B71: Phase II clinical trial of 6 mercaptopurine (6MP) and methotrexate in patients with BRCA defective tumours

Corran Roberts1,Lucy Boyle2,Victoria Strauss1,Sylwia Kopijasz2,Charlie Gourley3,Marcia Hall4,Ana Montes5,Jacinta Abraham6,Andrew Clamp7,Richard Kennedy8,Susana Banerjee9,Shibani Nicum10

1Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK,2Oncology Clinical Trials Office, University of Oxford, Oxford, UK,3University of Edinburgh Cancer Research UK Centre, MRC IGMM, Edinburgh, UK,4Mount Vernon Cancer Centre, Northwood, Middlesex, UK,5Guy’s and St. Thomas’ NHS Trust, London, UK,6Velindre Cancer Centre, Cardiff, UK,7The Christie NHS Foundation Trust and Institute of Cancer Sciences, University of Manchester, Manchester, UK,8Centre for Cancer Research and Cell Biology, Queen’s University of Belfast, Belfast, UK,9The Royal Marsden NHS Foundation Trust, London, UK,10Oxford University Hospitals NHS Trust, Oxford, UK

Presenting date: Tuesday 3 November
Presenting time: 12.20-13.10

Background

Tumour cells with BRCA1 and BRCA2 gene mutations demonstrate increased sensitivity to platinum and poly (ADP-ribose) polymerase (PARP) inhibitors. 6 mercaptopurine (6MP) was identified in a screen for novel drugs and was found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor AG014699, even after these cells had acquired resistance to a PARP-inhibitor or cisplatin.

Method

This multi-centre phase II single-arm trial investigated the activity of 6MP 55mg/m2 per day, and methotrexate 15mg/m2 per week in patients with advanced breast or platinum resistant ovarian cancer and a BRCA 1/2 germ line mutation, who had progressed after ?one line of chemotherapy. The primary outcome was objective response at 8 weeks, defined by RECIST v1.1 as complete response, partial response or stable disease (SD). Secondary outcomes included safety, overall survival (OS) and progression free survival (PFS).

Results

66 evaluable patients were recruited; 55 ovarian and 11 breast cancer patients. 23/66 (35%) and 11/66 (17%) had SD at 8 and 16 weeks, respectively. One patient had a partial response at 8 weeks which was maintained at 16 weeks. Median OS was 9.93 months (95%CI, 6.90-14.50 months) and median PFS was 1.91 months (95% CI, 1.71-3.32 months). 5 ovarian cancer patients and 1 breast cancer patient had stable disease for over 200 days. There were 6/55 (11%) ovarian cancer patients who had a Ca125 response according to the GCIG criteria. 17 of the 66 patients (26%) experienced CTCAE grade 3 or 4 neutropenia. Most frequent adverse events (AEs) of any grade were nausea (9%), fatigue (9%), neutropenia (7%) and vomiting (4%). 14% of the total AEs were grade 3/4.

Conclusion

The overall activity of 6MP in these patients was low, however, there was a small group of 6 patients (9%) who appeared to derive longer term clinical benefit.