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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 GG&C).
• 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
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/randomisation 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 > 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
optionalEvery 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) >1000/mcl = ANC 1.0 x 109/liter (L).Plt (platelets) 100,000/mcl = Plt 100 x 109/L.
• Dose reduction on Day 8 does not count as one of the two permitted protocol dose reductions for toxicity. The next cycle may be started at previous doses, provided that blood counts have recovered as detailed in 6.23 of protocol. If a dose reduction is required on Day 8 of a cycle, subsequent Day 8 doses should only be reduced in subsequent cycles if the criteria for reduction or omission of the day 8 doses are met on that cycle’s Day 8 of treatment.
Study Drug
ANC≥1000/mcl and Plt≥100,000/mcl
ANC 500-999/mcl OR Plt 50,000-90,000/mcl
ANC ‹500/mcl OR Plt‹50,000/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 manufacture’s 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
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.
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
• CTU Glasgow
- Main REC approval
- MHRA approval - Site Initiation Slides - Investigator File - Pharmacy File - Royal Mail Safeboxes
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
Initiation Process
SITE ACTIVATED
Activation of site Notification by email
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 CV’s
• 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: +44(0) 141 301 7197Fax: +44(0) 141 301 7946
E-mail: [email protected] E-mail: [email protected]
