Sequential or Up-front Triple Treatment With Durvalumab, Tremelimumab and Bevacizumab for Non-resectable Hepatocellular Carcinoma (HCC) Patients

NCT ID: NCT05844046

Last Updated: 2024-07-16

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 83 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-04-06
• Study Completion Date: 2026-12-31

Brief Summary

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).

Conditions

Hepatocellular Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A

Durvalumab (1500 mg q4w) plus tremelimumab (300 mg x 1) followed by addition of bevacizumab (15mg/kg) upon detection of radiological progression or in the absence of objective response after the second staging.

Group Type: EXPERIMENTAL

durvalumab, tremelimumab, bevacizumab

Intervention Type: BIOLOGICAL

durvalumab, tremelimumab and bevacizumab will be administered in the respective arms either as up-front triple treatment or as combined treatment with durvalumab and tremelimumab followed by the addition of bevacizumab

Arm B

Durvalumab plus tremelimumab followed by maintenance treatment with durvalumab and bevacizumab.

Group Type: EXPERIMENTAL

durvalumab, tremelimumab, bevacizumab

Intervention Type: BIOLOGICAL

durvalumab, tremelimumab and bevacizumab will be administered in the respective arms either as up-front triple treatment or as combined treatment with durvalumab and tremelimumab followed by the addition of bevacizumab

Interventions

durvalumab, tremelimumab, bevacizumab

durvalumab, tremelimumab and bevacizumab will be administered in the respective arms either as up-front triple treatment or as combined treatment with durvalumab and tremelimumab followed by the addition of bevacizumab

Intervention Type: BIOLOGICAL

Eligibility Criteria

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

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Enrico De Toni

OTHER

Sponsor Role: lead

Responsible Party

Enrico De Toni

Prof. Dr. Enrico De Toni

Responsibility Role: SPONSOR_INVESTIGATOR

Locations

Hospital of the University of Munich

Munich, , Germany

Site Status: RECRUITING

Klinikum Rechts der Isar of the Technical University Munich

Munich, , Germany

Site Status: RECRUITING

Würzburg University Hospital

Würzburg, , Germany

Site Status: RECRUITING

Countries

Germany

Facility Contacts

Enrico N De Toni, MD

Role: primary

enrico.detoni@med.uni-muenchen.de

+49 (0)894400-0

Ursula Ehmer, MD

Role: primary

ursula.ehmer@mri.tum.de

(0 89) 41 40 - 49 82

Role: backup

ursula.ehmer@mri.tum.de

Florian Reiter, MD

Role: primary

Reiter_F@ukw.de

+49 931 201-0

Role: backup

Reiter_F@ukw.de

+49 931 201-0

References

De Toni EN, Mayerle J, Oehrle B, Seidensticker M, Rimassa L, Philipp A, Roessler D, Khaled NB. Letter: Presence of progression or absence of response? Alternative trial designs for immunotherapy of advanced hepatocellular carcinoma. Aliment Pharmacol Ther. 2024 Jun;59(11):1462-1464. doi: 10.1111/apt.17985. Epub 2024 Apr 21. No abstract available.

Reference Type: BACKGROUND

PMID: 38643505 (View on PubMed)

Other Identifiers

2022-001201-48

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MONTBLANC

Identifier Type: -

Identifier Source: org_study_id