Presentation on theme: "SCOT Short Course Oncology Therapy"— Presentation transcript:
1 SCOT Short Course Oncology Therapy A Study of Adjuvant Chemotherapy in Colorectal Cancer
2 Study OrganisationSponsored 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 OxfordCR-UK CTU Glasgow and OCTO are responsible for setting up, day-to-day running, analysis and presentation of resultsChief Investigator is Professor Jim CassidySupported by a grant from the MRC
3 Study Team CR-UK CTU Glasgow Team Chief Investigator: Professor Jim CassidyProtocol Development and Co-Investigator: Dr Claire KellyTrial Statistician: Mr Jim PaulProject Management: Mrs Tracey McMahon/ Mrs Karen Carty/Mrs Andrea HarkinPharmacovigilance: Mrs Lindsey Connery/Miss Katie NocherQuality Assurance: Mrs Lindsey ConneryClinical Trial Co-ordinators: Karen WilsonOncology Clinical Trial Office (OCTO), Oxford TeamCo-investigator: Professor David KerrProject Management: Ms Sarah PearsonQuality Assurance: Ms Joanne Stokes/ Luise DunhamClinical Trial Co-ordinator: Javier Moreno-FarreClinical Trial Administrator: Ketan PujaraClinical Trial Support Officer: Gaynor Bates
4 Study SummaryStudy design: phase III, randomised controlled, two arm, multi-centre, non-inferiorityStudy treatment:Study recruitment: 9500 patients over 5 years (150 sites in the UK)Study population: patients with colorectal cancerTimelines:- Recruitment started in March 2008- Planned accrual completion is March 2013- Trial analysis and publication planned for 2016- Trial duration of 7 yearsRandomiseSTANDARD24 weeksXELOX/ OxMdGChemotherapy[4750 patients]EXPERIMENTAL12 weeks
5 Objectives & Endpoints Assessment of the efficacy of 12 weeks of treatment vs 24 weeks of treatment and comparison of the associated toxicityEconomic analysis to assess the cost-effectiveness of the two treatment alternativesComparison of two randomisation methodologiesEndpointsPrimary 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 chemotherapyPrior 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 RandomisationThe 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.
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 GlasgowEach patient registered will be allocated a unique study identifier.Contact GP (See GP Letter in the Protocol).RANDOMISATION SERVICECTU Glasgow randomisation serviceTel: 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 CentreChoice of regimenGenderDisease siteT-stageN-stage
12 Treatment armsArm A (Standard treatment) - 24 weeks of XELOX/OxMdG chemotherapyArm B (Experimental treatment) - 12 weeks of XELOX/OxMdG chemotherapyDose and administration of XELOX – 3 weekly cycle- Oxaliplatin 130mg/m2 IV on day 1- Capecitabine 1000mg/m2 PO twice daily for 14 daysDose 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 questionnaireCTU Glasgow/ OCTO- Main REC approval (Glasgow)- MHRA approval (Glasgow)- Site Initiation Calls- Investigator File- Pharmacy FileInitiation CallSite RandomisedNotification bySITE 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 protocolPatients 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 marginsNo evidence of residual or metastatic diseaseWithin 10 weeks of surgery at the time of randomisationWHO PS = 0 or 1Age > 18 yearsLife expectancy > 5 years with reference to non-cancer related morbidityWritten informed consentCEA within normal limits for your site
16 Exclusion CriteriaPrevious chemotherapy (Previous abdomino-pelvic radiotherapy, with the exception of short course pre-operative radiotherapy for rectal cancerModerate/severe renal impairment (GFR<30 ml/min), as calculated by the Cockcroft and Gault equationAbsolute neutrophil count<1.5x109/LPlatelet count <100x109/LHaemoglobin <9g/dLAspartate aminotransferase/alanine aminotransferase >2.5 x upper limit of normalClinically significant cardiovascular diseasePregnancy/lactation or of a child bearing potential and not using adequate contraceptionPrevious 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 yearsKnown 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 patientDate must be on or prior to randomisationMake one photocopy- Original to be filed in Investigator File- Original to be given to patient (+PIS)- Photocopy to be filed in hospital notesConsent Form must not be sent to your coordinating trials officeConsent 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 noteNew 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 postDuring clinic visitPatients 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 logIncrease 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 entryRandomisation must occur within 10 weeks of surgeryColonoscopy should be performed within 3 months of surgery if not performed prior to surgery. However this is NOT an entry requirementAssessments 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 TestCompletion of EORTC, EQ-5D & NTX questionnaires
20 CRFs/Questionnaires Site Randomisation Questionnaire Registration/Randomisation FormWeek 12 Randomisation FormConsent Notification FormTreatment FormFollow-up FormConsent Withdrawal Notification FormPregnancy Notification FormSAE FormEORTC quality of life questionnaireEQ-5D questionnaireGOG- NTX4 questionnairePatient Withdrawal questionnaire
21 CRF CompletionCRF completion guideline document will be provided to all sitesBlack ball-point penCorrection fluid etc. must not be usedErrors crossed out with a single stroke, correction inserted and change initialled and datedAn explanation can be written next to amendment if necessaryDate format: DD / MON / YYYYInformation on CRFs must be verifiable in source documentsTake photocopy of all completed CRFsOriginal to OCTO/CTU Glasgow
22 Follow-upPatients on the 12 week treatment arm will be reviewed monthly for 3 months after completion of chemotherapyAll patients will be assessed at 3 monthly intervals until month 12Then 6 monthly until month 24 and annually thereafterCT 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 FormIf 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 studiesCentres will be asked if they are willing to participate in Quality of Life collectionQuality of Life, economic and detailed toxicity data are required for approximately 700 patientsQuality of Life dataThe 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 dataThe EQ-5D questionnaire to be completed at the same frequency as QLQ questionnaires and at all follow up visits until study completionDetailed toxicity dataToxicity will be graded using the NCI-CTCAE Version 3.0GOG 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 WithdrawalThis 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 treatmentAll 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 irreversibleAll AE and toxicities must be graded according to the NCI-CTCAE Version 3.0Abnormal laboratory test should be recorded as an AE in the CRFAE 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 administeredAR 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 requiredAn 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 anyuntoward medical occurrence that is notnecessarily related to protocol treatment that:Results in deathIs Life-threateningRequires hospitalisation or prolongation of existing hospitalisationResults in persistent or significant disability or incapacityConsists of a congenital anomaly or birth defectIs 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 SAEsSerious 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 FormSites must complete the SAE report Form and fax the report to Pharmacovigilance at the Glasgow CTU fax numberThe CTU will create a SAE reference number and will send an acknowledgement fax to confirm receiptThe CTU will request additional information if the event is unexpectedCTU will raise queries for any inconsistent or missing informationSAEs 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 medicationAny 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 importantLD- suggest Serious Adverse Event (SAE) for 1st mentionStaff ‘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 formDocument only medically significant and pertinent lab findings in the SAE summary section.
32 SAE Report Form completion – weak areas - 1 Section 1 – Study/Patient DetailsReport 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 TreatmentsEnsure the frequency is correctly recorded (for capecitabine use the phrase as per protocol) and the correct cumulative doses are provided.Section 3.4 – Adverse eventsEnsure 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=definiteDo 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 SAEUse 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 MedicationList 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 ConneryTel: orat 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 SUSARsSAEs 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 proceduresAndUnexpected – that is the type of event is not listed in the Investigator Brochure, or Summary of Product Characteristics (SmPC) as an expected occurrenceReports 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 reliefIf 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 glucoseIf a SAE is considered to be an interaction between a NIMP and the IMP (the treatment drug) then it also requires to be reportedThe Chief Investigator is responsible for deciding if a SAR that is related to a NIMP requires expedited reporting
37 Annual Safety ReportsA report on the safety of trial participants from all trialsites will be prepared by the CTU Glasgow andsubmitted to the MHRA, Main REC, Sponsor & TrialInvestigators
38 Dose modifications for toxicity If grade 1 toxicity occurs treatment should continueDose modifications for diarrhoea, haematological and neurosensory toxicity can be found in the protocolFor all other toxicities > grade 3, treatment should be withheld until recovery to < grade 1 then restarted if medically appropriateIf patients take three weeks or longer to recover from chemotherapy-related toxicity they will receive no further treatmentIn the situation where oxaliplatin is discontinued due to toxicity, adjuvant treatment can continue with 5-FU aloneCrossover from capecitabine to 5-FU and vice versa is allowed for reasons of toxicityOnce the dose has been reduced it must not be escalatedLD- suggest ‘should’ rather than ‘will’ for 1st sentenceWhat about grade 2?
39 Study DrugAll IMPs for use in this trial should be taken from existing pharmacy shelf stock. There is no provision for funding, reimbursement or discounted stockIMPs should be stored under the correct conditions as per the SmPCAll products used in this study are licensed medications and will not be labelled specifically for the studyIMP 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 filePatients 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 samplesFull information will follow at a later stageCurrently 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 variablesTreatment detailRecurrences/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 SOPsSCOT is conducted in accordance with the EU Directive 2001/20/ECTrial 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 OfficeDepart of Clinical Pharmacology Level 0Old Road Campus Research Building Beatson West of Scotland Cancer CentreUniversity of Oxford Great Western RoadOld Road Campus Glasgow, G12 0YNOff Roosevelt DriveHeadingtonOxford, OX3 7DQTel: +44(0) Tel: +44(0)Fax: +44(0) Fax: +44(0)