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SCOT

SCOT. S hort C ourse O ncology T herapy A Study of Adjuvant Chemotherapy in Colorectal Cancer. Study Organisation. Sponsored by Greater Glasgow and Clyde Health Board (GGCHB)/ University of Glasgow (GU)

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SCOT

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  1. SCOT Short Course Oncology Therapy A Study of Adjuvant Chemotherapy in Colorectal Cancer

  2. 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

  3. 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 Tracey McMahon/ Mrs Karen Carty/ Mrs Andrea Harkin • Pharmacovigilance: Mrs Lindsey Connery/Miss Katie Nocher • Quality Assurance: Mrs Lindsey Connery • Clinical Trial Co-ordinators: Karen Wilson • Oncology Clinical Trial Office (OCTO), Oxford Team • Co-investigator: Professor David Kerr • Project Management: Ms Sarah Pearson • Quality Assurance: Ms Joanne Stokes/ Luise Dunham • Clinical Trial Co-ordinator: Javier Moreno-Farre • Clinical Trial Administrator: Ketan Pujara • Clinical Trial Support Officer: Gaynor Bates

  4. Randomise EXPERIMENTAL 12 weeks XELOX/ OxMdG Chemotherapy [4750 patients] STANDARD 24 weeks XELOX/ OxMdG Chemotherapy [4750 patients] 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

  5. 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

  6. 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

  7. SiteRegistration 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.

  8. Upfront Prior to treatment

  9. 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

  10. Patient Randomisation • All patients must be randomised onto the study prior to commencement of any treatment. • Check that patient has given written informed consent. • Check that patient fulfils eligibility criteria. • Check that randomisation is taking place within 10 weeks of surgery. • Complete Registration/Randomisation Form. • PHONE or FAX randomisation details to the randomisation team at the CTU Glasgow • Each patient registered will be allocated a unique study identifier. • Contact GP (See GP Letter in the Protocol). RANDOMISATION SERVICE • CTU Glasgow randomisation service • Tel: 0141 301 7195 Fax: 0141 301 7192* • 08:30 –17:00 Mon–Thurs, • 08.30-16.30 Friday, except public holidays • *Faxes received outside of office hours will be processed the next working day

  11. Stratification Factors • Centre • Choice of regimen • Gender • Disease site • T-stage • N-stage

  12. 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

  13. 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.

  14. 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 Site Set-up Initiation Call Site Randomised Notification by email SITE ACTIVATED

  15. Inclusion Criteria • Fully resected stage III colorectal cancer • High-risk stage II disease (defined as T4 disease, tumour perforation, obstruction, <10 nodes examined, poorly differentiated histology or extramural venous/lymphatic invasion) – see tumour staging guidelines in Appendix 11 of protocol • Patients with rectal cancer will be eligible unless they have had pre-operative combined chemotherapy and radiotherapy. Rectal patients must have had TME type surgery with negative (R0) resection margins • No evidence of residual or metastatic disease • Within 10 weeks of surgery at the time of randomisation • WHO PS = 0 or 1 • Age > 18 years • Life expectancy > 5 years with reference to non-cancer related morbidity • Written informed consent • CEA within normal limits for your site

  16. Exclusion Criteria • Previous chemotherapy (Previous abdomino-pelvic radiotherapy, with the exception of short course pre-operative radiotherapy for rectal cancer • Moderate/severe renal impairment (GFR<30 ml/min), as calculated by the Cockcroft and Gault equation • Absolute neutrophil count<1.5x109/L • Platelet count <100x109/L • Haemoglobin <9g/dL • Aspartate aminotransferase/alanine aminotransferase >2.5 x upper limit of normal • Clinically significant cardiovascular disease • Pregnancy/lactation or of a child bearing potential and not using adequate contraception • Previous malignancy other than adequately treated in situ carcinoma of the uterine cervix or basal or squamous cell carcinoma of the skin, unless there has been a disease-free interval of at least 5 years • Known or suspected dihydropyrimidine dehydrogenase deficiency (DPD)

  17. Informed Consent Process-1 • Two original Consent Forms must be completed by a clinician (or deputy listed on Staff Contacts & Responsibilities Sheet) • Both originals must be signed and completed by the patient • Date must be on or prior to randomisation • Make one photocopy - Original to be filed in Investigator File - Original to be given to patient (+PIS) - Photocopy to be filed in hospital notes • Consent Form must not be sent to your coordinating trials office • Consent Notification Form must be completed and sent to your coordinating trials office

  18. Informed ConsentProcess-2 • Errors noticed after consent - Add explanatory note/file note • New version of Patient Information Sheet must be provided to patients consented with previous version and this must be logged on the Patient Information Sheet distribution Log - Give to all patients regardless of treatment stage, By post During clinic visit • Patients who are still on active treatment will be required to repeat the consent process using the updated form - If not appropriate to re-consent patient (i.e. patient terminally ill) make a note on the re-consenting log

  19. Pre-registration/Randomisation Evaluations • CT scans of chest, abdomen & pelvis must be done within 16 weeks prior to randomisation/study entry • Randomisation must occur within 10 weeks of surgery • Colonoscopy should be performed within 3 months of surgery if not performed prior to surgery. However this is NOT an entry requirement • Assessments to be made 7 days before randomisation include: - Medical history and examination - WHO PS - ECG - Baseline laboratory tests (clotting only in patients on anti-coagulants) - Urine Pregnancy Test • Completion of EORTC, EQ-5D & NTX questionnaires

  20. CRFs/Questionnaires • Site Randomisation Questionnaire • Registration/Randomisation Form • Week 12 Randomisation Form • Consent Notification Form • Treatment Form • Follow-up Form • Consent Withdrawal Notification Form • Pregnancy Notification Form • SAE Form • EORTC quality of life questionnaire • EQ-5D questionnaire • GOG- NTX4 questionnaire • Patient Withdrawal questionnaire

  21. CRF Completion • CRF completion guideline document will be provided to all sites • Black ball-point pen • Correction fluid etc. must not be used • Errors crossed out with a single stroke, correction inserted and change initialled and dated • An explanation can be written next to amendment if necessary • Date format: DD / MON / YYYY • Information on CRFs must be verifiable in source documents • Take photocopy of all completed CRFs • Original to OCTO/CTU Glasgow

  22. Follow-up • Patients on the 12 week treatment arm will be reviewed monthly for 3 months after completion of chemotherapy • All patients will be assessed at 3 monthly intervals until month 12 • Then 6 monthly until month 24 and annually thereafter • CT scans for all patients are required at the following timepoints: • Month 6 (post rand) • Month 12 (post rand) • Month 18 (post rand) • Month 24 (post rand) • Month 36 (post rand) • Although CT scan is the preferred method of radiological assessment, it is acceptable to use US of liver and CXR as a substitute at month 6, 18 and 36 only. • Visualisation of entire colon should be performed as per local practice (please note if this has not been carried out pre surgery it must be performed within 12 months post surgery). • Any relapse or incidence of new colorectal and primary tumoursmust be confirmed by imaging and/or histology/cytology as appropriate and reported on the next FU Form • If the patient has completed treatment as per protocol or the treatment has been withdrawn due to recurrence or some other clinical decision, the patient should be followed-up as per protocol.

  23. Additional studies • Centres will be asked if they are willing to participate in Quality of Life collection • Quality of Life, economic and detailed toxicity data are required for approximately 700 patients Quality of Life data • The QLQ-C30/CR29 questionnaires should be completed by patient prior to randomisation, on day 1 of chemotherapy of each cycle of treatment and at follow up visits until year one. • Economic data • The EQ-5D questionnaire to be completed at the same frequency as QLQ questionnaires and at all follow up visits until study completion Detailed toxicity data • Toxicity will be graded using the NCI-CTCAE Version 3.0 • GOG Ntx 4 (neurotoxicity) questionnaire will be completed by patients at the same frequency as the QLQ Forms

  24. End of Treatment For all patients: • At the end of treatment, the decision to end treatment and date of last treatment should be recorded on the last Treatment CRF (Future Study Treatment section); For patients where the treatment has been withdrawn (full treatment not completed): • The reason for this should be recorded on the last Treatment CRF (Reasons for Early Treatment Withdrawal section); • If the treatment has been withdrawn due to recurrence, note the recurrence details on the 1st follow-up form;

  25. Consent Withdrawal • This is when the patient specifically asks to withdraw their consent at any point in the study; • If this occurs: • Complete the consent withdrawal form and keep a copy at site and a copy for the patient; • Send the consent withdrawal notification form to your coordinating centre; • No further follow-up should be collected on the patient from that point onwards.

  26. Pharmacovigilance Definition of an Adverse Event • An adverse event (AE) is defined as any untoward medical occurrence that is not necessarily related to protocol treatment • All AEs must be followed; - until resolution, - or for at least 30 days after discontinuation of study medication, - or until toxicity has resolved to baseline, - or < Grade 1, - or until toxicity is considered to be irreversible • All AE and toxicities must be graded according to the NCI-CTCAE Version 3.0 • Abnormal laboratory test should be recorded as an AE in the CRF • AE that are not defined as AR do not require to be recorded in the CRF

  27. Adverse Reactions Definition of an Adverse Reaction • An adverse reactions (AR) is any untoward and unintended responses to an investigational medicinal product related to any dose administered • AR information will only be collected on CRFs for a limited number of patients. • Once this information has been collected sites will be advised that AR information is no longer required • An exacerbation of a pre-existing AR after commencement of trial should be recorded on CRFs

  28. Definition of a SERIOUS ADVERSE EVENT A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that is not necessarily related to protocol treatment that: • Results in death • Is Life-threatening • Requires hospitalisation or prolongation of existing hospitalisation • Results in persistent or significant disability or incapacity • Consists of a congenital anomaly or birth defect • Is considered medically significant by the Investigator

  29. Definition of a SERIOUS ADVERSE EVENT- 2 Life threatening: • The patient is at immediate risk of death from the event as it occurred. It does not include an event that, had it occurred in a more serious form, might have caused death. Requires in-patient hospitalisation: • Is a hospital admission required for treatment of an adverse event even when the adverse event is not related to the protocol treatment.

  30. Reporting SAEs • Serious Adverse Events (SAEs) must be reported immediately (within 24 hours of knowledge of the event) • Sites must have a system for SAE reporting in the absence of the Research Nurse or Principal Investigator. • SAEs are reported using the CTU SAE report Form • Sites must complete the SAE report Form and fax the report to Pharmacovigilance at the Glasgow CTU fax number 0141 301 7213 • The CTU will create a SAE reference number and will send an acknowledgement fax to confirm receipt • The CTU will request additional information if the event is unexpected • CTU will raise queries for any inconsistent or missing information • SAEs must be reported locally by the PI at each site in accordance with the local practice at their site (i.e. Ethics Committee, R&D Office) • SAEs are required to be reported for up to 30 days after discontinuation of study medication • Any SAE that occurs after 30 days post treatment is also required to be reported if the PI thinks that the SAE is related to the protocol treatment, or is medically important

  31. SAE Report Form completion – General Tips • Always fax SAE report forms and SAE queries. • Do not post original SAE reports. • Keep and file original SAE reports and original copies of SAE queries with other patient CRFs. • SAE Reports are faxed to allow for the tight time frame for identifying and reporting SUSARs. • Always include a fax cover sheet when submitting an SAE report or queries. • The cover sheet should identify who is submitting the report/queries and their contact details. • Do not use abbreviations for completing any part of the SAE report or SAE queries. • Do not fax lab reports or test results with the SAE report form • Document only medically significant and pertinent lab findings in the SAE summary section.

  32. SAE Report Form completion – weak areas - 1 • Section 1 – Study/Patient Details • Report date should be the date of report completion, which is close to the report signature date and within a day of the date the report is faxed. • Post dating SAE reports to attempt to disguise late reporting is not acceptable. • Section 2 – Protocol Drug Treatments • Ensure the frequency is correctly recorded (for capecitabine use the phrase as per protocol) and the correct cumulative doses are provided. • Section 3.4 – Adverse events • Ensure that the adverse event section is completed and the adverse events listed are consistent with those recorded in the SAE summary. • Often additional AEs are mentioned in the SAE summary which do not appear in the adverse event section. • Section 3.4 – Adverse Events – • when submitting an initial report the adverse event section is a mandatory field. • Each adverse event that comprises the SAE must be listed using the appropriate CTCAE short name. Please do not enter adverse events that do not appear on CTCAE Version 3. • The relationship of each adverse event to each trial drug must be reported using the appropriate code: • 0=not applicable, 1=related, 2=possible, 3=probable 4=definite • Do not record the relationship to protocol treatment using a tick. • Please ensure the correct code is entered into the appropriate column for each trial drug.

  33. SAE Report Form completion – weak areas - 2 • Section 3.6 – Summary of SAE • Use clear and legible writing without abbreviations. • Describe the SAE with the correct chronology consistent with the adverse events listed in the adverse event section. • Section 4 – Concomitant Medication • List treatment in use before or at the time the SAE occurred, not that used for treatment of the SAE. • These medications should be recorded in the summary of the SAE section.

  34. SAE Report Form completion – Mandatory Information at Initial Notification • Trial drugs must be listed on the SAE report in Section 2: Protocol Drug Treatments. • Complete as much information as possible. It is important that dates of administration are reported. • The adverse event section and particularly the relationship to protocol treatment must be completed at initial notification of the SAE. • The relationship may change on a follow up report when there is more information or if the PI was unavailable to review the causality initially. • SAE report forms must be signed by the PI / designee as agreed on the staff contact and responsibility sheets. • If the PI / designee are unavailable to sign the report form please fax it unsigned and again as soon as it is signed. • If you are unsure if to report an event as an SAE or need any guidance on completing the SAE report form please contact Lindsey Connery Tel: 0141 301 7209 or Email: l.connery@clinmed.gla.ac.uk at Pharmacovigilance at the Cancer Research UK, Clinical Trials Unit, Glasgow.

  35. Procedure for Identifying and Reporting Unexpected and Related Events • A checklist of the events expected to occur in patients receiving the protocol treatment will be used to identify SUSARs • SAEs that meet the criteria for SUSARs will be reported to the MHRA, Main REC and Sponsor where in the opinion of the Chief Investigator the event was: • Related – that is, resulted from administration of any of the research procedures And • Unexpected – that is the type of event is not listed in the Investigator Brochure, or Summary of Product Characteristics (SmPC) as an expected occurrence • Reports of related and unexpected SAEs will be submitted within 7 days for fatal/life threatening events and 15 days for all other events. We will require sites assistance with gathering information for SUSARs reports

  36. Non-Investigational Medicinal Products (NIMPs) • NIMPs are any drug, mentioned in the protocol that is administered to patients in addition to the trial drug treatment. This includes rescue medication such as analgesics or antiemetics and medications for symptom relief • If a SAE is considered related to a NIMP then it requires to be reported and the NIMP (which is implicated) requires to be identified. The NIMP for this study is glucose • If a SAE is considered to be an interaction between a NIMP and the IMP (the treatment drug) then it also requires to be reported • The Chief Investigator is responsible for deciding if a SAR that is related to a NIMP requires expedited reporting

  37. Annual Safety Reports A report on the safety of trial participants from all trial sites will be prepared by the CTU Glasgow and submitted to the MHRA, Main REC, Sponsor & Trial Investigators

  38. Dose modifications for toxicity • If grade 1 toxicity occurs treatment should continue • Dose modifications for diarrhoea, haematological and neurosensory toxicity can be found in the protocol • For all other toxicities >grade 3, treatment should be withheld until recovery to < grade 1 then restarted if medically appropriate • If patients take three weeks or longer to recover from chemotherapy-related toxicity they will receive no further treatment • In the situation where oxaliplatin is discontinued due to toxicity, adjuvant treatment can continue with 5-FU alone • Crossover from capecitabine to 5-FU and vice versa is allowed for reasons of toxicity • Once the dose has been reduced it must not be escalated

  39. 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 Study Drug

  40. Translational research • We are planning to submit a grant application to CR-UK for sample collection and storage for blood, urine and tissue samples • Full information will follow at a later stage • Currently patients are asked to consent to this section of the study. Those patients who consent, at this time, are only consenting to us approaching them at a later date with full details of the translational research.

  41. 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.

  42. 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

  43. Contact Details OCTO, OxfordCR-UK CTU, Glasgow Oncology Clinical Trials Office Cancer Research UK Clinical Trials Office Depart of Clinical Pharmacology Level 0 Old 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

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