Overview

This is a randomized, open-label, multi-center, international, Phase II study to assess the efficacy and safety of sequential or up-front triple treatment with durvalumab, tremelimumab and bevacizumab for non-resectable hepatocellular carcinoma.

Patients will be randomized in a 1:1 ratio to one of the following arms:

Arm A: initial treatment with durvalumab plus tremelimumab followed by treatment escalation with the addition of bevacizumab upon radiological progression or in the absence of objective response

Arm B: up-front treatment with durvalumab, tremelimumab and bevacizumab

Patients will be stratified according to macrovascular invasion and etiology of liver disease (viral etiologies versus others).

Eligibility

KEY INCLUSION CRITERIA

Age ≥18 years at the time of study entry

Confirmed HCC based on histopathological findings from tumor tissues.

Must not have received prior systemic therapy for HCC.

        Not eligible for locoregional therapy for unresectable HCC. For patients who progressed
        after locoregional therapy for HCC, locoregional therapy must have been completed ≥28 days
        prior to the baseline scan for the current study.
        Barcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for locoregional
        therapy) or stage C
        Child-Pugh Score class A
        ECOG performance status of 0 or 1 at enrollment
        At least 1 measurable lesion, not previously irradiated, that can be accurately measured at
        baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have a short
        axis ≥15 mm) with computerized tomography (CT) or magnetic resonance imaging (MRI), and
        that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines. A lesion
        which progressed after previous ablation or TACE could be measurable if it meets these
        criteria.
        Adequate organ and marrow function
        KEY EXCLUSION CRITERIA
        Previous study drug(s) assignment in the present study.
        Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
        radiation within 28 days of the first dose of study drug(s).
        Major surgical procedure or significant traumatic injury within 28 days prior to the first
        dose of study drug(s), abdominal surgery, abdominal interventions, or significant abdominal
        traumatic injury within 60 days prior to randomization
        History of allogeneic organ transplantation (eg, liver transplant).
        History of hepatic encephalopathy within past 12 months or requirement for medications to
        prevent or control encephalopathy
        Clinically meaningful ascites
        Patients with main portal vein thrombosis (i.e., thrombosis in the main trunk of the portal
        vein, with or without blood flow) on baseline imaging.
        Patient currently exhibits symptomatic or uncontrolled hypertension
        Active or prior documented autoimmune or inflammatory disorders, diverticulitis. Patients
        without active disease in the last 5 years are excluded unless discussed with the Study
        Physician and considered appropriate for study participation.
        Patients co-infected with HBV and HCV, or co-infected with HBV and hepatitis D virus (HDV).
        History of another primary malignancy except for the exceptions defined by the study
        protocol.
        Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
        calculated from 3 ECGs (within 15 minutes at 5 minutes apart).
        Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
        History of active primary immunodeficiency.
        Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug(s).
        Note: Patients, if enrolled, should not receive live vaccine while receiving study drug(s)
        and up to 30 days after the last dose of study drug(s).
        Major gastrointestinal bleeding within 4 weeks prior to randomization.
        Patients with untreated or incompletely treated varices with bleeding or high-risk for
        bleeding. Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of
        varices (small to large) must be assessed and treated per local standard of care prior to
        enrollment. Patients who have undergone an EGD within 6 months prior to randomization do
        not need to repeat the procedure. Those who have received banding and/or sclerotherapy and
        with no bleeding event within the prior 6 months are eligible provided that a re-endoscopy
        is performed and that varices remained obliterated, minimal or Grade I
        Significant vascular disease including aortic aneurysm requiring surgical repair or
        peripheral arterial thrombosis with 6 months prior to randomization
        History of abdominal or tracheoesophageal fistula or gastrointestinal perforation, or
        intra-abdominal abscess within 6 months prior to randomization.
        Evidence of bleeding diathesis or significant coagulopathy
        Severe, nonhealing or dehisced wound, active ulcer, or untreated bone fracture
        Current or recent (within 10 days of randomization) use of acetylsalicyclic acid (=> 325
        mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol
        Current or recent (within 10 days prior to randomization) use of fulldose oral or
        parenteral anticoagulants or thrombolytic agents for therapeutic purpose. Prophylactic use
        of low molecularweight heparin is allowed.
        Female patients who are pregnant or breastfeeding, or male or female patients of
        reproductive potential who are not willing to employ effective birth control from screening
        to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of
        durvalumab plus tremelimumab combination therapy or bevacizumab therapy
        Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical
        study regardless of treatment arm assignment.