|
|
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) |
|
|
|
|
|
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
|
|
|
|