Tremelimumab in combination with Durvalumab preoperatively, followed by adjuvant Durvalumab for Carcinoma, Hepatocellular

Phase-Based Progress Estimates
1
Effectiveness
2
Safety
University of Milan, Milan, Italy
Carcinoma, Hepatocellular+2 More
Tremelimumab - Drug
Eligibility
18+
All Sexes
What conditions do you have?
Select

Study 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.

Eligible Conditions

  • Carcinoma, Hepatocellular
  • Liver carcinoma

Treatment Effectiveness

Effectiveness Progress

1 of 3

Other trials for Carcinoma, Hepatocellular

Study Objectives

1 Primary · 4 Secondary · Reporting Duration: 4 years

2 year
Overall response rate (ORR)
Pathological response rate
Rates of R0 resection
4 years
Changes in immune markers in tissue collected
Durvalumab and Tremelimumab and blood biomarkers expression
Number of greater than grade 3 adverse events (AEs) or immune related adverse events that leads to treatment cessation
Number of patients who experience a surgical delay due to treatment related adverse events (TRAEs)
Overall survival
PD-L1 expression
Recurrence free survival
Taxonomic profiling of gut microbiome

Trial Safety

Safety Progress

2 of 3
This is further along than 68% of similar trials

Other trials for Carcinoma, Hepatocellular

Side Effects for

Arm A: BI 1361849 mRNA Vaccine + Durvalumab
35%Decreased appetite
35%Fatigue
30%Chills
30%Anaemia
26%Diarrhoea
26%Hyponatraemia
26%Vomiting
26%Dyspnoea
26%Pruritus
22%Pyrexia
22%Hypokalaemia
22%Dizziness
22%Aspartate aminotransferase increased
22%Nausea
22%Hypercalcaemia
17%Pneumonia
17%Amylase increased
17%Dry Skin
17%Malignant neoplasm progression
17%Constipation
17%Pain in extremity
17%Weight increased
13%Hypotension
13%Oedema peripheral
13%Influenza like illness
13%Contusion
13%Lipase increased
13%Fall
13%Lymphocyte count decreased
13%Back pain
13%Weight decreased
13%Rash
13%Hypoalbuminaemia
13%Headache
13%Cough
13%Productive cough
9%Hypernatraemia
9%Alanine aminotransferase increased
9%Arthralgia
9%Non-cardiac chest pain
9%Axillary pain
9%Musculoskeletal pain
9%Blood creatinine increased
9%Neutrophil count decreased
9%Nasal congestion
9%Hyperkalaemia
9%Myalgia
9%Dry mouth
9%Abdominal pain
9%Hypomagnesaemia
9%Neck pain
9%Blood alkaline phosphatase increased
9%Insomnia
9%Hyperglycaemia
9%Urinary tract infection
4%Seizure
4%Acute respiratory failure
4%Spine fracture
4%Peripheral sensory neuropathy
4%Anxiety
4%Wheezing
4%Chest pain
4%Sudden death
4%Chronic obstructive pulmonary disease
4%Injection site reaction
4%Myocarditis
4%Pain
4%Periorbital oedema
4%Hypothyroidism
4%Myocardial infarction
4%Dysphagia
4%Depression
4%Dermatitis acneiform
4%Stent placement
4%Dehydration
4%Pleural effusion
4%Embolism arterial
0%Urinary incontinence
0%Embolism
0%Bronchial obstruction
0%Pulmonary embolism
0%Type 1 diabetes mellitus
0%Pancreatitis
0%Rash maculo-papular
0%Hypoxia
0%Musculoskeletal chest pain
0%Respiratory failure
0%Postoperative thoracic procedure complication
0%Pneumonitis
0%Palpitations
0%Lung infection
0%Atrial flutter
0%Cerebrovascular accident
0%Vision blurred
0%Metastases to spine
0%Death
0%Encephalopathy
This histogram enumerates side effects from a completed 2021 Phase 1 & 2 trial (NCT03164772) in the Arm A: BI 1361849 mRNA Vaccine + Durvalumab ARM group. Side effects include: Decreased appetite with 35%, Fatigue with 35%, Chills with 30%, Anaemia with 30%, Diarrhoea with 26%.

Trial Design

1 Treatment Group

Tremelimumab in combination with Durvalumab preoperatively, followed by adjuvant...
1 of 1
Experimental Treatment

28 Total Participants · 1 Treatment Group

Primary Treatment: Tremelimumab in combination with Durvalumab preoperatively, followed by adjuvant Durvalumab · No Placebo Group · Phase 2

Tremelimumab in combination with Durvalumab preoperatively, followed by adjuvant Durvalumab
Drug
Experimental Group · 1 Intervention: Tremelimumab · Intervention Types: Drug
Treatment
First Studied
Drug Approval Stage
How many patients have taken this drug
Tremelimumab
2017
Completed Phase 2
~3370

Trial Logistics

Trial Timeline

Approximate Timeline
Screening: ~3 weeks
Treatment: Varies
Reporting: 4 years
Closest Location: University Health Network · Toronto, Canada
Photo of Toronto 1Photo of Toronto 2Photo of Toronto 3
2005First Recorded Clinical Trial
5 TrialsResearching Carcinoma, Hepatocellular
271 CompletedClinical Trials

Who is running the clinical trial?

University of MilanOTHER
219 Previous Clinical Trials
288,162 Total Patients Enrolled
11 Trials studying Carcinoma, Hepatocellular
10,994 Patients Enrolled for Carcinoma, Hepatocellular
Clinica Universidad de Navarra, Universidad de NavarraOTHER
110 Previous Clinical Trials
47,896 Total Patients Enrolled
4 Trials studying Carcinoma, Hepatocellular
98 Patients Enrolled for Carcinoma, Hepatocellular
University Health Network, TorontoLead Sponsor
1,351 Previous Clinical Trials
471,605 Total Patients Enrolled
14 Trials studying Carcinoma, Hepatocellular
608 Patients Enrolled for Carcinoma, Hepatocellular
Bruno Sangro, MDPrincipal InvestigatorClinica Universidad de Navarra
3 Previous Clinical Trials
775 Total Patients Enrolled
3 Trials studying Carcinoma, Hepatocellular
775 Patients Enrolled for Carcinoma, Hepatocellular
Grainne O'Kane, MDStudy ChairUniveristy Health Network
Vincenzo Mazaferro, MDPrincipal InvestigatorUniversity of Milan
Gonzalo Sapisochin, MDStudy ChairUniveristy Health Network
5 Previous Clinical Trials
200 Total Patients Enrolled
1 Trials studying Carcinoma, Hepatocellular
Jennifer Knox, MDPrincipal InvestigatorUniveristy Health Network
7 Previous Clinical Trials
1,847 Total Patients Enrolled
2 Trials studying Carcinoma, Hepatocellular
935 Patients Enrolled for Carcinoma, Hepatocellular

Eligibility Criteria

Age 18+ · All Participants · 10 Total Inclusion Criteria

Mark “yes” if the following statements are true for you:
Patients with HCV infection must have management of this disease per local institutional practice throughout the study
Patients with HBV infection, which is characterized by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA (≥10 IU/ml or above the limit of detection per local lab standard), must be treated with antiviral therapy, as per institutional practice, to ensure adequate viral suppression (HBV DNA ≤2000 IU/mL) prior to study entry
You have histologically proven resectable hepatocellular carcinoma.
You are post-menopausal or pre-menopausal and have a positive serum pregnancy test for female patients.

About The Reviewer

Michael Gill preview

Michael Gill - B. Sc.

First Published: October 9th, 2021

Last Reviewed: August 12th, 2022

Michael Gill holds a Bachelors of Science in Integrated Science and Mathematics from McMaster University. During his degree he devoted considerable time modeling the pharmacodynamics of promising drug candidates. Since then, he has leveraged this knowledge of the investigational new drug ecosystem to help his father navigate clinical trials for multiple myeloma, an experience which prompted him to co-found Power Life Sciences: a company that helps patients access randomized controlled trials.

References