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

Hepatocellular Carcinoma Clinical Trial

— MONTBLANC  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05844046
• Other study ID #: MONTBLANC
• Secondary ID: 2022-001201-48
• Status: Recruiting
• Phase: Phase 2
• Start date: April 6, 2023
• Est. completion date: December 31, 2026

Study information

• Verified date: February 2024
• Source: Ludwig-Maximilians - University of Munich
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 83
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma

Intervention

Biological:
• 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

Locations

Country	Name	City	State
Germany	Hospital of the University of Munich	Munich
Germany	Klinikum Rechts der Isar of the Technical University Munich	Munich
Germany	Würzburg University Hospital	Würzburg

Sponsors (1)

Lead Sponsor	Collaborator
Enrico De Toni

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	DOR	Duration of response	24 months
Other	DCR	Disease control rate	24 months
Other	OS-18m	Proportion of patients alive at 18 months	18 months
Other	OS-24m	Proportion of patients alive at 24 months	24 months
Other	PFS-E	Progression-free survival from escalation treatment	24 months
Other	PFS on next treatment	PFS on next treatment	24 months
Other	TTFS	time to failure of strategy	24 months
Other	QOL	European Organisation for Research and Treatment of Cancer (EORTC) 30-item core quality of life questionnaire (QLQ-C30)	24 months
Other	QOL	EORTC 18-item hepatocellular carcinoma quality of life questionnaire	24 months
Primary	ORR	overall response rate	24 months
Secondary	mOS	median overall survival	24 months
Secondary	PFS	Progression-free survival	24 months
Secondary	TTP	Time to progression	24 months
Secondary	ORR-BICR	Objective response rate acc. to BICR	24 months