An International Multicentre Open Label Randomised Phase II Advanced Anal Cancer Trial Comparing Cisplatin plus 5-fluorouracil versus Carboplatin plus Weekly Paclitaxel in Patients with Inoperable Locally Recurrent or Metastatic Disease

An International Multicentre Open Label Randomised Phase II Advanced Anal Cancer Trial Comparing Cisplatin plus 5-fluorouracil versus Carboplatin plus Weekly Paclitaxel in Patients with Inoperable Locally Recurrent or Metastatic Disease

An International Multicentre Open Label Randomised Phase II Advanced Anal Cancer Trial Comparing Cisplatin plus 5-fluorouracil versus Carboplatin plus Weekly Paclitaxel in Patients with Inoperable Locally Recurrent or Metastatic Disease (10540)

Eva Segelov ¹

St Vincent's Hospital, Darlinghurst, NSW, Australia

AIMS - The primary objective of the study is to compare the activity, in terms of overall response rate (ORR), of two combination chemotherapy regimens (cisplatin plus 5-fluorouracil (5FU) vs. carboplatin plus weekly paclitaxel) for the first line treatment of patients with inoperable relapsed or metastatic squamous cell carcinoma of the anus (SCCA). The results of the study will be used to inform the design of future phase III trials testing the addition of a targeted agent to the preferred chemotherapy regimen. The secondary objectives of the study are to provide estimates of differences in survival, toxicity and quality-of-life (QoL) endpoints between the two study arms. Exploratory biomarker research will also be undertaken in order to further investigate the role of the epidermal growth factor (EGF) pathway and other molecular pathways in predicting response or resistance of SCCA to systemic chemotherapy.

BACKGROUND - The optimal palliative chemotherapy regimen for patients with inoperable relapsed or metastatic SCCA is still unknown. Various chemotherapy regimens as either monotherapy or combination chemotherapy have been reported to be active. There has been no systematic review of systemic therapies in inoperable relapsed or metastatic SCCA since there is a lack of robust evidence in this setting. The current available evidence is based on small phase II trials, retrospective series, and case reports, and there have been no prospective phase III studies or meta-analyses. This highlights the need for an adequately powered randomised trial aiming to define the standard of care.

Current guidelines recommending the use of cisplatin and 5FU in advanced SCCA are mainly based on small phase II data indicating modest survival benefit. However, this combination chemotherapy has never been evaluated within the context of a formal, randomised, clinical trial. Additionally the optimal chemotherapy backbone to which targeted agents can be potentially added is not known. Evidence has recently emerged suggesting that targeting the EGFR pathway could be potentially beneficial in SCCA. The need for a clinical trial designed to set a standard of care for inoperable relapsed or metastatic SCCA and to inform the design of a future trial with targeted therapy was acknowledged at the IRCI meeting held at the 2012 ASCO Annual Meeting.

Given current lack of evidence with regards to management of patients with metastatic/relapsed inoperable SCCA, this study will provide evidence for the optimal first line treatment option, thus setting the standard of care for this disease. It will also establish the optimal chemotherapy backbone to use in combination with new targeted agents in future trials.

This study will also offer the opportunity to confirm the feasibility of conducting an international trial on SCCA that entails global collaboration and global representation. This has not been done before in this setting and as such if this collaboration is successful it will pave way for future collaborative studies.

Biomarker research on blood and tissue samples collected from participating patients will enable the identification of a subpopulation of patients who have increased chances to respond to a particular

treatment. Moreover, the collection of fresh blood samples (at baseline and at disease progression) and tumour tissues (archival and also fresh at disease progression upon further patient consent) will also allow exploration of the biology of SCCA, identification of predictive/prognostic biomarkers and development of selective therapeutic strategies.

STUDY DESIGN - An international, multicentre, open label, randomised phase II trial. Patients will be randomised to receive either cisplatin plus 5-FU or carboplatin plus weekly paclitaxel. ECOG performance status (PS) (0-1 vs. 2), HIV status (positive vs. negative) and extent of disease (locally recurrent vs. metastatic) will be used as stratification factors. ORR is the primary endpoint. 36 patients are to be recruited to each arm (total 72).

STUDY PROGRESS - The Royal Marsden Hospital is currently finalising the protocol and first patient is expected in late Q4, 2013. A CRUK Grant Award has been awarded for the trial. An international collaboration is required to support the trial in its aim to recruit 72 patients. There are 15-18 potential sites in the UK, ECOG and EORTC are planning to participate. The AGITG Lower GI Working Party has reviewed the trial and an assessment of potential patient numbers in Australia will be done during the ASM presentation using a live poll.

TRANSLATIONAL RESEARCH - Explorative biomarker analysis including the collection of archived tumour tissue and blood sample at baseline and upon progression is planned.

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.

An International Multicentre Open Label Randomised Phase II Advanced Anal Cancer Trial Comparing Cisplatin plus 5-fluorouracil versus Carboplatin plus Weekly Paclitaxel in Patients with Inoperable Locally Recurrent or Metastatic Disease (10540)

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