LMS Study (GOG 0277)

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• LMS Study (GOG 0277)
• A Phase III randomised trial of gemcitabine plus
  docetaxel followed by doxorubicin versus
  observation for uterus limited, high grade
  uterine leiomyosarcoma
• EudraCT Number 2012-002852-17
• Pharmacy Initiation Slides Version 1.0 18th
  March 2014

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Study Organisation

• This trial is an Intergroup Trial jointly
  conducted by Gynecologic Oncology Group (GOG)
  from USA, the EORTC Gynaecology Group, EORTC Soft
  Tissue Bone Sarcoma Group and National Cancer
  Research Network NCRN United Kingdom.
• In the UK the trial is being run under the
  auspices of the NCRN/NCRI Sarcoma and Gynaecology
  Clinical Study Groups with funding from Cancer
  Research UK.
• The Cancer Research UK Clinical Trials Unit,
  Glasgow (CTU) is co-ordinating the UK
  participation in the trial on behalf of NCRI/NCRN
  and NHS Greater Glasgow Clyde (NHS GGC).
• The EORTC is the sole legal Sponsor for
  participants in the European Union.
• UK Chief Investigator is Dr Helen Hatcher
• Trial co-ordination costs for UK participation in
  the trial are supported by a grant from Cancer
  Research UK. This is an academic trial and is
  part of the NCRN portfolio.

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Study Team in UK

• UK Chief Investigator Dr Helen Hatcher
• Lead Pathologist UK Professor Cyril Fisher
• Project Manager Karen Carty
• Pharmacovigilance Via EORTC
• UK Study Pharmacist Dr Samantha Carmichael
• Quality Assurance Manager Michaela Rodger
• Clinical Trial Co-ordinator Diann Taggart
• Clinical Trial Monitor Jan Graham

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Pharmacy Initiation

• Protocol and treatment overview
• IMP Presentation
• LMS site file and documentation
• Site initiation process

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Design and Study Objectives

• Design
• Study is designed as a two arm, open label
  randomised phase III with an observation only
  control arm and experimental arm of multi-agent
  chemotherapy.
• Study Objectives
• Primary Objective
• - To determine whether overall survival of
  patients with uterus-limited high grade
  leiomyosarcoma is superior among patients
  assigned to treatment with adjuvant gemcitabine
  plus docetaxel followed by doxurubicin compared
  to patients assigned to observation
• Secondary Objectives
• - To determine whether treatment with adjuvant
  gemcitabine plus docetaxel followed by
  doxorubicin improves recurrence free survival of
  patients with uterus-limited high grade
  leiomyosarcoma compared to observation
• - To explore the impact of potential predictors
  of recurrence or death such as patient age, and
  institution reported tumour size, cervix
  involvement (yes or no) and mitotic rate

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Study Population

• Study Population
• - Patients with high risk uterine leiomyosarcoma
• - FIGO stage I (confined to corpus /- cervix)
• - Patients require to have had at least a
  complete hysterectomy (including removal of
  cervix)
• - All patients must have no evidence of
  persistent or metastatic disease as documented by
  a
• post-resection CT of the
  chest/abdomen/pelvis or by CT chest MRI
  abdomen/pelvis

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Inclusion Criteria (1)

• Patients will be eligible for the study if the
  following criteria are met
• Patients with high risk uterine leiomyosarcoma,
  FIGO stage I (confined to corpus /- cervix).
  Patients with known uterine serosa involvement
  are not eligible. Patients should have had, at
  least, a complete hysterectomy (including removal
  of the cervix). Bilateral salpingo-oophorectomy
  is not required.
• All patients must be no longer than 12 weeks (3
  months) from surgical resection of cancer at the
  time of the enrollment on study. If a patient
  requires a second operation to complete her
  surgery, i.e. trachelectomy to remove the cervix
  and/or BSO, the 12 weeks may be counted from the
  time of the second operation.
• All patients must have no evidence of persistent
  or metastatic disease as documented by a post
  resection CT scan of the chest, abdomen and
  pelvis or by CT scan of chest MRI of abdomen
  and pelvis. The post resection imaging should be
  performed within 4 weeks of registration/randomisa
  tion on study.

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Inclusion Criteria (2)

• Patients must have adequate
• - Bone Marrow Function
• - Renal Function
• - Hepatic Function
• - Neurologic Function
• Patients with GOG performance status of 0 or 1
  ECOG performance status of 0 or 1 or KPS gt 80
• Patients who have met the pre-entry requirements
  specified in section 7.0 of protocol
• Refer to Section 3 of protocol

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Inclusion Criteria (3)

• Patients must have signed an approved informed
  consent.
• Patients must be a minimum of 18 years of age.
• Patients should be free of active infection
  requiring antibiotics (with the exception of an
  uncomplicated Urinary Tract Infection UTI)

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Exclusion Criteria (1)

• Patients will be excluded from the study in the
  following circumstances
• Patients who have had prior therapy with
  docetaxel or gemcitabine or doxorubicin at any
  time in their history.
• Patients with a history of other invasive
  malignancies present within the last 5 years,
  with the exception of non-melanoma skin cancer.
• Patients with a history of severe
  hypersensitivity reaction to taxotere (docetaxel)
  or other drugs formulated with polysorbate 80.
• Patients with GOG performance status of 2,3 or 4
  or ECOG performance status of 2,3 or 4.
• Patients who are breast feeding
• Patients with a know history of congestive heart
  failure or cardiac ejection fraction.

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Exclusion Criteria (2)

• Patients with a history of prior whole pelvic
  radiation.
• Concurrent treatment with hormone replacement
  therapy is permitted at the discretion of the
  treating physician. Use of anti-hormonal agents
  (tamoxifen, medroxyprogesterone, aromatase
  inhibitors) is permitted at the discretion of the
  treating physician.
• Patients with recurrent uterine LMS
• Patients who are know to be HIV (human
  immunodeficiency virus) positive.
• Patients with gross residual or metastatic tumour
  findings following complete surgical treatment
  for uterine LMS

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Treatment and Duration

• Treatment
• REGIMEN I
• - Gemcitabine 900mg/m2 IV on days 1 and 8
• - Docetaxel 75mg/m2 IV on day 8
• - Filgrastim (GCSF) 5 micrograms/kg SC on days 9
  to 15 or Pegfilgrastim 6mg SC day 9 or 10
• Every 21 days for 4 cycles followed by
• - Doxorubicin 60mg/m2 IV on day 1
• - Filgrastim (GCSF) 5 micrograms/kg SC on days 2
  to 8 or Pegfilgrastim 6mg SC on day 2 or 3
• optional
• Every 21 days for 4 cycles
• REGIMEN II
• Observation only

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Duration of Study/ Study Visits

• Patients on REGIMEN 1 will receive therapy for a
  maximum of 8 cycles (4 cycles of gemcitabine
  docetaxel, followed by 4 cycles of doxorubicin)
  or until disease recurrence or toxicity
  intervenes
• A patient is considered off study treatment when
  the patient has recurred or died, a non-protocol
  drug or therapy (directed at the disease) is
  initiated or all study therapy is totally
  discontinued
• Patients on the observation arm (REGIMEN II) are
  considered off study treatment at the end of 24
  weeks from study entry.
• Patients who are considered off study treatment
  in both arms remain on study in terms of
  follow-up for evidence of recurrence and for
  survival status.
• Patients will be followed for recurrence with
  physical examination, history and imaging until
  recurrence, death or five years of follow-up is
  reached. If there is evidence of disease
  recurrence, patients will continue to be followed
  for survival for at least 5 years from study
  entry.
• Please refer to study protocol investigations
  tables for each arm of the study to ensure the
  correct observations and tests are performed at
  protocol specified time points.

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Treatment Modifications (REGIMEN I) -1

• Please refer to section 6.0 of the protocol for
  full details of treatment modifications/dose
  reductions/delays for haematological and non
  haematological toxicities for regimen 1
• (Brief details in relation to treatment
  modifications are provided on these slides)
• Gemcitabine and Docetaxel Dose Level Definitions
• Doxorubicin Dose Level Definitions
• Patients who require a dose reduction because of
  a toxicity meeting criteria specified in protocol
  are permitted ONE dose reduction. If toxicity
  recurs of a severity that would require another
  dose reduction, a second dose reduction is NOT
  permitted. Instead, treatment with the regimen
  that caused the additional toxicity should be
  discontinued.

Study drug 1 Level reduction Initial dose level
Gemcitabine 675mg/m2 over 70-90 minutes 900mg/m2 over 90 minutes
Docetaxel 60mg/m2 75mg/m2
Study drug 1 level reduction Initial dose level
Doxorubicin 45mg/m2 60mg/m2
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Treatment Modifications (REGIMEN I) -2

• Haematologic Toxicity during EITHER gemcitabine
  docetaxel OR doxorubicin
• Initial treatment modifications will consist of
  cycle delay and/or dose reduction.
• Refer to section 6.2 in protocol for full
  details.
• The use of hematopoietic cytokines and
  protective reagents are restricted .
• Refer to section 6.2 for full details

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Treatment Modifications (REGIMEN I) -3

• In addition to the dose modifications listed
  previously Day 8 Gemcitabine and Docetaxel dose
  adjustments should be made according to the table
  below
• Note ANC (absolute neutrophil count) gt1000/mcl
  ANC 1.0 x 109/liter (L).
• Plt (platelets) ? 100,000/mcl Plt 100 x 109/L.

Study Drug ANC1000/mcl and Plt100,000/mcl ANC 500-999/mcl OR Plt 50,000-90,000/mcl ANC 500/mcl OR Plt50,000/mcl
Gemcitabine 100 of dose For patients at the initial dose level give 675mg/m2 over 70-90 minutes. For patients at the 1 level dose reduction dose give 500mg/m2. Omit on day 8
Docetaxel 100 of dose For patients at the initial dose level give 60mg/m2. For patients at the 1 level dose reduction dose give 50mg/m2. Omit on day 8
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Treatment Modifications (REGIMEN I) - 4

• Hepatic dysfunction during gemcitabine
  docetaxel .
• Refer to section 6.3 of protocol for details
• Hepatic dysfunction during doxorubicin
• Refer to section 6.4 of protocol for details
• Hypersensitivity reactions to Docetaxel
• Refer to section 6.5 of protocol for details
• Other Non-Haematologic Toxicity likely
  attributable to gemcitabine and/or docetaxel or
  doxorubicin
• Refer to section 6.6 of protocl for details
• Other Non-Haematologic Toxicity likely
  attributable to gemcitabine and/or docetaxel or
  doxorubicin
• Refer to section 6.6 of protocol for details

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IMP Presentation and Management
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Investigational Medicinal Products

• The investigational medicinal products in this
  study are
• - Gemcitabine
• - Docetaxel
• - Doxorubicin
• All the IMPs for use in the trial will be from
  site own stock. There is no provision for
  funding, reimbursement or discounted stock.
• 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.
• Store in line with the SmPC or if dose banded
  manufactures recommended storage conditions
• Temperature logs must be maintained using
  calibrated temperature monitoring equipment in
  order to demonstrate that the IMP has been stored
  at all times under the correct storage conditions

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Dose Banding Requirements

• Chemotherapy doses may be dose banded if it is
  routine local practice to do so.
• The following must apply
• be routinely used for the treatment of patients
  out-with a clinical trial
• not be purchased specifically for use within
  the study
• procured as part of routine pharmacy stock
• labelled only in response to an individual
  patient response
• formal agreements in place with the supplier to
  ensure the product is of an appropriate quality
• the supplier must maintain an adequate audit
  trail that would permit the batch number of the
  original product and diluent to be traced should
  this be required
• the batch number , manufacturer and supplies of
  dose banded drugs must be recorded by pharmacy
  for every dose

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Non-Investigational Medicinal Products

• The following are designated Non-Investigational
  Medicinal Products (NIMPs) for the purpose of the
  study.
• - Filgrastim
• - Pegfilgrastim
• No additional accountability is required in
  addition to standard practice
• Store in line with the SmPC

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IMP Management at Pharmacy Sites
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Prescribing Dispensing Arrangements

• Study specific prescriptions must be used - a
  master copy must be placed in the pharmacy file
• electronic prescribing can be used but must
  clearly state that use is within the Uterine LMS
  study
• Prescriptions must
• clearly identify prescribing as part of the
  Uterine LMS study
• patients study number
• Sites are required to include the following
  information when labelling dispensed supplies for
  this study
• Uterine-LMS Study (GOG-0277)
• Principal Investigator xxxx
• EudraCT Number 2012-002852-17
• Sponsor European Organisation of Research and
  Treatment of Cancer (EORTC)
• For Clinical Trial Use Only
• Patient Trial Number xxxx
• Cycle No xxxx (if it 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 other additional labelling on
  dispensing can be added as per local practice.

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IMP ACCOUNTABILITY

• Each patient taking part in the study must have a
  patient log detailing the following information
• IMP supplied
• Date of Issue
• Cycle number
• Dose supplied
• Manufacturer, Batch number expiry date of the
  product supplied
• Logs can be provided by CR-UK CTU for use in this
  study , local documentation can be used only
  after approval by CR-UK CTU
• A separate log should be used for each drug
  product and each manufacturer
• Logs must be kept up to date at time of each
  dispensing and made available if requested for
  remote monitoring
• Aseptic worksheets must be retained

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Returns and Destructions

• 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.

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Defects, Recall Temperature Deviations

• Any complaints or defects regarding IMP supplies
  should be dealt with following local hospital
  procedure
• The CR-UK CTU should be informed of any
  complaints or product defects
• Recall will be managed via normal hospital
  practice for licensed products again the CR-UK
  CTU should be informed of any product recalls.
• In the event of a temperature excursion, follow
  local department procedure, ensure CR-UK CTU is
  informed and provide the following information
• Duration of temperature deviation please
  provide the maximum period of time the IMP may
  have exposed to temperatures out with those
  indicated above.
• 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.

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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

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

Initiation Process
Activation of site
Notification by email
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 CR-UK CTU website
• Lead pharmacist for the Uterine LMS study will
  complete a Pharmacy Site Assessment Form and
  return to CR-UK 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 file contents are kept up to date
• Ensure accountability logs are kept up to date
• Inform CR-UK 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
• E-mail jan.graham_at_glasgow.ac.uk

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