A Study of Atezolizumab Plus Bevacizumab Versus Active Surveillance as Adjuvant Therapy in Patients With Hepatocellular Carcinoma at High Risk of Recurrence After Surgical Resection or Ablation

Overview

This study will evaluate the efficacy and safety of adjuvant therapy with atezolizumab plus bevacizumab compared with active surveillance in participants with completely resected or ablated hepatocellular carcinoma (HCC) who are at high risk for disease recurrence.

Full Title of Study: “A Phase III, Multicenter, Randomized, Open-Label Study of Atezolizumab (Anti-PD-L1 Antibody) Plus Bevacizumab Versus Active Surveillance as Adjuvant Therapy in Patients With Hepatocellular Carcinoma at High Risk of Recurrence After Surgical Resection or Ablation”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: September 30, 2023

Interventions

  • Drug: Atezolizumab
    • Atezolizumab 1200 mg will be administered by IV infusion on Day 1 of each 21-day cycle.
  • Drug: Bevacizumab
    • Bevacizumab will be administered by IV infusion at a dose of 15 mg/kg on Day 1 of each 21-day cycle.

Arms, Groups and Cohorts

  • Experimental: Arm A (atezolizumab plus bevacizumab)
    • Participants will receive Atezolizumab + Bevacizumab until disease recurrence or unacceptable toxicity.
  • No Intervention: Arm B (active surveillance)
    • Active surveillance of participants.

Clinical Trial Outcome Measures

Primary Measures

  • Recurrence-Free Survival (RFS), as Determined by IRF
    • Time Frame: Baseline up to approximately 39 months
    • RFS is defined as the time from randomization to the first documented occurrence of intrahepatic or extrahepatic HCC as determined by an IRF, or death from any cause (whichever occurs first).

Secondary Measures

  • Overall Survival (OS)
    • Time Frame: Baseline up to approximately 91 months
    • OS is defined as the time from randomization to death from any cause.
  • RFS as Determined by the Investigator
    • Time Frame: Baseline up to approximately 91 months
    • RFS is defined as the time from randomization to the first documented occurrence of intrahepatic or extrahepatic HCC as determined by an investigator, or death from any cause (whichever occurs first).
  • Time to Recurrence (TTR)
    • Time Frame: Baseline up to approximately 91 months
    • TTR defined as the time from randomization to first documented occurrence of intrahepatic or extrahepatic HCC, as determined by the investigator and by an IRF.
  • RFS Rate at 24 and 36 Months, as Assessed by the IRF
    • Time Frame: Randomization up to 24 months and up to 36 months
  • RFS Rate at 24 and 36 Months, as Assessed by the Investigator
    • Time Frame: Randomization up to 24 months and up to 36 months
  • OS Rate at 24 and 36 Months
    • Time Frame: Baseline to 24 and 36 months
    • OS rate defined as the proportion of patients who have not experienced death from any cause at 24 and 36 months after randomization.
  • Time to Extrahepatic Spread (EHS) or Macrovascular Invasion
    • Time Frame: Baseline up to approximately 91 months
    • Time to EHS or macrovascular invasion after randomization, defined as the time from randomization to the first appearance of EHS or macrovascular invasion, as determined by the investigator.
  • RFS in Pd-L1-High Subgroup
    • Time Frame: Baseline up to approximately 91 months
    • RFS after randomization as determined by the investigator and by an IRF, among patients in the PD-L1-high subgroup.
  • Percentage of Participants With Adverse Events
    • Time Frame: Baseline up to approximately 91 months
  • Serum Concentration of Atezolizumab
    • Time Frame: Prior to any drug administration on Day 1 of Cycles 1, 2, 3, 4, 8, 12, and 16 (each cycle is 21 days)
  • Number of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab
    • Time Frame: Prior to any drug administration on Day 1 of Cycles 1, 2, 3, 4, 8, 12, and 16 (each cycle is 21 days)

Participating in This Clinical Trial

Inclusion Criteria

  • Participants with a first diagnosis of HCC who have undergone either a curative resection or ablation (radiofrequency ablation [RFA] or microwave ablation [MVA] only) within 4-12 weeks prior to randomization – Documented diagnosis of HCC that has been completely resected or ablated (RFA or MVA only) – Absence of major macrovascular invasion (except Vp1/Vp2) and extrahepatic spread – Absence of extrahepatic spread as confirmed by CT or MRI scan of the chest, abdomen, pelvis, and head prior to and following curative procedure – Full recovery from surgical resection or ablation within 4 weeks prior to randomization – High risk for HCC recurrence after resection or ablation – For patients who received post-operative transarterial chemoembolization: full recovery from the procedure within 4 weeks prior to randomization – For patients with resected HCC, availability of a representative baseline tumor tissue sample – ECOG Performance Status of 0 or 1 – Child-Pugh Class A status – Adequate hematologic and end-organ function – For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods – For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm Exclusion Criteria:

  • Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC – Evidence of residual, recurrent, or metastatic disease at randomization – Clinically significant ascites – History of hepatic encephalopathy – Prior bleeding event due to untreated or incompletely treated esophageal and/or gastric varices within 6 months prior to randomization – Have received more than 1 cycle of adjuvant TACE following surgical resection – Active or history of autoimmune disease or immune deficiency – History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan – Significant cardiovascular disease within 3 months prior to Day 1 of Cycle 1, unstable arrhythmia, or unstable angina – History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death – Active tuberculosis – Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications – Pregnant or breastfeeding, or intending to become pregnant during the study or within 5 months after the final dose of atezolizumab or within 6 months after the final dose of bevacizumab. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to Day 1 of Cycle 1. – Co-infection with HBV and HCV – Co-infection with HBV and hepatitis D viral infection – Clinical significant uncontrolled or symptomatic hypercalcemia – Any treatment for HCC prior to resection or ablation, including systemic therapy and locoregional therapy such as TACE – Treatment with systemic immunostimulatory or immunosuppressive agents – Inadequately controlled arterial hypertension – History of hypertensive crisis or hypertensive encephalopathy – Significant vascular disease – Evidence of bleeding diathesis or significant coagulopathy – Current or recent use of aspirin or full-dose oral or parenteral anticoagulants – Core biopsy within 3 days of Day 1 of Cycle 1 – History of GI fistula, GI perforation, or intra-abdominal abscess – Serious non-healing or dehiscing wound – Major surgical procedure within four weeks – Chronic daily treatment with a non-steroidal anti-inflammatory drug

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Hoffmann-La Roche
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Clinical Trials, Study Director, Hoffmann-La Roche

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