Purpose

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.

Condition

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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

Study Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Active Comparator
Stage 1: Atezolizumab + Bevacizumab
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.
  • Drug: Atezolizumab
    Atezolizumab will be administered at a dose of 1200 mg by IV on Day 1 of each 21 day cycle.
    Other names:
    • Tecentriq
  • Drug: Bevacizumab
    Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.
    Other names:
    • Avastin
  • 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.
    Other names:
    • Actemra
  • Drug: SAR439459
    SAR439459 will be administered at a dose of 22.5 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.
Experimental
Stage 1: Atezolizumab + Bevacizumab + Tiragolumab
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.
  • Drug: Atezolizumab
    Atezolizumab will be administered at a dose of 1200 mg by IV on Day 1 of each 21 day cycle.
    Other names:
    • Tecentriq
  • Drug: Bevacizumab
    Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.
    Other names:
    • Avastin
  • Drug: Tiragolumab
    Tiragolumab will be administered at a dose of 600 mg by IV infusion on Day 1 of each 21 day cycle.
Experimental
Stage 1: Atezolizumab + Bevacizumab + Tocilizumab
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.
  • Drug: Atezolizumab
    Atezolizumab will be administered at a dose of 1200 mg by IV on Day 1 of each 21 day cycle.
    Other names:
    • Tecentriq
  • Drug: Bevacizumab
    Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.
    Other names:
    • Avastin
  • Drug: Tocilizumab
    Tocilizumab will be administered at a dose of 8 mg/kg by IV infusion on Day 1 of each 21 day cycle.
    Other names:
    • Actemra
Experimental
Stage 1: Atezolizumab + Bevacizumab + SAR439459
Participants will receive atezolizumab plus bevacizumab plus SAR439459 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.
  • Drug: Atezolizumab
    Atezolizumab will be administered at a dose of 1200 mg by IV on Day 1 of each 21 day cycle.
    Other names:
    • Tecentriq
  • Drug: Bevacizumab
    Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.
    Other names:
    • Avastin
  • Drug: SAR439459
    SAR439459 will be administered at a dose of 22.5 mg/kg by IV infusion on Day 1 of each 21 day cycle.
Experimental
Stage 1: Atezolizumab + Bevacizumab + TPST-1120
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.
  • Drug: Atezolizumab
    Atezolizumab will be administered at a dose of 1200 mg by IV on Day 1 of each 21 day cycle.
    Other names:
    • Tecentriq
  • Drug: Bevacizumab
    Bevacizumab will be administered at a dose of 15 mg/kg by IV infusion on Day 1 of each 21 day cycle.
    Other names:
    • Avastin
  • 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.
Experimental
Stage 1: RO7247669 + Bevacizumab
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.
  • Drug: RO7247669
    RO7247669 will be administered at a dose of 2100 mg by IV infusion on Days 1 and 15 of each 28 day cycle.
  • Drug: Bevacizumab
    Bevacizumab will be administered at a dose of 10 mg/kg by IV infusion on Days 1 and 15 of each 28 day cycle.
    Other names:
    • Avastin

Recruiting Locations

Georgetown University Medical Center
Washington, District of Columbia 20007

More Details

Status
Recruiting
Sponsor
Hoffmann-La Roche

Study Contact

Reference Study ID Number: GO42216 www.roche.com/about_roche/roche_worldwide.htm
888-662-6728 (U.S. and Canada)
global.rochegenentechtrials@roche.com

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.