1 LOGS: A randomised phase II/III study to assess the efficacy of trametinib (GSK 1120212) in...

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LOGS: A randomised phase II/III study to assess the efficacy of trametinib (GSK 1120212) in patients with recurrent or progressive low grade serous ovarian cancer

or peritoneal cancer (GOG-0281)(EudraCT Number: 2013-001627-39)

UK Chief Investigator – Professor Charlie GourleyUK Sponsor – NHS Greater Glasgow & Clyde and University of Glasgow UK Co-ordinating Centre: CRUK Clinical Trials Unit, Glasgow

Initiation Slides – Version 1, 25th March 2015

Study Details

•Study will be conducted according to ICH GCP guidelines

•Study 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), Edinburgh (2000), Washington (2002), Tokyo (2004), Seoul (2008) amendments

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**Please note this presentation has been prepared as part of your site initiation. These slides are a compliment to the protocol and UK appendix to protocol, all site staff must

have read and understood the protocol, UK appendix to the protocol and the study requirements prior to signing off the initiation acknowledgement sheet.**

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Study Organisation

• This trial is an Intergroup Trial jointly conducted by Cancer Therapy Evaluation Program (CTEP)/ Gynecologic Oncology Group (GOG) from USA, and National Institute for Health Research (NIHR) Clinical Research Network Cancer, United Kingdom.

• GOG is the lead co-ordinating group for the study.

• The Sponsor of this clinical trial in the UK is NHS Greater Glasgow and Clyde (NHS GG&C) and The University of Glasgow (GU).

• In the UK the trial is being run under the auspices of the NIHR Clinical Research Network Cancer/NCRI Gynaecology Clinical Study Group. The study is endorsed by Cancer Research UK (CTAAC), and is part funded by GlaxoSmithKline under the terms of the collaboration with the NIHR Clinical Research Network Cancer, United Kingdom

• The Cancer Research UK Clinical Trials Unit, Glasgow (CTU) is co-ordinating the UK participation in the trial on behalf of NCRI/NIHR Clinical Research Network Cancer, NHS GG&C and GU.

• The UK Chief Investigator is Professor Charlie Gourley

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Study Team in UK

UK Chief Investigator: Professor Charlie Gourley

Lead Pathologist UK: Dr David Millan

Project Manager: Karen Carty

Pharmacovigilance: Lindsey Connery

Sponsor Pharmacy Contacts: Paula Morrison + Eliza Valentine

Clinical Trial Co-ordinator: Diann Taggart

Clinical Trial Monitor: Jan Graham

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Study Design

Design:

This is an un-blinded, randomized phase II/III study comparing trametinib to “standard therapy” (consisting of one of five commercially available agents) in patients with recurrent low-grade serous carcinoma of the ovary or peritoneum previously treated with platinum based chemotherapy.

Patients will be randomized in a 1:1 ratio to receive trametinib or standard of care (control arm). The randomization will be stratified using minimization by the following factors:

- Geographical region (UK or US)- Performance status (0 or 1)- Number of prior treatment regimens - Planned treatment regimen (if patient draws control arm)

Study sample size – 250 patients

Study Objectives (1)

Study Objectives

Primary Objective:To estimate the progression-free survival (PFS) hazard ratio of trametinib compared to that of

“commercially available therapies” consisting of one of five commercially available agents in women with recurrent low grade serous carcinoma of the ovary or peritoneum previously treated with platinum-based chemotherapy.

Secondary Objectives:- To determine the nature, frequency and maximum degree of toxicity as assessed by CTCAE v4

for each treatment arm.- To determine the quality of life, as assessed by the FACT-O- To compare trametinib to the control arm with regard to patients self reported acute (up to post

cycle 6) as measured by FACT-O-TOI.- To compare trametinib to the control arm with regard to patients self reported acute (up to post

cycle 6) neurotoxicity as measured by the FACT-GOG-NTX.- To estimate the objective response rate (RR) of patients in each arm.

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Study Objectives (2)

Exploratory Objectives:•To estimate the overall survival of patients in each treatment arm.•To estimate the tumour response rate in patients receiving trametinib after crossover from standard of care.•To compare trametinib to “endocrine standard therapy” with regard to patients self reported acute quality of life and neurotoxicity, as measured by FACT-O-TOI and FACT-GOG-NTX

Translational Research Objectives:•Next generation sequencing of DNA isolated from formalin-fixed, paraffin-embedded sections of tissue from primary diagnosis or recurrence, and pre-treatment core biopsies (the latter stored in nucleic acid friendly fixative) to allow mutational analyses of genes in the MAPK and P13K/AKT/mTOR pathways and to explore their relationship with tumour response in patients treated with trametinib.•To examine protein levels of ER, PR, pERK, and DUSP6 and explore their relationship with tumour response in patients treated with trametinib.•To perform a more comprehensive analysis of phosphoprotein activation using reverse phase protein array analysis and correlate this with response and outcome.•To identify transcriptional signatures by RNAseq or gene expression microarray analysis that will predict MEK addiction and sensitivity to trametinib.•To conduct studies of specific genes in cell-free DNA in plasma of patients and to explore their relationship with tumour response to trametinib.•To examine the pharmacokinetics of trametinib.

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Key Patient Selection Criteria

**Please refer to section 3.0 of the study protocol for full details of the eligibility criteria for the study (Brief details of the key selection criteria only is detailed on this slide)**

•Patients initially diagnosed with either low-grade serous or serous borderline tumour of ovarian or primary peritoneal origin that persists or recurs as low-grade serous carcinoma.•Pathological confirmation of low grade serous histology by central review must occur prior to study entry This can be performed on tissue from the recurrent carcinoma or from original diagnostic specimen. •Relapse or progression following platinum-based chemotherapy.• Patients may not have received all of the five choices in the “standard therapy” arm.•Disease assessable by RECIST criteria (version 1.1).•ECOG performance status 0 or 1.•Satisfactory pre-study ophthalmic assessment.•Patients agrees to fresh tumour biopsy (mandatory).

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Pre-randomisation/ Baseline Assessments

Baseline scanning assessments to be performed within 28 days prior to initiating protocol therapy:- Medical history and physical examination- Opthalmologic examination- CT or MRI scan of chest, abdomen and pelvis (scans must be reported to RECIST v1.1)- ECG- Echocardiogram or MUGA scan- CT/Ultrasound guided biopsy- Toxicity Assessment- Urinalysis- Quality of Life Assessment

Baseline assessments to be performed within 14 days prior to initiating protocol therapy: - Serum pregnancy test (for patients of childbearing potential)- Vital signs (Blood pressure, pulse rate, height and weight)- CA125

Baseline assessments to be performed within 7 days prior to initiating protocol therapy: - Full blood count (including haemoglobin, neutrophils, platelets, WBC + coagulation [PTT, PT/INR])- Biochemistry (Potassium, BUN, Creatinine, Calcium, Magnesium, Phosphate, Bilirubin, AST, Alkaline Phosphatase)

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Reporting to RECIST

• All radiological investigations must be reported as per protocol / RECIST version 1.1.

• Source documentation of this must be available for review if the original report has had to be supplemented to bring it in line with protocol requirements.

• CRUK CTU, Glasgow have produced a worksheet to assist with the documentation of study specific reporting and will make this available to any participating site upon request to the study monitor

Screening Process – Pathology review

• As patients are identified for the trial and once informed consent has been given, the Investigator or designee should complete screening form for pathology review then contact the CRUK Clinical Trials Unit, Glasgow immediately via fax to request a screening identifier for the patient.

Fax no: 0141 301 7228

• Sites should then organise to send 3 H&E stained slides from their pathology department obtained at primary surgery and/or relapse documenting low grade serous carcinoma to the UK Lead Pathologist for the study (Dr David Millan) at below address:

Dr David Millan, Department of Pathology Laboratory, Medicine + Facilities Management Building Southern General Hospital,1345 Govan Road, Glasgow, G52 4TF

• Once received the slides will be reviewed by the UK pathology review panel for the study and agreement reached as to whether the accepted criteria is met. A majority decision will be acceptable

• The review decision will be emailed to the CRUK Clinical Trials Unit, Glasgow who will subsequently inform the site.

• Patients who meet the accepted criteria will then be able to be randomised to the trial, following completion of registration/randomisation form.

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Registration/Randomisation Process

• UK Investigators/Sites will randomise patients only through CRUK Clinical Trials Unit, Glasgow. The CRUK Clinical Trials unit, Glasgow will perform the randomisation via the NCI Cancer Trials Support Unit (CTSU) online registration system “OPEN” on behalf of the UK sites.

• Sites require to do the following:

• Once sites have completed the registration/randomisation form for the study, which should be faxed to the CRUK CTU, Glasgow Fax No: 0141 301 7228 during office hours Monday- Friday.

** Please note prior to randomisation of patients, UK central pathological review requires to have taken place to confirm patient’s eligibility, the process for UK central pathology review is detailed on previous slide.**

• Each patient randomised will be allocated a unique study identifier XXX-0281-XXX (The first set [xxx] is the institution number, and the last set [xxx] is the sequential on study number, assigned at registration along with treatment allocation.

Check patient has given written informed consent

Check patient fulfils eligibility criteria per study protocol and within protocol stated timeframes

Complete Registration/Randomisation Form

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Treatment and Duration

For each arm, one cycle is 28 days. The first dose of study medication should be administered as close as possible after randomization.

Arm A (Control Arm)Clinician’s choice of ‘control’ arm is made from the list below prior to randomization:•Letrozole 2.5mg orally once daily continuous treatment until progression or unacceptable toxicity•Tamoxifen 20mg orally twice daily continuous treatment until progression or unacceptable toxicity•Paclitaxel 80mg/m2 IV infusion over one hour on days 1, 8, and 15 of a 28 day cycle until progression or unacceptable toxicity or until 6 cycles have been administered*•Pegylated Liposomal Doxorubicin 40 or 50mg/m2 IV infusion over one hour on day 1 every 28 days until progression or unacceptable toxicity or until 6 cycles have been administered*•Topotecan 4.0 mg/m2 IV infusion over 30 minutes on days 1, 8, and 15 of a 28 day cycle until progression or unacceptable toxicity or until 6 cycles have been administered* *more than 6 cycles of chemotherapy can be administered at investigator’s discretion

Arm B (Experimental Arm)•Trametinib 2 mg orally once daily continuous treatment until progression or unacceptable toxicity

Crossover

• In this study if a patient develops progressive disease on Arm A – Control Arm (as defined in study protocol section 8.134), the patient will be given the opportunity to crossover to Arm B -Experimental Arm [Trametinib Arm].

• Prior to crossover, the following must occur: • The patient’s progression must be fully documented on the relevant GOG electronic case report forms

(CRFs) and submitted via Medidata Rave Electronic Data Entry System (www.imedidata.com) online application which is being used for the study. The relevant CRFs require to be submitted prior to the patient starting crossover treatment.

• All eligibility criteria as defined in study protocol section 3 must be met (with the exception of 3.143, 3.15, and 3.114). This includes requirement that 4 weeks must elapse between the end of treatment with Arm A and start of treatment on Arm B. These requirements will be documented on the CRFs.

• If the patient meets all of the above noted requirements, she will be able to crossover and commence treatment on Arm B.

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Duration of Study/ Study Visits

• Patients will receive therapy until disease progression or intolerable toxicity intervenes. Patients can refuse the study treatment at any time.

• All patients will be treated until disease progression or study withdrawal. All patients will then be followed up (with physical examinations and histories) every three months for the first two years, then every six months for the next three years and then annually for the next 5 years. All patients will be monitored for delayed toxicity and survival for this 10 year period with follow-up forms submitted via Medidata Rave, unless consent is withdrawn.

• All patients will be followed for 10 years after removal from study or until death, whichever occurs first.

• Please refer to study protocol investigations tables for the study to ensure the correct observations and tests are performed at protocol specified time points.

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Treatment Modifications (1)

**Please refer to section 6.0 of the study protocol for full details of treatment modifications/dose reductions/delays (Brief details in relation to treatment modifications are provided on these slides)**

Doses will be reduced for haematological and other adverse events. Dose adjustments are to be made according to the greatest degree of toxicity. Adverse events will be graded using NCI CTCAE v4.0

Control Treatments (Arm A)Dose adjustments as per standard care

Trametinib (Arm B)The severity of adverse events will be graded using NCI CTCAE v4.0. Detailed guidelines for dose modifications and interruptions for management of common toxicities associated with the study treatment are provided in section 6.2 of the study protocol. The guidelines outline the dose adjustments for several toxic effects. If a patient experiences several adverse events and there are conflicting recommendations, use the recommended dose adjustment that reduces the dose to the lowest level. The table below outlines the dose levels to be used for any necessary trametinib dose modifications :

A maximum of two trametinib dose level reductions are allowed. If a 3 rd dose level reduction is required, treatment will be permanently discontinued.

Dose Level Trametinib Dose/Schedule0 2 mg QD (QD= once daily)-1 1.5 mg QD (QD=once daily)-2 1 mg QD (QD – once daily)

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Treatment Modifications (2)Trametinib (Arm B)

As documented on previous slide the detailed guidelines for dose modifications and interruptions for management of following common toxicities associated with the study treatment should be referred to:

- Hypertension- Rash- Ejection fraction changes- Pneumonitis- Diarrhoea - Liver chemistry- QTc prolongation- Visual changes

Treatment Modifications (3)Trametinib (Arm B)For the management of any other adverse events deemed related to Trametinib the following guidance table(s) (from section 6.21 of study protocol) should be used for dose modifications:

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General Pharmacy Information (1)

• The investigational medicinal products in this study are:- Letrozole- Tamoxifen- Paclitaxel- Pegylated Liposomal Doxorubicin- Topotecan- Trametinib (GSK1120212)

• All the IMPs for use in the trial with the exception of Trametinib (GSK1120212) will be from sites own stock. There is no provision for funding, reimbursement or discounted stock.

• Trametinib will be provided free of charge by GlaxoSmithKline(GSK) and supplied and distributed by Catalent to UK sites for use in the study.

• The CRUK CTU, Glasgow will trigger the initial supply of Trametinib for the UK sites at the time of site activation. Delivery will take approximately 5 working days.

• Details for re-supply ordering of Trametinib can be found in the IMP Management Document for the study .

• Although specific formulations are mentioned in the study protocol, UK sites are permitted to use locally approved formulations. This must be confirmed to the CR-UK Clinical Trials Unit during initiation process.

• Chemotherapy doses may be recalculated every cycle during treatment if it is local practice to do so (e.g. automatic updates by electronic prescribing systems). Where it is not local practice to recalculate every cycle the doses MUST be recalculated if the subject’s weight changes by greater than or equal to 10% from baseline.

General Pharmacy Information -2

• BSA calculations should be performed as routine local practice and capped at 2.0m 2

• Chemotherapy doses may be dose banded if it is routine local practice to do so. This must be confirmed to the CR-UK Clinical Trials Unit during initiation process.

• The Investigator or a delegated individual (e.g. pharmacist) must ensure all IMPs are stored and dispensed in accordance with study protocol, local standard operating procedures, applicable regulatory requirements and the information contained within the current summary of product characteristics/investigator brochure for each product

Accountability of IMPs:• IMP accountability logs will be provided by the UK Sponsor for recording the movement of all IMPs used within the study.

Each patient taking part in the study should have a log maintained of the IMP administered, the date of administration, the cycle number, the dose administered and the brand, batch number and expiry date of the product administered.

• Full accountability records for Trametinib are required, documenting receipt of bulk supplies as well as patient dispensing.

These must be accurately maintained and updated at the time of each dispensing or other drug movement for the duration of the study and should be kept in the study pharmacy file.

• Patients will be required to return all bottles of study medication at the beginning of each 28 day cycle. The number of tablets remaining must be documented in the accountability log.

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General Pharmacy Information -3

IMP Disposal & Destruction•For the control arm, used or partially used vials, dose-banded infusions or syringes may be disposed of at site according to local hospital policy with no additional accountability required. Oral products will require reconciliation of empty or part-used containers of IMP returned from patients, within the accountability logs, as a measure of patient compliance, before disposal as per local policy.

•Destruction of Trametinib un-dispensed stock, if necessary, should be undertaken after the UK Sponsor has given written permission, in line with local policies and procedures . Destruction of bulk supplies will be recorded on the LOGS IMP Accountability Log which will be provided for use.

•Full instructions regarding management, labelling and accountability is given in the IMP Management and Accountability Manual for the study which will be provided to sites in the pharmacy file.

•Separate initiation slides are also provided for pharmacy staff.

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Site Set-up

CTU Glasgow - REC approval - MHRA approval - Site Initiation Slides - Investigator File - Pharmacy File - Royal Mail Safeboxes - Sample Collection Kits

SITE - SSI - Staff Contact and Responsibilities Sheets - R&D Approval - CVs for Study Team - Clinical Trial Agreement - GCP Certificates for Study Team - PIS, Consent, GP Letter etc on trust headed paper - Laboratory normal ranges and accreditation certificates

(Haematology and Biochemistry) - PI completes FDA 1572 form, Financial Disclosure Form and Supplemental Investigator Data Forms - Confirmation of valid federalwide assurance number for site/institution

Initiation Process

SITE ACTIVATED

Activation of site

Notification by email

Informed Consent Process

Informed consent process:•Two original Consent Forms must be completed by a clinician (or deputy listed on delegation log)•Two originals signed and completed by the patient•Date must be prior to registration •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 FOR ERRORS NOTED AFTER CONSENT•Add explanatory note/file note•New version of Patient Information Sheet must be provided to patients consented with previous version. This must be given to all patients regardless of treatment stage, during next possible clinic visit.•Patients who are still on active treatment will be required to repeat the consent process using the updated form. If it is not appropriate to re-consent patient (i.e. patient terminally ill) please make a note regarding this in the patients case notes and on re- consent log which is filed in your study site file.

CONSENT WITHDRAWAL

This is when the patient specifically asks to withdraw their consent at any point in the study. If this occurs:– Document clearly in the patient notes that the patient has withdrawn consent, the level of consent withdrawal and

the reason (if the patient has given any) – Inform GOG via follow-up form in medidata rave;– No further follow-up should be collected on the patient from that point onwards.

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CRFs/CRF Completion

GOG Data Management Forms• Data collection for this study will be done through the Medidata Rave Clinical Data Management system. Full instructions

are included in the data submission section of the protocol: section 10.2 GOG Data Management. • Please refer to protocol section 10.3 Data Management Forms for details of the case report forms and schedule for the

submission of forms required for each patient.• There are training modules for medidata rave which must be completed by site staff before access to the system is granted.

Paper SAE – Pregnancy Notification Forms • Copies of the SAE Form and pregnancy notification forms and completion guidelines for the SAE and pregnancy notification

forms have been provided by the Pharmacovigilance Team, CRUK CTU, Glasgow a copy of which will be filed in Investigator Site File.

• SAE and pregnancy notification forms have to be completed and sent via fax to the Pharmacovigilance Office, CRUK CTU, Glasgow (Fax no 0141 301 7213)

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Translational Research (1)

• In this study, tissue specimens will be collected for future translational research.

• These specimens include a mandatory pre-treatment fresh tissue biopsy and non-mandatory collections of archival formalin fixed paraffin embedded (FFPE) specimen(s), plasma drawn at various points in the patient journey and optional on-treatment/post-progression tumour biopsies. Specimens will be collected from enrolled patients who have consented to the future translational research.

• Additional plasma specimens for PK testing will be collected from a subset of patients (approximately 12 UK patients)

Sample collection, storage and processing:• Detailed instructions for the processing, labelling, handling storage and shipment of these specimens will

be provided in the LOGS translational research manual • A table providing a summary of the specimen requirements for the study is detailed on the next slide.


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Summary of tumour specimen requirements for translational research

Required Specimen (Specimen Code) Collection Time Point Ship To

Fresh Recurrent Primary Biopsy (RRP01)1

Prior to trial treatment (either arm) Mandatory (eligibility requirement)

Edinburgh Cancer Centre within 1 week of registration2

FFPE Primary Tumor (FP01)1st Choice: block2nd Choice: 20 unstained slides (10 charged, 5µm + 10 uncharged 10 µm)

Prior to trial treatment (either arm) Optional3

Edinburgh Cancer Centre within 8 weeks of registration2

FFPE Metastatic Tumor (FM01) 1st Choice: block2nd Choice: 20 unstained slides (10 charged, 5µm + 10 uncharged 10 µm)


FFPE Recurrent Primary Tumor(FRP01)1st Choice: block2nd Choice: 20 unstained slides (10 charged, 5µm + 10 uncharged 10 µm)


FFPE Recurrent Metastatic Tumor (FRM01)1st Choice: block2nd Choice: 20 unstained slides (10 charged, 5µm + 10 uncharged 10 µm)


Fresh Progression Tumour Biopsy (PTB01)3

Within 4 weeks of documented disease progressionOptional3

Edinburgh Cancer Centre within 1 week of being taken2

1. Please note the protocol-specific biopsy processing instructions described in the laboratory manual.2. Please ship all specimens to: Mr Alex MacLellan, Edinburgh ECMC.3. Centres are encouraged to submit optional specimens wherever possible.


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Summary of blood specimen requirements (ctDNA) for translational research

1. Please note the protocol-specific biopsy processing instructions described in the laboratory manual.2. Please ship all specimens to: Mr Alex MacLellan, Edinburgh ECMC.3. Centres are encouraged to submit optional specimens wherever possible.4. Please note the protocol-specific plasma processing instructions described in the laboratory manual


Pre-Treatment Plasma (PB01) prepared from 7-10mL of blood drawn into a K2 EDTA tube4


Samples will be batch transferred from sites to Edinburgh Cancer Centre periodically e.g. every 6 months or annually depending on recruitment2

C3D1 Pre-Treatment Plasma (PB06) prepared from 7-10mL of blood drawn into a K2 EDTA tube4

Cycle 3, day 1, prior to administering treatmentOptional3


Cycle 6, day 1, prior to administering treatmentOptional3

Disease Progression Plasma (PB09) prepared from 7-10mL of blood drawn into a K2 EDTA tube4

Within 4 weeks of documented disease progressionOptional3



C1D15 4-8 Hour Post-Treatment (PB02) prepared from 7-10mL of blood drawn into a K2 EDTA tube1

Cycle 1, day 15, 4 to 8 hours (±15 minutes) after administering trametinib

Samples will be batch transferred from

sites every 6 months to Covance in US.


The last day of cycle 1, prior to administering trametinib

C1D29 2 Hour Post-Treatment Plasma (PB04) prepared from 7-10mL of blood drawn into a K2 EDTA tube1

The last day of cycle 1, 2 hours (±15 minutes) after administering trametinib

C2D1 30 Minute Post-Treatment Plasma (PB05) prepared from 7-10mL of blood drawn into a K2 EDTA tube1

Cycle 2, day 1, 30 minutes (±5 minutes) after administering trametinib

C3D1 30 Minute Post-Treatment Plasma (PB07) prepared from 7-10mL of blood drawn into a K2 EDTA tube1

Cycle 3, day 1, 30 minutes (±5 minutes) after administering trametinib

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Additional plasma specimens for PK testing to be collected from a subset of patients

Central Radiographic Image Review

• Retrospective central radiographic review is planned for this study. It is therefore a requirement for sites to send anonymised scans on disc for patients for all scans the patient receives whilst on study.

• The CRUK CTU, Glasgow will provide a batch of CDs for use within the trial before the trial site opens to recruitment. The CRUK CTU, Glasgow should be contacted for further supplies.

• Full instructions for the preparation and transfer of the scans to the CRUK CTU, Glasgow are detailed in section 14 of the UK appendix to the protocol.

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Pharmacovigilance

ICH GCP and the EU Directive 2001/10 EC require that both investigators and sponsors follow specific procedures when notifying and reporting adverse events/reactions in clinical Trials. These procedures are described below and on subsequent slides:

• Investigators require to document Adverse Events (AEs) in patient notes and the CRF as required.• Investigators report Serious Adverse Events (SAEs) immediately and no later than 24 hours from the time the

investigator/staff become aware of the event to the Pharmacovigilance Office, CRUK Clinical Trials Unit, Glasgow (CRUK CTU).

• The CRUK CTU Pharmacovigilance Team will assess all SAEs which occur in the trial in UK to identify trial SUSARs and will prepare SUSAR reports for submission.

• The CRUK CTU Pharmacovigilance Team will be responsible for submitting the SUSARs to the MHRA, Research Ethics Committee, CRUK CTU Contacts and UK trial sites.

• The CRUK CTU Pharmacovigilance Team will enter all SAE reports which occur in UK into the US safety reporting system CTEP AERS (Adverse Event Reporting System).

• CRUK CTU Pharmacovigilance Team will produce and provide the Development Safety Update Reports (DSURs) for the study in conjunction with the US Sponsor.

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Definition of Adverse Event (AE)

• An adverse event is defined as “any untoward medical occurrence in a subject to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product.”

• An adverse event can therefore be any unfavourable and unintended signs (such as rash or enlarged liver), symptoms (such as nausea or chest pain), an abnormal laboratory finding (including results of blood tests, x-rays or scans) or a disease temporarily associated with the use of the protocol treatment, whether or not considered related to the investigational medicinal product

• 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

• The severity of all AEs (serious or non serious) in this trial must be graded according to the NCI-CTCAE Version 4.0. A copy of this can be downloaded from the following website:

http://ctep.cancer.gov

http://ctep.cancer.gov/

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Definition of a SERIOUS ADVERSE EVENT (1)

A Serious Adverse Event (SAE) is defined as untoward medical occurrence or effect in a patient , whether or not considered related to the trial treatment which:

• Results in death • Is Life-threatening (i.e. a the time of the event)* in which the subject was at risk of death at the time of the

event; it does not refer to an event which hypothetically might have caused death if it was more severe) • Requires inpatient hospitalization or prolongation of existing patient hospitalization **• Results in persistent or significant disability or incapacity • Is a congenital anomaly or birth defect • Is considered medically significant by the Investigator ***

*Life threatening means that the patient was 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 should be defined as a hospital admission required for treatment of an AE.***Considered medically significant by the Investigator are events that may not result in death, are not life threatening, or do not

require hospitalisation, but may be considered a serious adverse experience when, based upon appropriate medical judgement, the event may jeopardise the patient and may require medical or surgical intervention to prevent one of the outcomes listed above.

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Definition of a SERIOUS ADVERSE EVENT (2)

Please note in addition to definitions of an SAE noted on previous slide for this study there are additional SAE reporting requirements for this study as detailed below:

A table is provided in the protocol and UK appendix to the protocol of the Comprehensive Adverse Event and Potential Risks list (CAEPR) in the safety reporting section.

The CAEPR provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system.

In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions which require to be reported as SAEs (except as noted below).

NOTE: Report AEs on the SPEER as an SAE ONLY IF they exceed the grade noted in parentheses next to the AE in the SPEER.

Prior to recruitment commencing at sites, it is essential for sites to familiarize themselves with the additional SAE reporting requirements for the study.

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Reporting Procedure for SAEs (1)

• Serious Adverse Events (SAEs) must be reported immediately (and no later than 24 hours of from the time the investigator or staff became aware of the event)

• SAEs are reported using the CRUK CTU SAE report form provided for the study

• Sites must complete the CRUK CTU SAE report form and fax the report to: Pharmacovigilance Office, CRUK CTU, Glasgow Fax number: 0141 301 7213

This procedure applies to all Serious Adverse Events (SAEs) occurring from the time a subject is randomised until :

30 days after last administration of study treatment and to any SAE that occurs outside of the SAE trial treatment period (after the 30-days period), if it is considered to have a reasonable possibility to be related to the protocol treatment or study participation.

• All reporting must be done by the principal investigator or authorized staff member (i.e. on the signature list) to confirm the accuracy of the report.

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Reporting Procedure for SAEs (2)

• To enable the Sponsor to comply with regulatory reporting requirements, all initial SAE reports should include the following minimal information:

- Trial Identifier (Patient Trial Identifier)- Suspect medicinal product (if applicable)- Identifiable reporting source (the reporter and name of PI)- Description of medical event and seriousness criteria- Casuality assessment by investigator (if related or not to the trial drugs)

• Site staff and Investigators must promptly provide full and detailed information for all SAEs on each SAE report. Failure to do so will compromise the ability of the CTU to meet US legal safety reporting requirements and therefore may result in sanctions for the reporting Investigator.

• A follow-up report must be completed when the SAE resolves, is unlikely to change, or when additional information becomes available. If the SAE is a suspected SUSAR then follow-up information must be provide as quickly as possible as requested by the CRUK CTU and Chief Investigator

• Queries sent out by the CRUK CTU, Glasgow Pharmacovigilance Office need to be answered within 5 days.• All forms need to be dated and signed by the principal investigator or authorised staff member

Procedure for Reporting SAEs and SAE Report Processing

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Pregnancy Reporting

• Pregnancy occurring in a clinical trial participant while not considered an AE or a SAE, requires monitoring and follow-up. The Investigator must collect pregnancy information for female trial subjects. This includes subjects who become pregnant while participating in a clinical trial of an investigational medicinal product or during a stage where the foetus could have been exposed to the IMP.

• Any pregnancy occurring in a female subject who becomes pregnant while participating in a trial will be reported by the Principal Investigator (PI) to the Pharmacovigilance Office of the CRUK CTU, Glasgow using the Pregnancy Notification Form (PNF).

• This notification must be made immediately of the PI first becoming aware of the pregnancy. The PI will update the PNF with the outcome of the delivery or if there is a change in the subject’s condition such as miscarriage. The updated PNF must be sent to Pharmacovigilance Office of the CRUK CTU, Glasgow as soon as the information becomes available.

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Monitoring All participating study sites will be monitored by a member of the CR-UK Clinical Trials Unit, Glasgow, Monitoring Team

The 1st visit will take the form of a simple telephone monitoring call to be completed within 10 working days of the site being activated. This call is simply to ensure that trial specific training is being undertaken, and that no site specific facility problems have been encountered and assist with any site specific problems at an early stage.

The 2nd visit will be an Telephone Monitoring Visit. (This is scheduled to take place 8 weeks after first patient randomised at each site)

The 3rd visit will be an On-Site Monitoring Visit. (This is scheduled to take place 12 months after first patient randomised at each site)

The 4th visit will be an On-Site Monitoring Visit. (This is scheduled to take place 24 months after first patient randomised at each site)

The 5th visit will be a remote or On-Site monitoring visit at the end of trial

Site closeout visit, this may be combined with a routine on-site monitoring visit.

Telephone & Remote Monitoring: The time & date will be agreed with a member of the Site Study Team & a separate time & date agreed with a member of

the Clinical Trials Pharmacy Department.

A pro forma covering the questions which will be covered during the telephone monitoring visit will be sent with confirmation of the agreed date.

Please set aside 50 to 70 minutes for this call.

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On Site Monitoring• All patient source documentation should be made available to enable Source Document Verification by the Clinical Trial

Monitor.

• A full working day is required for on-site visits & arrangements should be in place to facilitate the monitor access on the agreed date.

• If sites are able to provide printed results/reports these must be filed in the source documents.

• If a site is using electronic data reporting systems or electronic records & hard copies are not available – the clinical trial monitor must be permitted access to the system either by being issued with a temporary login or a member of staff available for the duration of the visit to facilitate electronic access to authorised reports/results.

• Pharmacy visits will include review of Pharmacy Site File – Temperature Logs – Drug Returns – Drug Accountability Logs and Destruction of drug.

• All findings will be discussed at an end of visit meeting and any unresolved issues raised as Action Points.

• Action Points will be followed up by the monitor until resolved.

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Investigators Responsibilities (1)

The following principles are from ICH GCP Topic E6 and apply to clinical trials of Investigational Medicinal Products:

• Qualifications & Agreements:- The Investigator should be qualified by education, training & experience. - Thoroughly familiar with protocol & medicinal products.- Comply with GCP and applicable regulations.- Permit – monitoring and audit by the sponsor and inspection by regulatory authorities.- Maintain a delegation logs of staff involved in the clinical trial at the trial site.- Ensure that all persons assisting with the trial are adequately informed about the – protocol, IMP and their duties and functions.

• Resources:- The Investigator should have sufficient time to properly conduct and complete the trial within the agreed period.- Have available adequate facilities and qualified staff to conduct the trial properly and safely.

• Medical Care of Trial Subjects:- A qualified physician who is an Investigator (or co-investigator) should be responsible for all trial related medical decisions.- During and following participation the Investigator should ensure adequate medical care for any adverse events (AEs).- The Investigator should make as reasonable effort to ascertain reasons for withdrawal from the trial (although a subject is not obliged to give reasons)

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Investigator Responsibilities (2)

• Ethics:- Before initiating the trial there should be written and dated approval/favourable opinion from the Ethics

Committee for the protocol, patient information sheet/consent form and any amendments.

• Compliance with Protocol:- The Investigator should conduct the trial in compliance with the protocol.- Not implement any deviation from the protocol without prior approval/favourable opinion of

the IEC and the sponsor.- The Investigator should document and explain any deviation from the protocol.

• The IMP :- Investigator has responsibility for IMP accountability at trial site.- Some/all IMP duties at the trial site may be assigned to suitably qualified pharmacist.- Records must be maintained: delivery, inventory, use and destruction- Storage of the IMP should be as specified by the sponsor/regulatory requirements.- The IMP should only be used in accordance with the protocol.- The Investigator (or designee) should explain the correct use of the IMP to each patient.

• Randomisation:- The Investigator should follow the trial’s randomisation procedures as detailed in the protocol.

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Investigator Responsibilities (3)• Informed consent:

- In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement (s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki.

• Reports & records – The investigator is responsible for accuracy, completeness, legibility and timeliness of the data reported to the sponsor.- Data reported on CRFS, from source documents should be consistent with source documents or discrepancies explained.- Corrections should be : dated, initialled, explained (if necessary) and should not obscure the original entry.- All trial documents should be maintained as specified in ICH GCP E6, Section 8 (Essential documents for the conduct of a clinical trial).

• Safety reporting:- Investigators must report Serious Adverse Events to the sponsor (EORTC) as soon as they become aware of the event.

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Other Staff

The Principal Investigator has overall responsibility for the conduct of the clinical trial at the trial site.BUT

• All staff must comply with GCP.• Staff should only perform tasks delegated to them.• Staff should ensure that their details are available to the Investigator.• Staff should maintain appropriate confidentiality at all times

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Contact Details for CRUK CTU, Glasgow

CRUK CTU, Glasgow Cancer Research UK Clinical Trials Unit Level 0, Beatson West of Scotland Cancer Centre

1053 Great Western Road, Glasgow, G12 0YN

Karen Carty, Project Manager Tel no : 0141 301 7197 E-mail: [email protected]

Diann Taggart ,Clinical Trial Co-ordinatorTel no: 0141 301 7234 Email: [email protected]

Jan Graham, Clinical Trial MonitorTel no: 0141 301 7956 Email: [email protected]

mailto:[email protected]



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