Durvalumab and Tremelimumab in Resectable HCC

Summary

Hepatocellular Carcinoma (HCC) is the third most common cause of death from cancer world wide and the incidence is rising globally. Despite surgical resection in appropriate patients, many patients recur.

The results of the IMbrave150 study have established PD-L1 inhibition in combination with VEGF inhibition as a new standard of care highlighting the role of immune checkpoint inhibition in advanced HCC. In addition, the combination of Tremelimumab and Durvalumab has demonstrated efficacy in advanced HCC; the HIMALAYA trial has now completed accrual in treatment naïve patients with advanced HCC. Furthermore the earlier use of immune checkpoint inhibitors in this disease are being explored with adjuvant combination strategies, including the EMERALD-2 trial (NCT03847428). Neoadjuvant treatment in HCC allows for delivery of treatment pre surgery and may enhance pathological responses and improve outcomes. The delivery of combination CTLA-4 and PD-L1 inhibition has demonstrated efficacy in other tumour types in the neoadjuvant setting where the impact on the tumour microenvironment has also been evaluated. The safety and feasibility of Durvalumab and Tremelimumab in resectable HCC has yet to be established.

Hypotheses Pre-operative (pre-op) Durvalumab and Tremelimumab treatment is safe and feasible in pre surgical setting for upfront resectable HCC The combination of Durvalumab and Tremelimumab pre-op will result in changes in immune and molecular characteristics within the tumour microenvironment.

Overall Study Design This is a phase II, open-label multi-centre study to assess safety of Durvalumab and Tremelimumab treatment in pre-op setting for upfront resectable HCC, followed by adjuvant Durvalumab.

28 patients are expected to enrol at three sites. Patients will receive pre-op: 1 dose Tremelimumab (300mg) (T300) with Durvalumab (1500mg) at cycle 1 and 1 further cycle of Durvalumab (1500mg) only. Post-surgical resection, adjuvant therapy will consist of Durvalumab Q4W for up to a maximum of 12 months in total or 13 cycles of Durvalumab (11 cycles post op).

All participants will be treated until progressive disease or unacceptable toxicity or withdrawal of consent or another discontinuation criterion is met. All participants will be followed for survival until the end of study.

No dose reductions of Tremelimumab and Durvalumab will be allowed. Statistics The primary objective of this study is to assess safety of pre-op treatment with Durvalumab and Tremelimumab.

For safety, with the null proportion of patients who discontinue treatment due to AEs, imAEs or SAE is 30% versus the alternative proportion is 10% or less than 10%, a sample size of 28 provides 80% power to detect the proportion difference with a two-sided alpha level of 0.1.

The sample size estimate is based on the two-sided exact test for binomial proportion considering Binomial Enumeration method.

Conditions

• Hepatocellular Carcinoma

Interventions

DRUG

Tremelimumab

Pre-operatively Tremelimumab will be administered first for 1 hour; the Durvalumab infusion (1hr) will start approximately 1 hour (maximum 2 hours) after the end of the Tremelimumab infusion. Post-operatively patients will receive Durvalumab Q4W to complete up to 12 months of treatment or a maximum of 11 cycles of adjuvant Durvalumab

Sponsors & Collaborators

• Clinica Universidad de Navarra, Universidad de Navarra

  collaborator OTHER

• University of Milan

  collaborator OTHER

• University Health Network, Toronto

  lead OTHER

Principal Investigators

• Gonzalo Sapisochin, MD · Univeristy Health Network

• Grainne O'Kane, MD · Univeristy Health Network

• Jennifer Knox, MD · Univeristy Health Network

• Bruno Sangro, MD · Clinica Universidad de Navarra

• Vincenzo Mazaferro, MD · University of Milan

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2023-10-26

Primary Completion

2025-11-30

Completion

2026-11-30

Countries

• Canada
• Italy
• Spain

Study Locations