Award Title: A phase II study combining pembrolizumab and olaparib in metastatic pancreatic adenocarcinoma patients with high tumour mutation burden
Funder: Medical Research Council

Abstract: Aim of the research_x000D_
To test whether the combination of drugs, pembrolizumab and olaparib, are effective treatment for a specific subgroup of patients with metastatic pancreatic ductal adenocarcinoma (mPDA). _x000D_
_x000D_
Background _x000D_
mPDA is an aggressive form of cancer with very poor outcomes. It is generally treated with traditional chemotherapy, but even with chemotherapy, average life expectancy of patients with mPA is under 1 year. In the search for treatments to improve life expectancy for cancer patients, immunotherapy drugs that boost the immune system, like pembrolizumab, are increasingly being used. Unfortunately, so far, they have not helped people suffering from mPDA. Olaparib works by preventing cancer cells repairing themselves.  Combining olaparib with pembrolizumab may be a better way of boosting the immune system. We think that the people most likely to benefit from combining these 2 drugs are those mPDA patients whose tumours contain very high amounts of genetic changes that will help the body’s immune system seek out and kill the cancer cells more easily. These tumours are described as having high mutational burden, or high TMB. High TMB can be identified by examining tumour samples, or biopsies. While currently this is done as part of a national research programme, eventually it is hoped that this will be part of routine care. We plan to identify patients with both mPDA and high TMB and offer them treatment with pembrolizumab plus olaparib in this national clinical trial. _x000D_
_x000D_
Methods_x000D_
Twenty patients with mPDA and high TMB will be invited to take part in this trial. Eligible patients may choose to take part in this trial as their initial treatment, or after conventional chemotherapy. Pembrolizumab is given into the vein once every 3-6 weeks.  Olaparib is a tablet taken by mouth twice a day. Treatment duration is for as long as the patient is benefitting, but for a maximum of 2 years. The side effects of both drugs are well known and the treatment is expected to be well tolerated, with about a 1 in 10 chance of unpleasant side effects that can usually be easily managed. _x000D_
We will measure if the treatment works by doing CT scans every 9-12 weeks. We will record any side effects and ask patients to complete quality-of-life surveys. We will also be able to find out what proportion of cancers have high mutation rates and how this reflects the treatment being given.  The test to identify high TMB is very expensive and is currently done in a specialist laboratory, but we think we can get the same information more affordably with a simpler test run in local hospital laboratories. We will find out whether this is possible as an added benefit of our trial. Finally, to help understand how the immune system is working in these treated patients, we will seek permission to use any tumour samples collected before starting treatment for our research._x000D_
_x000D_
Patient and Public Involvement_x000D_
Advice has been sought from Patient Advisory Groups, Pancreatic Cancer UK and the Elizabeth Coteman Trust. The National Cancer Research Institute pancreatic cancer workstream patient representative is a named co-applicant._x000D_
_x000D_
Dissemination _x000D_
The trial results will be shared with patients, carers and advocacy groups, as well as NHS commissioners. Trial findings will be published and presented at conferences.

Lay Abstract: Research Question_x000D_
Does treatment with pembrolizumab plus olaparib improve outcomes for patients with metastatic pancreatic adenocarcinoma (mPDA) and high tumour mutation burden (TMB)? _x000D_
_x000D_
Background_x000D_
Outcomes for patients with mPDA are extremely poor, despite optimal anticancer therapy. Recent breakthroughs with modern immunotherapy reported for many cancer types have not been replicated in mPDA, which is a disease generally characterised by an immunosuppressive microenvironment and low TMB. However, not all PDAs are the same. In a small minority of PDAs, defective DNA damage repair mechanisms exist which generate very high TMB and these patients have the potential to benefit from immunotherapy. Some 2% of PDA patients could be eligible to access the immune checkpoint inhibitor (CPI), pembrolizumab, which was recently approved in the USA to treat cancers with the highest mutation rates caused by defects in DNA mismatch repair genes. However, currently there is no European access to pembrolizumab for this indication.  Furthermore, even for the most immunoresponsive cancers, only the minority of treated patients benefit from CPIs, so more effective combination strategies are needed. Pembrolizumab blocks the programmed death-1 receptor on T lymphocytes  which unleashes their ability to seek out and kill cancer cells. Emerging evidence suggest that drugs like olaparib, traditionally thought of as DNA repair targeted agents, can enhance response to CPIs. _x000D_
_x000D_
Aims_x000D_
We aim to conduct a single arm prospective trial evaluating pembrolizumab plus olaparib in patients with mPDA and high TMB.  The primary outcome is objective response rate (ORR); secondary outcomes are safety, duration of response and progression-free survival; exploratory outcomes are overall survival and additional response biomarkers._x000D_
_x000D_
Methods_x000D_
Patients with high TMB mPDA will be identified via national research and other molecular screening platforms. Eligible patients will be invited to consent to receive treatment as either first or second line therapy for their disease.  The regimen is pembrolizumab 200mg IV every 3 weeks plus olaparib 300mg orally twice a day, for as long as there is benefit, but maximum 2 years. Patients continuing beyond 27 weeks can switch to pembrolizumab 400mg IV 6 weekly. Patients will be scanned every 9 weeks for 27 weeks, then and every 12 weeks for the second year, or until disease progression. Thereafter, they will be followed for survival._x000D_
We will collect blood samples before starting treatment, at 9 weeks, then at 1 year or on disease progression, whichever is sooner. We will use pre-treatment tumour samples to explore molecular and immune markers of response_x000D_
We will recruit 20 evaluable patients to assess ORR, with early stopping rules._x000D_
_x000D_
Timelines for delivery_x000D_
Study set up complete: month 9_x000D_
First patient first visit: month 12 _x000D_
Stage 1 interim assessment: month 30 _x000D_
Stage 2 interim assessment: month 40 _x000D_
Stage 3 final ORR assessment: month 54 _x000D_
Final report, close out: month 60_x000D_
_x000D_
Anticipated impact and dissemination_x000D_
This signal-seeking trial will offer the first robust evidence of immunotherapy being an effective treatment strategy for a biomarker-stratified cohort of mPDA patients. A positive outcome will justify an international registration trial. The findings will be presented at conferences, published and shared with patients, carers, advocacy groups and commissioners

Research Activity Codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS