SCOTShort Course Oncology Therapy

A Study of Adjuvant Chemotherapy in Colorectal Cancer

Study Organisation

• Sponsored by Greater Glasgow and Clyde Health Board (GGCHB)/ University of Glasgow (GU)

• Coordinated by CR-UK Clinical Trials Unit in Glasgow and Oncology Clinical Trials Office (OCTO) in Oxford

• CR-UK CTU Glasgow and OCTO are responsible for setting up, day-to-day running, analysis and presentation of results

• Chief Investigator is Professor Jim Cassidy

• Supported by a grant from the MRC

Study Team• CR-UK CTU Glasgow Team

– Chief Investigator: Professor Jim Cassidy– Protocol Development and Co-Investigator: Dr Claire Kelly– Trial Statistician: Mr Jim Paul– Project Management: Mrs Andrea Harkin– Pharmacovigilance: Mrs Lindsey Connery/Miss Katie Nocher– Quality Assurance: Mrs Lindsey Connery– Clinical Trial Co-ordinators: Ms Karen Wilson/ Mrs Sian Shirley– Clinical Trial Monitor: Laura Alexander

• Oncology Clinical Trial Office (OCTO), Oxford Team– Co-investigator: Dr Rachel Midgley– Project Management: Mrs Sarah Pearson– Quality Assurance: Dr Joanna Black– Clinical Trial Co-ordinator: Ms Michelle Masterson– Clinical Trial Administrator: Ms Gaynor Bates– Clinical Trial Support Officer: Mr Matthew Goff– Clinical Trial Monitors: Christine Harvey & Zia Sherrell

Study Summary• Study design: phase III, randomised controlled, two arm, multi-centre,

non-inferiority• Study treatment:

• Study recruitment: 9500 patients over 5 years (150 sites in the UK)• Study population: patients with colorectal cancer• Timelines:

- Recruitment started in March 2008 - Planned accrual completion is March 2013 - Trial analysis and publication planned for 2016 - Trial duration of 7 years

Randomise

STANDARD24 weeks

XELOX/ OxMdGChemotherapy[4750 patients]

EXPERIMENTAL12 weeks

XELOX/ OxMdGChemotherapy[4750 patients]

Objectives & Endpoints

Objectives

• Assessment of the efficacy of 12 weeks of treatment vs 24 weeks of treatment and comparison of the associated toxicity

• Economic analysis to assess the cost-effectiveness of the two treatment alternatives

• Comparison of two randomisation methodologies

Endpoints

• Primary Endpoint:- Disease free survival (3 year)

• Secondary Endpoint:- Overall survival- Cost-effectiveness- Toxicity- Quality of life

Site Registration Process

All sites will be randomised to Upfront Randomisation after a decision made by the Trial Steering Committee (June 2009)

- Upfront: Randomisation at commencement of adjuvant treatment to either 24 or 12 weeks of chemotherapy

• Prior to June 2009 some sites were randomised to the delayed randomisation time point.

- Delayed: Randomisation after 12 weeks of adjuvant treatment to either stopping, or continuing with a further 12 weeks of chemotherapy

Site Registration Process

• From the outset of the trial it was specified that a decision would be made in relation to the 2 randomisation time points approx 1 year after the study opened to recruitment.

• The independent members of the TSC decided that the study should continue with upfront randomisation time point only for the remaining duration of the trial.

Reason for Amendment to Randomisation• The decision was based on the data presented in the first interim

analysis report. • The data showed a 32% drop out rate of patients prior to the

delayed week 12 randomisation, compared to a 7% dropout of patients stopping treatment before completing 12 weeks of treatment on the upfront randomisation arm.

Upfront

Fully resected high-risk stage II/Stage III colorectal cancer

Register/ Randomise

Standard Arm24 weeks

adjuvant chemotherapy

Study Arm12 weeks

adjuvant chemotherapy

Follow-up (max 7 years)

Prior to treatment

Site Registration Process

• Prior to site activation, a site questionnaire will need to be completed. The questionnaire will require the following information:

- List of all the sites that the PI is responsible for and which are

going to participate in SCOT.

- Responsible CTU for your site.

- Which sites are willing to participate in the QoL questionnaires.

- Estimate the total annual recruitment for all the listed hospitals.

• Return the questionnaire to CTU Glasgow by Fax.• Fax Number +44 (0) 141 301 7192

Stratification Factors

• Centre• Choice of regimen• Gender• Disease site• T-stage• N-stage

Treatment arms

• Arm A (Standard treatment) - 24 weeks of XELOX/OxMdG chemotherapy

• Arm B (Experimental treatment) - 12 weeks of XELOX/OxMdG chemotherapy

• Dose and administration of XELOX – 3 weekly cycle- Oxaliplatin 130mg/m2 IV on day 1- Capecitabine 1000mg/m2 PO twice daily for 14 days

• Dose and administration of OxMdG – 2 weekly cycle- Oxaliplatin 85mg/m2 IV on day 1 concurrently with- I-folinic acid 175mg or folinic acid 350 mg followed by- 5-FU 400mg/m2 IV bolus injection over 5 minutes followed by- 5-FU 2400mg/m2 IV continuous infusion over 46 hours

Dose Guidelines for XELOX Regimen

• At randomisation you will be asked for the patient’s starting dose of Capecitabine.

• Patients with a creatinine clearance of 30-50mls/min must commence treatment with capecitabine at 75% of the full dose.

• Patients > 70 years of age should be considered for treatment with capecitabine at 75% of the full dose but, in light of differences in standard practice between sites, this will be left to the discretion of the Investigator depending on the fitness of the individual patient. The decision not to dose-reduce must be documented in the patient notes.

• At the Investigator’s discretion, patients can be commenced on a minimum starting dose of capecitabine of 800 mg/m2 if clinically indicated. The starting dose of capecitabine will be requested at baseline registration/randomisation.

• Capecitabine dose banding tables are provided in appendix 3 of the protocol.

Site Set-up

• CTU Glasgow/ OCTO - Main REC approval (Glasgow) - MHRA approval (Glasgow) - Site Initiation Calls - Investigator File - Pharmacy File

• SITE - Staff Contact & Responsibilities Sheets - SSI - R&D Approval - Investigator CVs and Lead Pharmacist - Clinical Trial Agreement - GCP Certificates for PIs - PIS, Consent, GP Letter etc on Trust

headed paper - Site Randomisation questionnaire

Initiation Call

SITE ACTIVATED

Notification by emailSite Randomised

Study Drug

• All IMPs for use in this trial should be taken from existing pharmacy shelf stock. There is no provision for funding, reimbursement or discounted stock

• IMPs should be stored under the correct conditions as per the SmPC• All products used in this study are licensed medications and will not be labelled

specifically for the study• IMP accountability logs will be provided for use, these must be maintained for the

duration of the study and must be kept in the study pharmacy file• Patients should be asked to return any unused capecitabine tablets at each study

visit

Pharmacy File

• Contact Information• Study Summary• Randomisation• Protocol• Ethics and Regulatory documents• Critical Documents• Subject Information Documents• Monitoring• Drug Information• GCP guidelines• Study correspondence

Monitoring Plan

• All patients monitored for:– Consent– Stratification variables– Treatment detail

• Recurrences/deaths/SAEs will be monitored as per SCOT monitoring plan.

• Pharmacy visit.• Monitoring of Site File.

Ethical and Regulatory Standards

• SCOT is conducted according to ICH GCP guidelines and CTU/ OCTO SOPs

• SCOT is conducted in accordance with the EU Directive 2001/20/EC

• Trial carried out in accordance with the World Medical Association Declaration of Helsinki (1964) and the Tokyo (1975), Venice (1983), Hong Kong (1989), South Africa (1996) amendments

Contact Details

OCTO, Oxford CR-UK CTU, Glasgow Oncology Clinical Trials Office Cancer Research UK Clinical Trials Office Depart of Clinical Pharmacology Level 0Old Road Campus Research Building Beatson West of Scotland Cancer

Centre University of Oxford 1053 Great Western Road Old Road Campus Glasgow, G12 0YN Off Roosevelt Drive Headington Oxford, OX3 7DQ

Tel: +44(0) 186 561 7018 Tel: +44(0) 141 301 7191 Fax: +44(0) 186 561 7010 Fax: +44(0) 141 301 7184

E-mail: scot@octo-oxford.org.uk E-mail: scot@clinmed.gla.ac.uk