Transcript Pharmacy Initiation Slides - Clinical Trials Unit Glasgow

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
**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 will be conducted according to ICH GCP guidelines
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Study conducted in accordance with the EU Directive 2001/20/EC
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Trial carried out in accordance with the World Medical Association Declaration of Helsinki
(1964) and the Tokyo (1975), Venice (1983), Hong Kong (1989), South Africa (1996),
Edinburgh (2000), Washington (2002), Tokyo (2004), Seoul (2008) amendments
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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)
Clinician’s choice of ‘control’ arm is made from the list below prior to randomization:
• Letrozole 2.5mg orally once daily continuous treatment until progression or
unacceptable toxicity
• Tamoxifen 20mg orally twice daily continuous treatment until progression or
unacceptable toxicity
• Paclitaxel 80mg/m2 IV infusion over one hour on days 1, 8, and 15 of a 28 day cycle
until progression or unacceptable toxicity or until 6 cycles have been administered*
• Pegylated Liposomal Doxorubicin 40 or 50mg/m2 IV infusion over one hour on day 1
every 28 days until progression or unacceptable toxicity or until 6 cycles have been
administered*
• Topotecan 4.0 mg/m2 IV infusion over 30 minutes on days 1, 8, and 15 of a 28 day cycle
until progression or unacceptable toxicity or until 6 cycles have been administered*
*more than 6 cycles of chemotherapy can be administered at investigator’s discretion
Arm B (Experimental Arm)
• Trametinib 2 mg orally once daily continuous treatment until progression or
unacceptable toxicity
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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).
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Prior to crossover, the following must occur:
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The patient’s progression must be fully documented on the relevant GOG electronic case
report forms (CRFs) and submitted via Medidata Rave Electronic Data Entry System
(www.imedidata.com) online application which is being used for the study. The relevant CRFs
require to be submitted prior to the patient starting crossover treatment.
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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.
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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:
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Patients aged 18 years of age or older with the following tumours:
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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.
See study protocol for full inclusion/exclusion criteria
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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 <1 (except
alopecia) at the time of randomization.
See study protocol for full inclusion/exclusion criteria
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Key Inclusion Criteria (3)
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Patients must have a left ventricular ejection fraction > lower limit of normal by ECHO or MUGA
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Patients must have adequate:
Bone Marrow Function:
Absolute neutrophil count (ANC) > to 1.5 x 109/l
Platelets > 100 x 109/l, Haemoglobin > 9.0g/dl
Renal Function:
Serum creatinine < 1.5 mg/dl OR calculated creatinine clearance (Cockroft-Gault formula) > 50ml/min or
24 hour urine creatine clearance > 50ml/min
Hepatic Function:
Bilirubin < 1.5 X ULN, ALT < 2.5 X ULN, AST < 2.5 X ULN, Albumin > 2.5
Coagulation:
PT and APTT <1.5 X ULN
**All samples must be taken within 7 days prior to treatment**
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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:
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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.
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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.
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Patients may not have received prior MEK, KRAS, or BRAF inhibitor therapy
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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. John’s 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)
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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)
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Patients with a history or evidence of cardiovascular risk
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Patients with a history or current evidence/risk of retinal vein occlusion .
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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 subject’s safety, obtaining informed consent or compliance to
the study procedures.
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Patients who require use of a concomitant medication that can prolong the QT
interval. See the table in section 6.28 of protocol
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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:
Dose Level
0
-1
-2
Trametinib Dose/Schedule
2 mg QD
1.5 mg QD
1 mg QD
(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.
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**Please refer to section 6.0 of the study protocol for full details of treatment modifications/dose reductions/delays
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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
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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.
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Trametinib will be provided free of charge by GlaxoSmithKline(GSK) and supplied and
distributed by Catalent to UK sites for use in the study.
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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.
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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 subject’s 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
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Study specific prescriptions must be used – a master copy must be placed in the pharmacy file
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Prescriptions must
– Clearly identify prescribing as part of the LOGS study including protocol
– Patients study number
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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
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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.
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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.
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Trametinib tablets should be stored in a secure area within a refrigerator at a
temperature of 2oC – 8oC
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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
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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.
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PSF will include the following:
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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 R&D Sponsor Pharmacy Team.
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IMP Accountability (Control Arm A - IV)
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Each patient taking part in the study must have a patient log detailing the following
information for traceability purposes:
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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)
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Each patient taking part in the study must have a patient log detailing the following
information for traceability purposes:
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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
– PATIENT RETURNS
• Date
• Quantity returned
• Received by
– DISPENSING
• Patient study ID and Initials
• Quantity dispensed
• Batch No and expiry date
• Dispensed by/checked 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
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Complaints or Defects regarding Trametinib:
 Complete a copy of the LOGS IMP Temperature Deviation & Defect Form and forward to CRUK CTC and R&D
Pharmacy Team.
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Complaints or Defects regarding all other IMP:
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Should be dealt with by following local hospital procedures.
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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
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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
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SITE
Staff Contact & Responsibilities Sheets – SSI - R&D 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.
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INITIATION PROCESS
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DRUG SUPPLY
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SITE ACTIVATED
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Pharmacy Initiation Process
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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
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Lead pharmacist for the LOGS study will complete a Pharmacy Site Assessment Form and return to
CRUK CTU
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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
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Acknowledgement sheet- Each member of the study who has viewed the initiation slide
presentation requires to complete an acknowledgement sheet to confirm this.
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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
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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.
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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 7197
Fax: +44(0) 141 301 7946
E-mail: [email protected] (project manager)
E-mail: [email protected] (trial co-ordinater)
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