Transcript Document

SCOT
Short 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
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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
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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
Study Summary
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Study design: phase III, randomised controlled, two arm, multi-centre, non-inferiority
Study treatment:
Randomise
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STANDARD
24 weeks
XELOX/ OxMdG
EXPERIMENTAL
12 weeks
XELOX/ OxMdG
Chemotherapy
[4750 patients]
Chemotherapy
[4750 patients]
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
Objectives & Endpoints
Objectives
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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
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Primary Endpoint:
- Disease free survival (3 year)
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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
Prior to treatment
Register/ Randomise
Standard Arm
24 weeks
adjuvant chemotherapy
Study Arm
12 weeks
adjuvant chemotherapy
Follow-up (max 7 years)
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
Patient Randomisation
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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
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Tel: 0141 301 7195
Fax: 0141 301 7192*
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08:30 –17:00 Mon–Thurs,
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08.30-16.30 Friday, except public holidays
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*Faxes received outside of office hours will be processed the next working
day
Stratification Factors
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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
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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 dosereduce 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
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CTU Glasgow/ OCTO
- Main REC approval (Glasgow)
- MHRA approval (Glasgow)
- Site Initiation Calls
- Investigator File
- Pharmacy File
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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 Randomised
Notification by email
SITE ACTIVATED
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 preoperative 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
Exclusion Criteria
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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)
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
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
Pre-registration/Randomisation
Evaluations
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CT scans of chest, abdomen & pelvis must be done within 16 weeks prior to
randomisation/study entry
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Randomisation must occur within 10 weeks of surgery
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Colonoscopy should be performed within 3 months of surgery if not
performed prior to surgery. However this is NOT an entry requirement
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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
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Completion of EORTC, EQ-5D & NTX questionnaires
CRFs/Questionnaires
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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
CRF Completion
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CRF completion guideline document will be provided to all sites
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Black ball-point pen
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Correction fluid etc. must not be used
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Errors crossed out with a single stroke, correction inserted and
change initialled and dated
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An explanation can be written next to amendment if necessary
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Date format: DD / MON / YYYY
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Information on CRFs must be verifiable in source documents
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Take photocopy of all completed CRFs
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Original to OCTO/CTU Glasgow
Follow-up
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Patients on the 12 week treatment arm will be reviewed monthly for 3 months after completion of chemotherapy
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All patients will be assessed at 3 monthly intervals until month 12
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Then 6 monthly until month 24 and annually thereafter
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CT scans for all patients are required at the following timepoints:
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Month 6 (post rand)
Month 12 (post rand)
Month 18 (post rand)
Month 24 (post rand)
Month 36 (post rand)
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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.
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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).
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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
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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.
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
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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
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;
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.
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
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
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
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.
Reporting SAEs
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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
SAE Report Form completion –
General Tips
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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.
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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.
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Do not use abbreviations for completing any part of the SAE report or SAE queries.
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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.
SAE Report Form completion –
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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.
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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.
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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.
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Section 3.4 – Adverse Events –
– when submitting an initial report the adverse event section is a mandatory field.
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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.
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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.
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Please ensure the correct code is entered into the appropriate column for each trial drug.
SAE Report Form completion –
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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.
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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.
SAE Report Form completion –
Mandatory Information at Initial Notification
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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.
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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.
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SAE report forms must be signed by the PI / designee as agreed on the staff contact and
responsibility sheets.
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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
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Tel: 0141 301 7209 or
Email: [email protected]
at Pharmacovigilance at the Cancer Research UK, Clinical Trials Unit, Glasgow.
Procedure for Identifying and Reporting
Unexpected and Related Events
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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
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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
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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
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
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
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 chemotherapyrelated 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
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
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.
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
Oncology Clinical Trials Office
Depart of Clinical Pharmacology
Old Road Campus Research Building
University of Oxford
Old Road Campus
Off Roosevelt Drive
Headington
Oxford, OX3 7DQ
Tel: +44(0) 186 561 7018
Fax: +44(0) 186 561 7010
E-mail: [email protected]
CR-UK CTU, Glasgow
Cancer Research UK Clinical Trials Office
Level 0
Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow, G12 0YN
Tel: +44(0) 141 301 7191
Fax: +44(0) 141 301 7184
E-mail: [email protected]