus - (HBV) and hepatitis C virus (HCV)

• Negative HIV test at screening

• For women of childbearing potential: agreement to remain abstinent or usecontraception and for men: agreement to remain abstinent or use contraception, andagreement 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 experiencingunacceptable toxicity not related to atezolizumab or RO7247669 or loss of clinicalbenefit as determined by the investigator while receiving Stage 1 treatment

• Availability of a tumor specimen from a biopsy performed upon discontinuation ofStage 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 ifGilbert'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 orinhibitors 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 ofstudy, or non-recovery from side effects of any such procedure

• Untreated or incompletely treated esophageal and/or gastric varices with bleeding orat high risk for bleeding

• Prior bleeding event due to esophageal and/or gastric varices within 6 months priorto 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 thrombolyticagents for therapeutic (as opposed to prophylactic) purpose

• Core biopsy or other minor surgical procedure within 3 days prior to initiation ofstudy

• History of abdominal or tracheoesophageal fistula, GI perforation, orintra-abdominal abscess, intestinal obstruction and/or clinical signs/symptoms of GIobstruction

• 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 locatedmediastinal 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 toinitiation of study with the exception of palliative radiotherapy to bone lesionswithin 7 days prior to initiation of study

• Major surgery, open biopsy, or significant traumatic injury within 28 days prior toinitiation of study; or abdominal surgery, abdominal interventions or significantabdominal traumatic injury within 60 days prior to initiation of study; oranticipation of need for major surgery during study or non-recovery from sideeffects 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 recurrentdrainage procedures

• Uncontrolled or symptomatic hypercalcemia

• Active or history of autoimmune disease or immune deficiency

• History of IPF, organizing pneumonia, drug-induced or idiopathic pneumonitis, orevidence of active pneumonitis on screening chest CT scan

• Active TB

• Significant CV disease within 3 months prior to initiation of study, unstablearrhythmia, or unstable angina

• Major surgery, other than for diagnosis, within 4 weeks prior to initiation ofstudy, 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 initiationof study

• Prior allogeneic stem cell or solid organ transplantation

• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation ofstudy, or anticipation of need for such a vaccine during atezolizumab treatment orwithin 5 months after the final dose of atezolizumab

• History of severe allergic anaphylactic reactions to chimeric or humanizedantibodies or fusion proteins

• Known allergy or hypersensitivity to any of the study drugs or any of theirexcipients

• Treatment with systemic immunostimulatory, immunosuppressive agents within 4 weeksor 5 drug-elimination half-lives (whichever is longer) prior to initiation of study

• Treatment with systemic immunosuppressive medication within 2 weeks prior toinitiation of study

• Grade >= 3 hemorrhage or bleeding event within 8 weeks prior to initiation of studytreatment

• Patients entering Stage 2: immunotherapy-related adverse events that have notresolved to Grade 1 or better or to baseline at time of consent