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.
Phase:
Phase 2
Details
Lead Sponsor:
University Health Network, Toronto
Collaborators:
Clinica Universidad de Navarra, Universidad de Navarra University of Milan