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

Sponsor

Enrico De Toni (Other)

Overall Status

Recruiting

CT.gov ID

NCT05844046

Collaborator

(none)

Enrollment

Locations

Arms

44.8

Anticipated Duration (Months)

27.7

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma	Biological: durvalumab, tremelimumab, bevacizumab	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

83 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Apr 6, 2023

Anticipated Primary Completion Date :

Dec 31, 2026

Anticipated Study Completion Date :

Dec 31, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	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
Experimental: Arm B Durvalumab plus tremelimumab followed by maintenance treatment with durvalumab and bevacizumab.	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

Arm

Intervention/Treatment

Experimental: 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.

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

Experimental: Arm B

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

Biological: durvalumab, tremelimumab, bevacizumab

Outcome Measures

Primary Outcome Measures

ORR [24 months]
overall response rate

Secondary Outcome Measures

mOS [24 months]
median overall survival
PFS [24 months]
Progression-free survival
TTP [24 months]
Time to progression
ORR-BICR [24 months]
Objective response rate acc. to BICR

Other Outcome Measures

DOR [24 months]
Duration of response
DCR [24 months]
Disease control rate
OS-18m [18 months]
Proportion of patients alive at 18 months
OS-24m [24 months]
Proportion of patients alive at 24 months
PFS-E [24 months]
Progression-free survival from escalation treatment
PFS on next treatment [24 months]
PFS on next treatment
TTFS [24 months]
time to failure of strategy
QOL [24 months]
European Organisation for Research and Treatment of Cancer (EORTC) 30-item core quality of life questionnaire (QLQ-C30)
QOL [24 months]
EORTC 18-item hepatocellular carcinoma quality of life questionnaire

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Hospital of the University of Munich	Munich	Germany	81377
2	Klinikum Rechts der Isar of the Technical University Munich	Munich	Germany	81675
3	Würzburg University Hospital	Würzburg	Germany