12 Dec 2017

The PIONEER team in Glasgow has been working through the Combinations Alliance and having huge success in doing so. We caught up with them to find out more about their research.

Q.     Describe the PIONEER trial and the anticipated patient benefit.  

PIONEER is a Phase I, open-label, non-randomised, multi-centre, dose escalation trial of the PARP inhibitor, Olaparib, administered in combination with standard capecitabine-based chemo-radiation combined modality therapy in patients with locally advanced, inoperable pancreatic ductal adenocarcinoma.

The objectives of this trial are to explore the safety and toxicity of this regime, to identify the dose-limiting toxicities and the maximum tolerated dose, and to recommend a dose of Olaparib for phase II clinical trials.  Once the recommended dose has been determined, an additional cohort of patients with “borderline” resectable pancreatic ductal adenocarcinoma will be recruited to determine the feasibility of recruiting patients into a trial of “neo-adjuvant” chemo-radiation therapy, to determine the tolerability of the regimen in this patient population, and to explore preliminary data on whether this regimen can potentially down-stage their disease.

One of the key aims of the study is to exploit our understanding of the molecular and cellular basis of pancreatic cancer development and progression in order to develop therapeutic strategies that will improve overall survival and quality of life in patients with pancreatic cancer.  Ultimately, we propose to exploit the radio-potentiating effect of PARP inhibitors to enhance local disease control, and possibly survival, by chemo-radiation in locally advance pancreatic cancer, and to increase the rate of potentially curative surgical resection for those with “borderline operable” disease. 

This study is co-ordinated by the Cancer Research UK Clinical Trials Unit, Glasgow and co-sponsored by the University of Glasgow/NHS Greater Glasgow and Clyde.  We currently have 3 centres open to recruitment – The Beatson West of Scotland Centre (Glasgow), Belfast City Hospital and Guy’s and St Thomas’ (London).

Q.     Would you have considered such a trial if not working through the Alliance? 

We have co-ordinated a number of studies through the Combinations Alliance (CA). The CA and partners (AstraZeneca in this instance), give access to a portfolio of drugs of which otherwise we would not have the opportunity to explore in such cancers i.e. pancreatic. 

The infrastructure is there for funding via the New Agents Committee and also additional operational support which allows for contracting with others e.g. Covance for PK analyses. The Alliance has also allowed us to explore early phase chemotherapy – radiotherapy combination studies such as PIONEER, which would be almost impossible other than in an academic, non-commercial, research environment

Q.     What have been the particular challenges for the set-up and delivery of PIONEER to date?

Initially challenging was setting up the study, particularly with requirements for Radiotherapy QA. Evolving changes to clinical practice between the initial study design and when the study opened to recruitment meant that the induction chemotherapy which was standard (GEMCAP) had broadened and we were missing out on patients who were receiving single agent GEM and FOLFIRINOX. We had to amend the protocol to reflect these changes and update the inclusion criteria. 

There were delays in recruitment when the PI at one site retired and so we had to find a new site to come on board instead.  This has meant that we have had to re-base our study timelines with both AstraZeneca and the New Agents Committee who have been very supportive.  Furthermore, the DLT assessment period is longer in this study, due to a protracted (chemo)radiotherapy regimen, than is the case with systemic therapy which can be challenging if a patient is non-evaluable towards the end of the DLT assessment period and needs to be replaced.   

Q.     PIONEER opened in August 2015, can you tell us what has been achieved and what is yet to be realised? 

We are currently on dose cohort 3 of a possible 4 dose cohorts within the protocol.  Due to the rolling six design we were able to confirm x3 patients assessable with no DLTs and dose escalate while another 3 patients were being screened.  This meant that they could be quickly registered on the next dose cohort and are currently receiving treatment. 

This is a good example of the rolling six design working as it should.  We are looking forward to completing the dose escalation part of the study and moving on to the dose expansion.  We have also established the assays for the PD studies in Glasgow and Belfast, utilising the expertise of the ECMC – funded Translational Pharmacology Laboratory in Glasgow (Fiona Thomson), a Cancer Research UK CDD Biomarkers Centre of Excellence.

Q.    Has the experience been different working through the Combinationa Alliance? What would you say are the key benefits of working through the Alliance? 

Opportunity for funding for translational work associated with your clinical trials.  There are a number of trials running at any one time and these are discussed intermittently at the JSC for the clinicians and there is also the CA Trial Co-ordinators meeting where common issues can be discussed. 

There are also different funding models and arrangements for CA studies.  There is lots of support and encouragement from the CA team in particular Zoe Boylan, Cathy McDowell and Lyndall McLellan.  The CA provides access to a portfolio of drugs from a range of pharma partners which may otherwise be inaccessible. 

Q.     Would you have any advice to others about to undertake a similar role?

We would strongly advise the Combinations Alliance route for anyone considering an academic early phase trial if this is available.