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)

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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 Gourley
• UK 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

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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

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 GGC) 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 GGC 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 11 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

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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

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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 HE 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/randomi
  sation 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 patients
  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)
• Clinicians 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 investigators discretion
• Arm B (Experimental Arm)
• Trametinib 2 mg orally once daily continuous
  treatment until progression or unacceptable
  toxicity

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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 patients 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 3rd dose level
  reduction is required,
• treatment will be permanently
  discontinued.

Dose Level Trametinib Dose/Schedule
0 2 mg QD (QD once daily)
-1 1.5 mg QD (QDonce 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

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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 subjects weight
  changes by greater than or equal to 10 from
  baseline.

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General Pharmacy Information -2

• BSA calculations should be performed as routine
  local practice and capped at 2.0m2
• 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

• SITE
• - SSI
• - Staff Contact and Responsibilities Sheets
• - RD 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

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

Initiation Process
Activation of site
Notification by email
SITE ACTIVATED
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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)

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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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Translational Research (2)
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 block 2nd 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 block 2nd 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 Recurrent Primary Tumor (FRP01) 1st Choice block 2nd 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 Recurrent Metastatic Tumor (FRM01) 1st Choice block 2nd 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    
Fresh Progression Tumour Biopsy (PTB01)3 Within 4 weeks of documented disease progression Optional3 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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Translational Research (3)
Summary of blood specimen requirements (ctDNA)
for translational research
Required Specimen (Specimen Code) Collection Time Point Ship To
Pre-Treatment Plasma (PB01) prepared from 7-10mL of blood drawn into a K2 EDTA tube4 Prior to trial treatment (either arm)   Optional3   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 treatment Optional3     Samples will be batch transferred from sites to Edinburgh Cancer Centre periodically e.g. every 6 months or annually depending on recruitment2      
C6D1 Pre-Treatment Plasma (PB08) prepared from 7-10mL of blood drawn into a K2 EDTA tube4 Cycle 6, day 1, prior to administering treatment Optional3   Samples will be batch transferred from sites to Edinburgh Cancer Centre periodically e.g. every 6 months or annually depending on recruitment2      
Disease Progression Plasma (PB09) prepared from 7-10mL of blood drawn into a K2 EDTA tube4 Within 4 weeks of documented disease progression Optional3   Samples will be batch transferred from sites to Edinburgh Cancer Centre periodically e.g. every 6 months or annually depending on recruitment2      
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
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Translational Research (4)
Additional plasma specimens for PK testing to be
collected from a subset of patients
Required Specimen (Specimen Code) Collection Time Point Ship To
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.          
C1D29 Pre-Treatment Plasma (PB03) prepared from 7-10mL of blood drawn into a K2 EDTA tube1 The last day of cycle 1, prior to administering trametinib             Samples will be batch transferred from sites every 6 months to Covance in US.          
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             Samples will be batch transferred from sites every 6 months to Covance in US.          
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             Samples will be batch transferred from sites every 6 months to Covance in US.          
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             Samples will be batch transferred from sites every 6 months to Covance in US.          
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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 lt 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

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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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33
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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34
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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35
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

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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 subjects
  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.

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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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41
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 trials
  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
  karen.carty_at_glasgow.ac.uk
• Diann Taggart ,Clinical Trial Co-ordinator
• Tel no 0141 301 7234 Email diann.taggart_at_glasg
  ow.ac.uk
• Jan Graham, Clinical Trial Monitor
• Tel no 0141 301 7956 Email jan.graham_at_glasgow.
  ac.uk

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