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
• Pharmacy Initiation Slides Version 1.0 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 and the
study requirements prior to signing off the
initiation acknowledgement sheet.
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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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Pharmacy Initiation

• Protocol and Treatment overview
• IMP Presentation and Management
• LOGS site file and documentation
• Site initiation process

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• LOGS Protocol and treatment overview

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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 low-grade serous
  carcinoma of the ovary or peritoneum previously
  treated with platinum based chemotherapy in women
  with recurrent low grade serous.
• 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.

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Treatment and Duration

• In each arm of the study, 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

• If a patient develops progressive disease in 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).
• 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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Key Inclusion Criteria (1)

• Patients will be eligible for the study if the
  following criteria are met
• Patients aged 18 years of age or older with the
  following tumours
• Patients initially diagnosed with low-grade
  serous ovarian or peritoneal carcinoma that recur
  as low-grade serous carcinoma (invasive
  micropapillary serous carcinoma or invasive grade
  I serous carcinomas as defined by GOG, FIGO WHO
  or Silverberg).
• Patients initially diagnosed with serous
  borderline ovarian or peritoneal carcinoma that
  recur as low-grade serous carcinoma (invasive
  micropapillary serous carcinoma or invasive grade
  I serous carcinomas as defined by GOG, FIGO WHO
  or Silverberg).
• At least 4 weeks must have elapsed since the
  patient underwent any major Surgery
• Patients must have documented low-grade serous
  carcinoma.
• All patients must have measurable disease as
  defined by RECIST 1.1.  
• Prior therapy
• - Patients must have recurred or progressed
  following at least one platinum-based
  chemotherapy
• regimen.
• - Patients may have received an unlimited
  number of prior therapy regimens.
• - Patients may not have received all of the
  five choices in the standard therapy arm.
• - Any hormonal therapy directed at the
  malignant tumor must be discontinued at least one
  week prior to
• registration
• - Any other prior therapy directed at the
  malignant tumor, including chemotherapy and
  radiation therapy, must be
• discontinued at least 4 weeks prior to
  registration. Any investigational agent must be
  discontinued at least 28 days
• prior to registration.

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Key Inclusion Criteria (2)

• Women of child-bearing potential and men must
  agree to use a highly effective method of
  contraception prior to study entry, during the
  study participation, and for six months after the
  last dose of the drug. Women of child-bearing
  potential must have a negative serum pregnancy
  test within 14 days prior to randomization,
  cannot be breast-feeding, and must agree to use a
  highly effective form of contraception throughout
  the treatment period and for 6 months after the
  last dose of study treatment.
• Patients must have signed an approved informed
  consent.
• Patient must have a performance status of 0 or 1.
• Patients must have ability to swallow and retain
  orally administered medication..
• All prior treatment-related toxicities must be
  CTCAE v4 grade lt1 (except alopecia) at the time
  of randomization.
• See study protocol for full inclusion/exclusion
  criteria

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Key Inclusion Criteria (3)

• Patients must have a left ventricular ejection
  fraction gt lower limit of normal by ECHO or MUGA
• Patients must have adequate
• - Bone Marrow Function
• Absolute neutrophil count (ANC) gt to 1.5 x
  109/l
• Platelets gt 100 x 109/l, Haemoglobin gt 9.0g/dl
  
• - Renal Function
• Serum creatinine lt 1.5 mg/dl OR calculated
  creatinine clearance (Cockroft-Gault formula) gt
  50ml/min or
• 24 hour urine creatine clearance gt 50ml/min
• - Hepatic Function
• Bilirubin lt 1.5 X ULN, ALT lt 2.5 X ULN, AST lt
  2.5 X ULN, Albumin gt 2.5
• - Coagulation
• PT and APTT lt1.5 X ULN
• All samples must be taken within 7 days prior
  to treatment
• If letrozole is selected as the control therapy,
  patients must be postmenopausal, either following
  bilateral oophorectomy or at least 5 years after
  spontaneous menopause. Patients within 5 years of
  spontaneous menopause or who have had a
  hysterectomy without bilateral oophorectomy must
  have postmenopausal LH and FSH levels. Patients
  on HRT must agree to withdrawal of hormone
  therapy before letrozole is started.
• See study protocol for full inclusion/exclusion
  criteria

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Key Exclusion Criteria (1)

• Patients will be excluded from the study in the
  following circumstances
• Patients who have had chemotherapy or
  radiotherapy within 4 weeks (6 weeks for
  nitrosoureas or mitomycin C) prior to entering
  the study or those who have not recovered from
  adverse events due to agents administered more
  than 4 weeks earlier.
• Use of other investigational drugs within 28 days
  (or five half-lives, whichever is shorter with a
  minimum of 14 days from the last dose) preceding
  the first dose of trametinib or standard of care
  agent.
• Patients may not have received prior MEK, KRAS,
  or BRAF inhibitor therapy
• Current use of a prohibited medication. The
  following medications or non-drug therapies are
  prohibited
• - Patients may not be receiving any
  other anti-cancer or investigational agents.
• - Because the composition, PK, and
  metabolism of many herbal supplements are
  unknown, the concurrent use of
• all herbal supplements is prohibited
  during the study (including, but not limited to
  St. Johns Wort, kava, ephedra
• ma huang, gingko biloba,
  dehydroepiandrosterone DHEA, yohimbe, saw
  palmetto, or ginseng).
• See study protocol for full inclusion/exclusion
  criteria

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Key Exclusion Criteria (2)

• Patients with known leptomeningeal or brain
  metastases or spinal cord compression.
• Patients with a bowel obstruction or any other
  gastrointestinal condition that might affect
  absorption of the oral drug should be excluded.
• Patients with a history of interstitial lung
  disease or pneumonitis.
• Patients with a previous or current malignancy
  at other sites should be excluded, with the
  exception of
• a.) Curatively treated local tumours such
  as carcinoma-in-situ of the cervix, basal or
  squamous cell carcinoma of the skin.
• b.)Tumours for which no relapse has
  been observed within 5 years
• Patient with known Hepatitis B Virus (HBV), or
  Hepatitis C Virus (HCV) infection (patients with
  chronic or cleared HBV and HCV infection are
  eligible). Patients with Human Immunodeficiency
  Virus (HIV) are not eligible if on
  anti-retroviral medications.
• Known immediate or delayed hypersensitivity
  reaction or idiosyncrasy to drugs chemically
  related to Trametinib, or excipients, or to
  dimethyl sulfoxide (DMSO), or to Cremophor EL
  (polyoxyethylated castor oil). Please note,
  exclusion for Cremophor is unnecessary unless
  paclitaxel is the only agent available and the
  patient randomizes to the conventional therapy
  option.
• See study protocol for full inclusion/exclusion
  criteria

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Key Exclusion Criteria (3)

• Patients with a history or evidence of
  cardiovascular risk
• Patients with a history or current evidence/risk
  of retinal vein occlusion .
• Any patients with a serious and/or unstable
  pre-existing medical disorder (aside from
  malignancy exception above), psychiatric
  disorder, or other conditions that could
  interfere with subjects safety, obtaining
  informed consent or compliance to the study
  procedures.
• Patients who require use of a concomitant
  medication that can prolong the QT interval. See
  the table in section 6.28 of protocol
•  Pregnant or lactating women. Women of
  childbearing potential should be advised to avoid
  pregnancy.
• See study protocol for full inclusion/exclusion
  criteria

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Treatment Modifications

• 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
• (Please note QD ONCE Daily)
• A maximum of two trametinib dose level
  reductions are allowed. If a 3rd dose level
  reduction is required,
• treatment will be permanently
  discontinued.
• Please refer to section 6.0 of the study
  protocol for full details of treatment
  modifications/dose reductions/delays

Dose Level Trametinib Dose/Schedule
0 2 mg QD
-1 1.5 mg QD
-2 1 mg QD
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• LOGS IMP Presentation and Management

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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) experimental agent
• 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 .

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General Pharmacy Information (2)

• 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.
• 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.

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Prescribing and Dispensing Arrangements

• Study specific prescriptions must be used a
  master copy must be placed in the pharmacy file
• Prescriptions must
• Clearly identify prescribing as part of the LOGS
  study including protocol
• Patients study number
• Sites are required to include the following
  information when labelling dispensed supplies for
  this study
• LOGS Study
• Principal Investigator
• Eudract Number
• Sponsor NHS Greater Glasgow and Clyde and
  University of Glasgow
• For Clinical Trials Use Only
• Patient Trial Number xxxx
• Cycle No xxxx(if this is local practice to do
  so)
• (xxxx to be completed locally as appropriate
• There is no stipulation on the format or layout
  of the labels. Any additional labelling on
  dispensing can
• be added as per local practice.

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Formulation and Presentation of IMP

• Trametinib (GSK 1120212) tablets are immediate
  release tablets for oral administration. Tablets
  will be supplied to sites in high density
  polyethylene (HDPE) bottles that contain a
  desiccant with a child resistant closure that
  includes an induction seal liner.
• Trametinib (GSK120212) 2mg are pink, round
  tablets and Trametinib (GSK1120212) 0.5mg are
  yellow, modified oval tablets. Each pack will
  contain 32 tablets. All supplies for the LOGS
  study will be labelled as study specific clinical
  trial stock.
• Trametinib tablets should be stored in a secure
  area within a refrigerator at a temperature of
  2oC 8oC
• All other IMP will be stored and handled as per
  SmPC

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• LOGS site file and documentation

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Pharmacy Site File

• All pharmacy sites will be provided with a
  pharmacy file containing key documentation and
  initiation training slides. The pharmacy file
  must be kept up-to-date and be available for
  inspection by the study monitors at monitoring
  visits, regulatory authorities and on request
  from the sponsor if required.
• PSF will include the following
• LOGS IMP Accountability for Trametinib 0.5mg tabs
• LOGS IMP Accountability for Trametinib 2mg tabs
• LOGS IMP Emergency Supply Log
• LOGS Study Specific Training Record
• LOGS Study Identification Log
• LOGS Study Patient Subject Accountability Log
  Arm A (IV)
• LOGS Study Patient Subject Accountability Log
  Arm A (orals)
• LOGS Supply and Receipt Form
• LOGS Temperature Deviation Defect Form

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Accountability Logs

• Logs must be kept up to date at time of each
  dispensing and made available if requested for
  remote monitoring.
• Logs can be provided by CRUK CTC for use in this
  study but local documentation can be used only
  after approval by CRUK CTC and RD Sponsor
  Pharmacy Team.

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IMP Accountability (Control Arm A - IV)

• Each patient taking part in the study must have a
  patient log detailing the following information
  for traceability purposes
• IMP supplied
• Date of Issue
• Cycle
• Dose
• Manufacturer, Batch number expiry date of
  the product supplied
• Diluent batch number expiry date (where
  applicable)
• Vehicle, batch number expiry date
• Dose banded manufacturer, batch number expiry
  date (where applicable)
• Aseptic worksheets should be retained
• Dose banded is permitted

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IMP Accountability Log (Control Arm A- Orals)

• Each patient taking part in the study must have a
  patient log detailing the following information
  for traceability purposes
• IMP supplied
• Date of Issue
• Cycle
• Dose and frequency
• Quantity
• Manufacturer, Batch number expiry date of
  the product supplied

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IMP Accountability (Experimental Arm B-
Trametinib)A single Bulk/ Patient IMP
accountability log for each strength of
trametinib for patients taking part in Arm B must
be used detailing the following information

• SHIPMENT
• Date
• Invoice number
• Batch number and expiry date
• Quantity received
• DISPENSING
• Patient study ID and Initials
• Quantity dispensed
• Batch No and expiry date
• Dispensed by/checked by

• PATIENT RETURNS
• Date
• Quantity returned
• Received by
• PATIENT DESTRUCTION/BULK IMP DESTRUCTION
• Date destroyed
• Quantity
• Signature
• Balance remaining on site

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Returns and Destruction

• Patient Returns
• Tablet counts for Control Arm A (orals) must
  be performed and recorded on the Patient specific
  Subject Accountability Log.
• Tablet counts for Experimental Arm B must be
  performed on IMP accountability log for
  Trametinib 0.5mg and 2mg tabs. This is a single
  log that incorporates both patient and bulk
  supplies. A separate log should be used for each
  strength.
• Destructions
• Patient returns can be destroyed once all
  accountability has been completed and any
  discrepancies resolved.
• Sites must request permission from sponsor to
  destroy any expired, damaged or unused stock.

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Defects and Temperature Deviations

• Complaints or Defects regarding Trametinib
• Complete a copy of the LOGS IMP Temperature
  Deviation Defect Form and forward to CRUK CTC
  and RD Pharmacy Team.
• Complaints or Defects regarding all other IMP
• Should be dealt with by following local hospital
  procedures.
• Temperature deviations regarding Trametinib
• Complete the LOGS Temperature Deviation Defect
  Form and forward to CRUK CTC for providing the
  following information
• Duration of temperature deviation please provide
  the maximum period of time the IMP may have been
  exposed to temperatures out with those indicated
• Maximum/ minimum temperature achieved
• Quantity of packs and batch number of affected
  stock
• Reason for temperature excursion/any action
  already taken
• Wherever possible please include a copy of the
  temperature log
• Temperature deviation regarding all other IMP
• follow local department procedure but must be
  notified to the CTU. Further advice will be given
  as appropriate on a case by case basis.

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• LOGS Pharmacy Site Initiation Process

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Site Set-up

• CTU GLASGOW
• Main REC approval - MHRA approval - Site
  Initiation Slides
• - Investigator File - Pharmacy File - Sample
  Collection Supplies
• ?
• SITE
• Staff Contact Responsibilities Sheets SSI
  - RD Approval
• - Investigator CVs and Lead Pharmacist -
  Delegation log - Clinical Trial Agreement
• - GCP Certificates for PIs - PIS, Consent, GP
  Letter etc on Trust headed paper
• - Lab normal ranges (Haem Biochem),
  Accreditation certificates.
• ?
• INITIATION PROCESS
• ?
• DRUG SUPPLY
• ?
• SITE ACTIVATED

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Pharmacy Initiation Process

• Site initiation process - Each member of the
  study team is required to participate in site
  initiation to ensure compliance with the protocol
  and training on study procedures. Initiation for
  the study will be done by site staff accessing on
  line initiation slides via CRUK CTU website
• Lead pharmacist for the LOGS study will complete
  a Pharmacy Site Assessment Form and return to
  CRUK CTU
• A Staff Contact and Responsibilities Sheet must
  be completed for the lead pharmacist and any
  other pharmacy clinical trial staff who are
  delegated IMP management responsibilities. These
  staff will be required to provided evidence of
  GCP training and current CVs
• Acknowledgement sheet- Each member of the study
  who has viewed the initiation slide presentation
  requires to complete an acknowledgement sheet to
  confirm this.
• Initiation Accreditation call - Prior to
  activation of the site a short initiation call
  will be completed with the main contact for the
  site.

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Post Approval

• Site Responsibilities
• Ensure Pharmacy Site File contents are kept up to
  date
• Ensure accountability logs are kept up to date
• Inform CRUK CTU Glasgow of any changes in
  contacts or arrangements for pharmacy
• Action amendments where required.
• Sponsor Responsibilities
• Forward amendments in a timely manner
• Review and amend IMP management process as
  required
• Help solve problems provide support as required
  

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Contact Details for CR-UK CTU, Glasgow

• CR-UK CTU, Glasgow
• Cancer Research UK Clinical Trials Office
• Level 0, Beatson West of Scotland Cancer Centre
• 1053 Great Western Road, Glasgow, G12 0YN
• Tel [phone]
• Fax [phone]
• E-mail karen.carty_at_glasgow.ac.uk (project
  manager)
• E-mail diann.taggart_at_glasgow.ac.uk (trial
  co-ordinater)