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

5. Objectives & Endpoints
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. 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.

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)

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: Fax: *
08:30 –17:00 Mon–Thurs,
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. Site Set-up Initiation Call Site Randomised Notification by email
- 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
CTU Glasgow/ OCTO
- Main REC approval (Glasgow)
- MHRA approval (Glasgow)
- Site Initiation Calls
- Investigator File
- Pharmacy File
Initiation Call
Site Randomised
Notification by
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 Consent Process-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
Increase font size to 20

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 tumours must 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
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
LD- suggest Serious Adverse Event (SAE) for 1st mention
Staff ‘Contact’ and………………..
Capital for SAE ‘F’’orm

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: or
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
LD- suggest ‘should’ rather than ‘will’ for 1st sentence
What about grade 2?

39. 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

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, Oxford CR-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 Great Western Road
Old Road Campus Glasgow, G12 0YN
Off Roosevelt Drive
Headington
Oxford, OX3 7DQ
Tel: +44(0) Tel: +44(0)
Fax: +44(0) Fax: +44(0)