ASCOLT: Aspirin for Dukes C and High Risk Dukes B Colorectal Cancer, an international, multi-centre double blind, randomised placebo controlled phase II trial.

ASCOLT: Aspirin for Dukes C and High Risk Dukes B Colorectal Cancer, an international, multi-centre double blind, randomised placebo controlled phase II trial.

ASCOLT: Aspirin for Dukes C and High Risk Dukes B Colorectal Cancer, an international, multi-centre double blind, randomised placebo controlled phase II trial. (10548)

Eva Segelov ¹

St Vincent's Hospital, Darlinghurst, NSW, Australia

AIMS - The aim of the ASCOLT study is to determine if aspirin improves disease free survival (DFS) and overall survival (OS) in patients with stage III and high risk stage II colorectal cancer following surgery and adjuvant chemotherapy. The primary endpoint is disease free survival (DFS), as well as DFS for colon cancer (high risk Dukes B and Dukes C colon cancer). The secondary objectives include overall survival (OS) at 5 years, and DFS and OS in different ethnic groups, cancer sub-groups and compliant vs non-compliant patients.

BACKGROUND - The ASCOLT study is an international randomised phase III trial investigating the effect of aspirin on disease free survival and overall survival as adjuvant treatment in patients with resected stage II and III colorectal cancer (CRC). This important study trialling a cost effective and familiar medication is testing a critical question aimed at improving the survival of Australian patients with potentially curable but high risk localized colorectal cancer.

Evidence is emerging that aspirin has anticancer properties, particularly in gastrointestinal cancers. High quality evidence based on five meta-analyses from randomised trials in patients with vascular disease showed that long term use of aspirin reduces the primary incidence of CRC by about 40-50 percent. Randomised trials performed in patients at high risk for colorectal cancer reported that aspirin can reduce the development of polyps, the precursors of CRC and incidence of CRC in that patient group as well. Although several cohort studies have suggested that aspirin improves survival in patients with a diagnosis of localised CRC, prospective evaluation of the benefit of aspirin as an adjuvant agent in patients with a history of CRC remains to be determined. To be considered standard of care for patients following current therapy for localised CRC, it is essential that robust efficacy, safety and compliance evidence is obtained. Investigating the role of aspirin was ranked as the highest priority by Australian consumers, clinicians and researchers at a recent national forum.

Recently data has emerged that aspirin may have anti-tumour effects by blocking the PI3K signalling pathway. Up-regulation of PI3K stimulates cancer-cell growth and suppresses apoptosis. Mutations of the PIK3CA oncogene, encoding for the catalytic subunit p110α of PI3K, are present in approximately 14-17% of patients with CRC.

Provocative results were presented from analysis of two large cohort studies recently published in the New England Journal of Medicine. In a subset of 964 CRC patients, patients on aspirin whose tumours had a mutated PIK3CA gene had a superior CRC-specific survival as compared to patients on aspirin with tumours that had wild type PIK3CA. Interestingly regular use of aspirin was associated with significantly superior survival in patients with both PIK3CA mutation and high PTGS2 (COX-2) protein expression. Importantly, patients without the PIK3CA mutation did not appear to derive benefit from aspirin. Some clinicians have already adopted this in clinical practice, as mutation testing for PIK3CA is commercially available. However, as these findings are derived from cohort studies subject to retrospective non-randomised analyses, the results need to be confirmed by prospective randomized trials specifically designed to assess the role of aspirin in the treatment of cancer and the potential value of PIK3CA as a predictive biomarker, prior to widescale clinical adoption. The ASCOLT trial, by including large numbers, is likely to have adequate power

to identify subgroups that derive higher than estimated benefit from aspirin. In this way aspirin may be confirmed as a personalised or targeted therapy which would improve further the utility and cost effectiveness of the drug as it will then be able to be administered only to patients likely to benefit.

The ASCOLT trial will provide definitive proof of the role of aspirin in secondary prevention of CRC and will set a new standard nationally and internationally. As aspirin is cheap, readily available and familiar to consumers, any impact on increased survival is highly likely to be cost effective.

STUDY DESIGN - ASCOLT is a multi-centre international Phase III trial with Dukes C colon cancer, high risk Dukes B colon cancer, Dukes B rectal cancer or Dukes C rectal cancer patients who have completed the resection of primary tumour treated with standard therapy (chemotherapy ± radiotherapy). Within 90 days of completion of the standard therapy patients will be randomised to the study in 1:1 ratio to either:

- Aspirin arm: 200 mg Aspirin once a day for 3 years

- Placebo arm: 200 mg matching placebo once a day for 3 years.

A total of 2660 patients will be randomised in 5 years from international centres with competitive recruitment to the planned total of 2660 patients. After randomisation, patients will have 3 monthly assessments for 3 years (month 3 to month 36) followed by 6 monthly assessments for additional 2 years (month 42 to month 60); this is in keeping with standard follow-up protocols.

STUDY PROGRESS - The ASCOLT trial is an international trial coordinated by the National Cancer Centre Singapore and is currently open in Singapore, Taiwan, Saudi Arabia, Malaysia, Indonesia, Hong Kong, China, India and South Korea. Worldwide recruitment to September 2013 is 360 patients of a total of 1200 patients, planned to be recruited by the end of 2015.

A Cancer Australia Project Grant application was submitted in March 2012 to support AGITG participation with an anticipated 200 patients to be recruited over 2 years from Australia.

The AGITG feasibility survey of medical oncologists demonstrated that the majority thought ASCOLT will answer an important clinical question, with strong interest from investigators for participation. Additionally, investigating the role of aspirin was ranked as the highest priority by Australian consumers, clinicians and researchers at the national forum “Prioritising Gaps in colorectal cancer research” in August 2011.

Prior to the grant outcome notification, the AGITG will fund a pilot phase of the study for up to 50 patients in Australia. Site selection and finalisation of the pilot model is underway.

TRANSLATIONAL RESEARCH - Locally, the AGITG is collecting tumour tissue (formalin-fixed paraffin-embedded tumour tissue blocks) and blood (for recovery of serum and plasma) at 3 time points (0, 6, 12 months). Future translational studies will include gene mutation analysis of PIK3CA (exons 9 and 20), BRAF, KRAS, NRAS; COX-2 protein expression in tumour tissue; Tag single nucleotide polymorphism (SNP) analyses (of interest given the varying ethnicities of the study population); cytokine (various) and C-reactive protein levels.

Current translational research conducted by lead group in Singapore includes:

1) PIK3CA mutations Exon 9 and 20 mutations (may eventually move to using customized Sequonom panel for BRAF, KRAS, NRAS and PIK3CA mutations)

2) Paraffin IHC for Cox-2 expression

3) Tag SNPs – using PCR and Sanger Sequencing

4) Serum CRP at 0,6,12 months

5) Archiving serum /plasma for cytokine multiplex analysis

Authors contributing to this presentation.

Segelov, E

Professor Eva Segelov was appointed as the Professor and Director of Oncology at Monash Health and Monash University in February 2017. She is an Honorary Associate of the NHMRC Clinical Trials Centre, Sydney Medical School and previously Associate Professor at the University of New South Wales and Senior Medical Oncologist at St Vincent’s Hospital, Sydney. She is a recognised national and international expert in the fields of gastrointestinal cancer, including neuroendocrine tumours, and breast cancer, with a 20-year history of management of patients in a multidisciplinary setting. Professor Segelov is an active member of the Australian Gastrointestinal Trials Group (AGITG), as a Board Member and Convenor of the Annual Scientific Meeting. She is Chair of the Gastrointestinal Group of the Clinical Oncological Society of Australia (COSA). In 2016 she was nominated as a European Society of Medical Oncology (ESMO) faculty member for the CUP, Endocrine Tumours, and Others group. She is an Associate Editor of Journal of Global Oncology (ASCO); Editorial Board member of JoVE Cancer Research; ESMO 2019 Scientific Sub-Committee member for Neuroendocrine cancer; co-Track Chair of Gastrointestinal Cancer for the 2017 ESMO Asia Annual Scientific Meeting and co-founder of the Commonwealth Neuroendocrine Tumour Society (CommNETS), an international research collaborative. Professor Segelov has led multiple national and international oncology clinical trials, including investigator-initiated studies. Her research interests relate to translational studies of targeted therapies in defined subpopulations to increase benefit and reduce the toxicity of cancer treatments. She has published over 80 articles, expert reviews, and book chapters and is a frequent invited speaker at national and international conferences. Professor Segelov has a particular interest in professional development using innovative learning techniques and has developed the Seminal Advances Preceptorship in Cancer courses, now being run through Monash University. She was awarded the UNSW Vice Chancellors Award for Teaching Excellence in 2006.

ASCOLT: Aspirin for Dukes C and High Risk Dukes B Colorectal Cancer, an international, multi-centre double blind, randomised placebo controlled phase II trial. (10548)

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