Petal
Research type
Research Study
Full title
A phase Ib study of Pembrolizumab following Trans-Arterial chemoembolization in primary Liver carcinoma.
IRAS ID
223814
Contact name
David Pinato
Contact email
Sponsor organisation
Imperial College London
Eudract number
2017-000471-85
Duration of Study in the UK
3 years, 3 months, 1 days
Research summary
Lay summary of study results: Study Title: A Phase Ib Study of Pembrolizumab following Trans-Arterial Chemoembolization in Primary Liver Carcinoma (PETAL) The PETAL trial aimed to evaluate the safety and tolerability of pembrolizumab following transarterial chemoembolization (TACE) treatment, in patients who were diagnosed with a common type of liver cancer called hepatocellular carcinoma (HCC), that was still confined to the liver.
TACE is a procedure where a high-dose of chemotherapy is administered directly into the arteries of the liver, so that it can be delivered as close to the liver tumour as possible. Following this, the blood vessels are closed off to block the liver’s blood supply, preventing oxygen and nutrients reaching the liver tumour. This combination of chemotherapy and blocked blood flow can help to control the size of the tumour and prolong survival of patients. TACE treatment is recommended for patients whose HCC is still confined to the liver, and who still have adequate function of their liver and can perform their daily activities. This group of patients are known as having ‘intermediate stage’ HCC.
Pembrolizumab (also known by its brand name, Keytruda®), is a type of immunotherapy known as an immune checkpoint inhibitor (ICI), and is approved for use in a number of different cancer types. ICIs work by targeting proteins on the surface of immune cells and blocking their activity. Pembrolizumab targets a protein called programmed death receptor-1 (PD-1) on a type of immune cell called a ‘T cell’. Blocking this activity allows the T cells to be activated and target cancer cells. This pathway is commonly ‘hijacked’ by tumours to supress the immune system from attacking the tumour. Pembrolizumab is widely used as a treatment for advanced HCC.
TACE is an established treatment option for intermediate HCC, however it only produces a tumour response in approximately 35% of patients, and improves 2-year survival in only 14%. TACE can be combined with other anti-cancer treatments, however there has not been any proven benefit in survival rates, as well as showing increased side effects from the combination of treatments.
There had been no previous research evaluating the effects of the combination of TACE and pembrolizumab. In this study, researchers wanted to evaluate whether TACE and pembrolizumab is safe and tolerable, and also whether it has an enhanced combined effect in treating liver-confined HCC. Researchers also wanted to investigate the impact to participants’ quality of life, as well as in-depth analysis of how the treatment worked by analysing blood, tissue, urine and stool samples donated by the participants.
The study was conducted in 2 parts. In Part 1, 6 participants received TACE treatment followed by 200mg of pembrolizumab every 3 weeks, starting 30 days after their TACE treatment. In Part 1, participants were observed for any dose-limiting toxicities (DLTs). DLTs are severe adverse reactions to a treatment that mean it is not safe to increase the dose any further in a clinical trial. After Part 1, a safety analysis was conducted to confirm it is safe to continue recruitment to Part 2. As no participants experienced any DLTs in Part 1, a further 9 patients were enrolled and received treatment in Part 2. Overall, 15 patients were included in the analysis of safety and treatment efficacy data.
Adverse reactions related to the treatments occurred in 93% of patients, most commonly rash (40%), followed by diarrhoea, pruritus (itchy skin), and fatigue occurring in 4 participants each (26.7%). The only severe adverse reaction was a skin rash reported in 1 participant that required steroid treatment; upon completion of steroid treatment the rash resolved, and the participant could resume trial treatment.
Efficacy of the treatment was measured using Progression-Free Sur vival (PFS) rates at 12-weeks following TACE treatment. PFS is defined as the length of time after a treatment that a patient lives with a disease before the disease progresses, or worsens. Participants’ disease responses were assessed using Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) scans, comparing the tumour(s) at baseline (pre-treatment) and at 12-weeks post-TACE. A PFS rate of 93.3% was achieved in this trial, meaning that 93% of patients’ tumours had not progressed at 12-weeks post-TACE. The median duration that participants remained progression-free was 10.3 months.
Quality of life was measured using questionnaires completed by the participants before, during and after the treatment. Analysis showed that following combination treatment, patients’ quality of life overall did not worsen.
This study has helped researchers to demonstrate that the combination of TACE followed by pembrolizumab was tolerated well by participants, and did not cause increased combination of toxicities, including in the liver. The PETAL trial confirms the combination treatment is feasible and could support large scale trials in the future.
This study was sponsored by Imperial College London, and funded by Merck Sharpe & Dohme (MSD). The study was conducted at Imperial College Healthcare NHS Trust, King’s College Hospital NHS Foundation Trust and St George’s University Hospitals NHS Foundation Trust, starting in January 2018 and ending in March 2023. Patients with liver cancer were involved in reviewing the study design and participant documents, and provided valuable feedback that was incorporated into the final study design and documents.
You can find out more information about this study by visiting clinicaltrials.gov: Study Details | NCT03397654 | Study of Pembrolizumab Following TACE in Primary Liver Carcinoma | ClinicalTrials.gov, or contacting the Chief Investigator, Professor David Pinato: d.pinato@imperial.ac.uk.
Thank you to all participants in this study.This study is an open label, single arm, sequential phase study evaluating safety, tolerability and preliminary efficacy of sequential Trans-Arterial chemoembolization (TACE) followed by pembrolizumab in patients with primary liver carcinoma.
TACE works in two ways to kill the tumour: by giving a high dose of chemotherapy drug directly into the tumour and by cutting off the blood supply to the tumour. Pembrolizumab is designed to help the patients’ own immune systems to attack cancer cells. Combining the two treatments together may be more effective than giving TACE alone.
The safety profile of this combination has not been explored. The primary aim of this Phase Ib study is therefore to provide confirmatory evidence of safety of pembrolizumab in combination with TACE and to preliminarily evaluate the efficacy of the combination. The study will be conducted in two parts, performed at 1-3 sites in the UK and will recruit up to of 32 patients.
The study will be conducted in two parts, performed at 1-3 sites in the UK and will recruit up to of 32 patients.Participants will be assessed up to 14 days prior to TACE to confirm eligibility and be recruited onto the trial. Once they have completed 30 days post TACE they will receive pembrolizumab every 3 weeks until radiologically confirmed disease progression, unacceptable toxicity or a maximum of 1 year of treatment has been completed.
Part 1 of the study will consist of up to 6 patients treated with pembrolizumab after TACE at the clinically recommended dose of 200 mg every 3 weeks. Participants will be observed for determination of dose limiting toxicities over a 21 day time window with weekly laboratory assessments in Cycle 1 only. The decision to undertake Part II at 200 mg dose or continue at a lower dose of 100 mg will be made by an Independent Safety Monitoring Committee. Once the dose level has been determined in part I a further 26 patients will be recruited into Part II at that dose level.
REC name
London - Westminster Research Ethics Committee
REC reference
17/LO/1180
Date of REC Opinion
18 Oct 2017
REC opinion
Further Information Favourable Opinion