Transcript Initiation Slides - Clinical Trials Unit Glasgow

PLUTO (U185)
A randomised phase II study investigating Pazopanib versus
weekly Paclitaxel in relapsed or progressive transitional cell
carcinoma (TCC) of the urothelium
EudraCT Number: 2011-001841-34
ISCRTN73030316
INITIATION SLIDES
(VERSION 4: 11th October 2013)
PLUTO - Study Details
• The study is part of the NCRN/GlaxoSmithKline collaboration
• The study is being co-ordinated via the Cancer Research UK Clinical Trials
Unit, Glasgow.
• Sponsor of the study is Greater Glasgow Health Board (GGHB) and
University of Glasgow (GU)
• Joint Chief Investigators are Dr Rob Jones (Beatson West of Scotland
Cancer Centre) and Dr Tom Powles (St. Bart’s Hospital, London)
• Study is being funded by an educational grant from GlaxoSmithKline and is
endorsed by CTAAC (Cancer Research U.K.)
PLUTO - Study Team
• Joint Chief Investigator :
Dr Robert Jones
• Joint Chief Investigator:
Dr Tom Powles
• Study Statistician:
Jim Paul / Caroline Bray
• Project Manager:
Judith Dixon
• Pharmacovigilance:
Lindsey Connery
• Clinical Trial Coordinator:
Anna Morris
• Clinical Trial Monitor:
Eileen Smillie
PLUTO – Study Design
Study Design
A two-arm, open label, randomised controlled Phase II trial
Study Treatment
PLUTO – Population and Aims
Study population
• 140 patients with progressive disease during or after one prior platinum-based
chemotherapy regimen for advanced disease or as peri-operative therapy for
muscle-invasive / node positive disease (if completed < 12 months prior to
documented disease progression). The regimen must have included either
cisplatin or carboplatin
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Study Aims
Primary Objective: To provide preliminary evidence on whether there is a survival
advantage for Pazopanib compared to weekly Paclitaxel as second line treatment
for advanced urothelial cancer
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Secondary Objectives:
To estimate the difference in progression-free survival
To assess clinical benefit after 12 and 24 weeks of treatment
To observe the safety, toxicity and Quality of Life (QoL) of both treatments
PLUTO – Study Eligibility
Inclusion Criteria:
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Histologically or cytologically confirmed TCC (bladder, renal pelvis, ureter, urethra) which is locally
advanced or metastatic (T4b and/or N 1-3 and/or M1). Patients with mixed or differentiation pattern
pathology will be permitted entry providing that TCC is a component pathology
Progressive disease during or after one prior course of platinum based chemotherapy for advanced
disease or as peri-operative therapy for muscle invasive/node positive disease (if completed <12 months
prior to documented disease progression). The course of chemotherapy must have included either
Cisplatin and/or Carboplatin. Patients who have had two courses of platinum containing chemotherapy
are eligible if one of these was given peri-operatively, and provided that there was a chemotherapy free
interval of at least 12 months between completing the first course and commencing the second course of
chemotherapy. Chemotherapy given during radical radiotherapy as a radiosensitizer will not be
considered as chemotherapy treatment for the purposes of study eligibility
Age ≥ 18 years
Measurable disease by RECIST 1.1
Adequate organ function (see protocol for details)
Signed and dated informed consent
Negative pregnancy test for women of childbearing potential
Life expectancy of 3 months or more
ECOG 0, 1 or 2
PLUTO – Study Eligibility
Exclusion Criteria:
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Congestive heart failure, myocardial infarction, coronary artery bypass graft or
thrombotic cerebrovascular event in the previous 6 months, or ongoing severe or
unstable arrhythmia requiring medication
History of clinically significant bleeding in the 6 months prior to study initiation
Major surgery or trauma within 28 days prior to first dose of investigational
product and/or presence of any unhealed wound, fracture or ulcer
Cerebrovascular accident including transient ischemic attack, pulmonary
embolism or DVT within the past 6 months
History of another malignancy in the last 5 years
Ongoing major gastrointestinal disease including unstable inflammatory bowel
disease or bleeding peptic ulcer
Known endobronchial lesions which have a high risk of pulmonary haemorrhage
Previously identified brain or CNS metastases at baseline (see protocol for
exceptions)
Pregnant or breastfeeding
PLUTO – Study Eligibility
Exclusion Criteria continued:
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Administration of any investigational drug within 28 days or 5 half lives prior to
receiving the first dose of study treatment
Radiation therapy, surgery or tumour embolisation within 14 days of study drug
Chemotherapy, immunotherapy, biological therapy or investigational therapy
within 28 days of study treatment
Peripheral neuropathy of grade 2 or more
Any ongoing toxicity from prior anti-cancer therapy that is > grade 1 and/or that is
increasing in severity
Other severe or uncontrolled systemic disease or evidence of any other significant
clinical disorder or lab findings that makes it undesirable for the patient to
participate in the study
Any psychological, familial, sociological or geographical consideration potentially
hampering compliance with study protocol
Known HIV or other chronic immunosuppressive disease
QTc that is immeasurable or > 480 msec on screening ECG
PLUTO – Study Eligibility
Exclusion Criteria continued:
• History of symptomatic peripheral vascular disease within 6
months prior to trial entry
• Uncontrolled hypertension (BP > 150/90 at screening visit)
• Evidence of active bleeding or bleeding diathesis
• Recent haemoptysis
• Patients who are unable or unwilling to withdraw potent
CYP3A4 inhibitors, inhibitors of P-glycoprotein or BCRP
• Prior hypersensitivity to cremophor or known sensitivity to
any component of pazopanib
• Prior treatment with pazopanib or paclitaxel
PLUTO – Site Set Up
CTU GLASGOW
Main REC approval - MHRA approval - Site Initiation Slides
- Investigator File - Pharmacy File
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SITE
Staff Contact & Responsibilities Sheets – SSI - R&D Approval
- Site Staff CVs and GCP certificates - Clinical Trial Agreement
- - 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 OF PAZOPANIB
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SITE ACTIVATED
PLUTO – Informed Consent Process
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Two original Consent Forms must be completed by a clinician (or deputy listed on Staff
Contacts & Responsibilities Sheet)
Two originals signed and completed by the patient
Date must be prior to registration/ randomisation.
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
Consent Notification Form must be completed and sent CR-UK Clinical Trials Unit, Glasgow
Errors noticed after consent
- Add explanatory note/file note
New version of Patient Information Sheet must be provided to patients consented with
previous version
- Give to all patients regardless of treatment stage, during clinic visit
Patients who are still on active treatment will be required to repeat the consent process
using the updated form
- If 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.
PLUTO – Consent Withdrawal
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This is when the patient specifically asks to withdraw their consent at any point in
the study
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Ensure that the level of consent withdrawal is clearly documented in the source
data
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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);
– Complete the consent withdrawal notification form
– Send the consent withdrawal notification form to the CR-UK CTU
– No further follow-up should be collected on the patient from that point
onwards.
PLUTO – Randomisation Process
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All patients must be randomised onto the study prior to commencement of any treatment.
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Check that patient has given written informed consent as per the informed consent process.
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Check that patient fulfils eligibility criteria as per study protocol.
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Complete Registration Form.
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Site staff must contact the Cancer Research Clinical Trials Unit, Glasgow to randomise the
patient. Registration to the study can be done by either telephone or fax on the following
numbers:
Tel no: ++ 44 141 301 7232
Fax no: ++ 44 141 301 7228*
08.30-17.00 Mon-Thurs
08.30-16.30 Friday, except public holidays
* Faxes received outside of office hours will be processed the next working day
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Each patient randomised will be allocated a unique sequential patient ID number for the
study.
PLUTO – Pre Randomisation Evaluations
Prior to commencing any study related procedures, all participants will
be fully informed about the risks, benefits and procedures involved in
study participation, and will sign a consent form confirming this
process. All patients will then undergo a period of screening during the
28 days prior to initiation of study treatment.
Screening will consist of:
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Complete medical history including diagnosis of bladder cancer and comorbidities
Concomitant medication and their indications
Physical examination including weight, height and performance status
CT or MRI of chest pelvis and abdomen reported to RECIST v1.1
PLUTO - Pre randomisation Evaluations
In addition, during the 7 days prior to initiation of study
treatment all patients will undergo the following evaluations:
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Baseline symptoms evaluation
Vital signs including pulse and BP
ECG (if QTC > 480 msec repeat until average result obtained)
Haematology including FBC and Coag
Biochemistry
Pregnancy test
Archived paraffin embedded tissue collection*
Plasma blood sample collection*
Whole blood sample collection*
Urine Sample collection*
Protocol treatment must commence within 7 days of registration.
* Only applicable for patients participating in the translational component of the trial.
PLUTO -Treatment and Duration
Arm A:
• Patients will receive paclitaxel for up to 24 weeks.
Infusions of paclitaxel 80 mg/m2 will be
administered on day 1, day 8 and day 15 of each
28 day cycle
Arm B:
• Patients will receive pazopanib 800mg po od until
progression (or toxicity/patient choice)
PLUTO –Pazopanib Dose Modifications
Patients will be monitored closely for toxicity and the pazopanib dose may be
adjusted according to individual patient tolerance
If dose reduction is necessary, two dose reductions are permitted in stepwise
fashion (initially to 600mg and subsequently 400mg). A direct dose reduction
from 800mg to 400mg is also permitted in high toxicity.
If the toxicity does not recur or worsen, the dose can then be increased step wise
back to 600mg and 800mg after monitoring for 10-14 days at each step if toxicity
does not recur or worsen
Dose interruptions are permitted for up to 14 days after which the patient should
come off study. Participating centres are encouraged to liaise with the PLUTO
trials office if the delay is over 7 days.
Pazopanib –Management of Hypertension
It is recognised that some patients exhibit ‘white coat syndrome’ during hospital visits. If
the BP during the visit is high dose modification is not required if there is evidence
documented of controlled BP
Event
Dose Modification
(1). Asymptomatic and persistent systolic blood
pressure (SBP) of ≥150 and <170 mmHg, or DBP ≥90
and <110 mmHg, or a clinically significant increase in
DBP of ≥20 mmHg
Step 1: Continue study treatment at same dose.
Step 2: Adjust current dose of or initiate new
antihypertensive medication(s).
Step 3: Titrate antihypertensive medication(s) during
next 2 weeks as indicated to achieve well-controlled
SBP). If BP is not well-controlled within 2 weeks, follow
Step (1) in scenario (2) below.
(2) Symptomatic, or SBP ≥170 mmHg or DBP ≥110
mmHg, or failure to achieve well-controlled BP within 2
weeks in scenario (A).
Step 1: Interrupt study treatment. Symptomatic
hypertension may require emergency treatment
Step 2: Restart study treatment at same dose or lower
dose at discretion of investigator once BP is wellcontrolled. This reintroduction of pazopanib should
occur with an alteration of antihypertensive
medication, particularly if there has been no dose
reduction. Close observation of blood pressure during
this period should occur.
(3) Two or more symptomatic episodes of hypertension
despite modification of antihypertensive medication(s)
and reduction of study medication dose.
Discontinue study treatment and continue follow-up
per protocol.
Pazopanib - Management of Treatment Emergent Hepatotoxicity
Event
Dose Modification
(A). ALT of ≤ 3.0 x ULN
Continue pazopanib at current dose with full panel LFTs monitored as per protocol
(B) ALT > 3.0 ULN to ≤ 8.0 ULN without bilirubin elevation
(defined as total bilirubin < 1.5x ULN or direct bilirubin ≤
35%) and without hypersensitivity symptoms (e.g. fever,
rash)
Step 1: Continue pazopanib at current dose levels
Step 2: Monitor subject closely for clinical signs and symptoms; perform full panel LFTs
weekly or more frequently if clinically indicated until AST/ALT is reduced to grade 1
(C) ALT > 8.0 x ULN without bilirubin elevation (defined as
total bilirubin < 1.5x ULN or direct bilirubin ≤ 35%) and
without hypersensitivity symptoms (e.g. fever, rash)
1st Occurrence:
Step 1: Interrupt pazopanib until toxicity resolves to ≤ grade 1 or baseline. Report the
event to CTU Pharmacovigilance as an SAE within 24 hours of learning of its
occurrence. Make every reasonable attempt to have subjects return to the clinic
within 24 to 72 hours for repeat liver chemistries and liver event follow-up
assessments
Step 2: Liver imaging and other laboratory investigations should be considered as
clinically appropriate
Step 3: Monitor subjects closely for clinical signs and symptoms; perform full panel
LFTs weekly or more frequently if clinically indicated until AST/ALT is reduced to grade
1
Step 4: If the subject is benefitting from study treatment , contact Chief Investigator
for possible re-challenge. Re-treatment may be considered if ALL following criteria are
met:
-AST/ALT reduced to grade 1
-Total bilirubin < 1.5 x ULN or direct bilirubin < 35%
-No hypersensitivity signs or symptoms
-Subject is benefitting from therapy
Recurrence
Discontinue pazopanib permanently and monitor subjects closely for clinical signs and
symptoms; perform full panel LFTs weekly or more frequently if clinically indicated
until ALT/AST is reduced to grade 1
Pazopanib – Management of prolonged QTc
If QTc > 500msec or an increase of > 60 msec from baseline is noted on a scheduled or
unscheduled ECG then 2 additional ECGs should be obtained over a brief period of
time (e.g. within 15-20 mins) to confirm abnormality. The average QTc will be
determined from the 3 readings and will be used to determine the appropriate
next steps.
If the average QTc ≤ 500 msec and < 60msec increased from baseline then the subject
can continue therapy
If the average QTc is > 500 msec or > 60 msec increased from baseline the following
steps should be taken
• Study treatment should be interrupted immediately
• Electrolytes, particularly k and mg should be checked and corrected if abnormal
• Con meds with a potential for QTc interval prolongation should be discontinued
• A cardiologist should be consulted to assist with the management of the subject
• Communicate findings to PLUTO trials office
Pazopanib –Dose Reduction for other toxicities
Haematological
Platelets – No dose modification or interruption is required is the platelet
count remains ≥ 50 x109l
Neutrophils – No dose modification or interruption is required if the
neutrophil count remains ≥ 1.0 x109/l
Other Adverse Events
Grade 1 or 2 – continue study treatment at same dose; monitor and treat as
clinically indicated.
Grade 3/4
Step 1 – interrupt study treatment until toxicity reduces to ≤ grade 1
Step 2 – Restart study treatment at same dose or lower at discretion of
investigator
Recurrent grade 3/4
Step 1 – interrupt study treatment until toxicity reduces to ≤ grade 1
Step 2 – Restart study treatment at lower dose
Pazopanib –Prohibited Concomitant Therapies
Co-administration of pazopanib and medications which are
substrates for the CYP450 enzymes and have the potential to
cause serious or life-threatening adverse events is prohibited
from 14 days prior to the first dose of pazopanib through to
study discontinuation. These medications include:
Strong inhibitors of CYP3A4 (see appendix VI)
Some oral hypoglycemics
Ergot derivatives
Some neuroleptics
Some antiarrhythmics
Some immune modulators
Miscellaneous (theophylline, quetiapine, risperidone,
clozapine,)
Pazopanib Compliance
• Empty pazopanib bottles and any remaining medication is to
be returned at each patient visit.
• These are then returned to pharmacy where a count takes
place.
• Sites will need to have a local process where pharmacy and
research staff review patient returns in a timely manner in
order to assess patient compliance.
• Over or under compliance should be escalated to the study
team.
• Any patient non-compliant for more than 14 days should be
taken off study.
PLUTO –Paclitaxel Dose Modifications
The major adverse effects of paclitaxel which limit dose are:
• Myelosuppression: neutropenia, thrombocytopenia and
anaemia
• Peripheral neuropathy and asthenia are the predominant
non-haematological toxicities
• Myalgia, arthralgia
Paclitaxel Dose levels
Dose levels (DL) Paclitaxel
Starting dose
-1
-2
80mg/m2 IV weekly
70mg/m2
60 mg/m2
Paclitaxel – Dose modification for haematological
adverse events
Nadir absolute
Platelets
neutrophil (x109/L) (x109/L)
Paclitaxel
≥1
≥75
Full dose
<1
<75
Omit unil
recovered then
reduce 1 DL
Use of GCSF is permitted at the discretion of the investigator. As with all
concomitant medications its use should be accurately documented
Paclitaxel – Dose modification for non-haematological toxicity
Event
Management / Next Paclitaxel dose
≤ grade 1
No change in dose
Grade 2
Omit paclitaxel until ≤ grade 1 – resume at same dose *
(*excludes alopecia. Patients with grade 2 neurotoxicity
will require a dose reduction
Grade 3 or 4** / *****
Hold*** until ≤ grade 1 – resume at 1 DL if indicated****
(**excludes brief, sub-optimally managed
nausea and vomiting, rash, arthralgia and
myalgia)
(***patients requiring more than to treatment omissions
should go off protocol therapy)
(*****In the case of grade 3 or 4 cardiac
failure study treatment will be
discontinued)
(****patients requiring more than 2 dose reductions
should go off protocol therapy)
Paclitaxel– Dose modification for cumulative neuropathy
Neuropathy
grade 2
First incidence
1st dose reduction
to 70 mg/m2
Second incidence
(or worsening
despite reduction)
2nd dose reduction
to 60 mg/m2
Third incidence (or Off study
persistence despite
dose reduction)
Once dose reduced, patients should not be dose escalated even if neuropathy
improves. Patients with grade 3 motor or sensory neuropathy should be
discontinued from the trial
Paclitaxel –Concomitant Therapies
Caution should be exercised during concurrent
administration of active substances which are
metabolised in the liver as these may inhibit the
metabolism of paclitaxel.
Caution should be exercised when administering
paclitaxel concomitantly with medicines known to
inhibit or induce either CYP2C.
Strong inhibitors of CYP3A4 are prohibited during
administration of Pazopanib
PLUTO - Translational Research
• The most recent archived paraffin embedded tissue available
will be collected and stored for future biomarker studies
• Whole blood samples will be collected at baseline for
pharmacogenomics
• Plasma and urine samples will be taken at baseline, weeks 4
and 12 and at confirmed progression
• The blood and urine sample collection aspect of the trial is
optional to patients, and samples should only be collected for
patients who have consented to this.
• The samples must be collected for all patients who have
consented to the translational aspects of the study on the
consent form, please ensure all samples are taken for all
consenting patients
PLUTO - Assessment and Follow Up
Formal clinical assessment for week 1-25:
• During the first 24 weeks of the study patients should be seen formally on a 4 weekly basis in
clinic.
• Radiological assessments will occur at 12 weekly (+/- 7 days) intervals until disease
progression - CT or MRI scan of chest, abdomen and pelvis reported to RECIST v1.1
• ECG - only required for patients receiving pazopanib (Arm B)
• ECOG Performance Status
• Toxicity Assessment
• Concomitant medication review
• Blood pressure and pulse
• Haematology - including full blood count with WBC, ANC, platelets count and haemoglobin
• Biochemistry - including LFTs (including ALT, bilirubin), U + E, magnesium, calcium, alkaline
phosphatase, potassium, LDH, C-reactive protein and albumin.
• Urinalysis
• Plasma Blood sample collection**
• Urine sample collection**
**Only applicable to centres/patients participating in the translational component of the trial.
PLUTO - Assessment and Follow Up
From 24 weeks onwards all patients will be seen on a 6 weekly basis
6-weekly from Week 31 onwards until progression or death
• Both Arm A and Arm B patients should receive:
• ECOG Performance Status
• Toxicity Assessment (if pazopanib ongoing or if unresolved toxicity)
• Arm B (pazopanib) patients should also receive:
• Concomitant medication review (if pazopanib ongoing)
• Blood pressure and pulse
• Haematology - including full blood count with WBC, ANC, platelets count and haemoglobin
• Biochemistry - including LFTs (including ALT, bilirubin), U + E, magnesium, calcium, alkaline phosphatase,
potassium, LDH, C-reactive protein and albumin
• Urinalysis
• Thyroid function testing (12 weekly if pazopanib ongoing)
12-weekly from Week 31 onwards
Both Arm A and Arm B patients should receive:
• Radiological Assessment – CT scan of the chest, abdomen and pelvis, or MRI. The same modality should be
used as for the baseline/previous 12 weekly scans. Scans should be performed 12 weekly until
progression. A window of +/- 7 days is permitted. Scans must be reported to RECIST v1.1
• FACT-Bl (QoL) form (to be collected 12 weekly from Week 37 onwards)
Assessments after 2 years Post Randomisation
• For those patients still alive and progression-free after 24 months on trial, further follow up and cross
sectional imaging will be at the discretion of the treating physician
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.
• 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.
RECIST Worksheet
PLUTO - CRFs
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Consent Notification Form
Randomisation Form
Pre-treatment Form
FACT-Bl QoL Form
Treatment Form
Response Form
Follow–up Form
Concomitant Medication Form
Consent Withdrawal Notification Form
Pregnancy Notification Form
PLUTO – CRF Completion
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CRF completion guidelines for the study are currently being developed and will
provided to sites when available
Entries to the CRFs will be made in black ball-point pen and must be legible
Correction fluid etc. must not be used
Any errors must be crossed out with a single stroke, correction inserted and
change initialled and dated
An explanation can be written next to amendment if necessary
Date format: DD/ MON/ YYYY
Please ensure all data submitted on the CRFs is verifiable in source documents
Take photocopy of all completed CRFs. Originals to be sent to CR-UK CTU Glasgow
PLUTO – CRF Completion Timelines
Timelines for entry
of required data in the CRF
Timelines for resolution of
data queries
Timelines for receipt of CRFs
at CR-UK CTU, Glasgow
Within 4 weeks of patient visit
Within 4 weeks of receipt
Within 2 weeks of form
completion
PLUTO Trial - Pharmacovigilance
Clinical Trial Regulations require:
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Investigators document Adverse Events (AEs) in patient notes and the CRF
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Investigators report Serious Adverse Events (SAEs) immediately to the CR-UK Clinical
Trials Unit, Glasgow (CTU)
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The CTU (on behalf of the Sponsor) make expedited reports of Suspected Unexpected
Serious Adverse Reactions (SUSARs) to the Regulatory Authority (MHRA), Main REC GSK
& Sponsor
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The CTU will produce the Development Safety Update Reports (DSURs)
PLUTO Trial – Adverse Event Reporting
• 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 < Grade 1,
- or until toxicity is considered to be irreversible
• All AE and toxicities must be graded according to the NCI-CTCAE Version
4.0
• An exacerbation of pre-existing condition is an AE
Definition of a SERIOUS ADVERSE EVENT
A Serious Adverse Event (SAE) is defined as any
untoward medical occurrence, not necessarily
related to protocol treatment, that:
• Results in death
• Is life-threatening
• Requires hospitalisation or prolongation of existing
hospitalisation
• Results in persistent or significant disability or incapacity
• Consists of a congenital anomaly or birth defect
• Is considered medically significant by the Investigator
Definition of a SERIOUS ADVERSE EVENT
Life threatening:
• The patient is 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:
• Is as a hospital admission required for treatment of
an adverse event even when the adverse event is not
related to the protocol treatment
PLUTO - Reporting SAEs
• SAEs must be reported immediately (within 24 hours of
knowledge of the event)
• SAEs are reported using an electronic system developed on
behalf of the Sponsor by the Robertson Centre for
Biostatistics
• Sites input details for each SAE on the electronic system
• The CTU will acknowledge receipt of each new initial report
• The SAE report will be forwarded to GSK
• The CTU will request additional information if the event is
unexpected
• CTU will raise queries for any inconsistent or missing
information
PLUTO – Procedure for Reporting SAEs and SAE Report Processing
CTU
generates
Patient
SAE and DCF
SAE
queries
form
completed
Site
submit
by
Patient
SAESAE
and report
SAE form
adding a completed
new SAE report
to electronic SAE system
CTU
queries
to
Patientfax
SAE
and SAE
reporting
site
form completed
CTU
faxSAE
SAE
report
Patient
and
SAE
acknowledgment
form completed
receipt to site
Site
resolves
queries
Patient
SAE and
SAE
withincompleted
7 days
form
PI logs into system and
Patient SAE and SAE form
verifies SAE report with
completed
an electronic signature
Site queries to be signed
Patient SAE and SAE form
by Principal Investigator
completed
or delegated doctor
Yes
CTU
check
SAE
Patient
SAE
andreport
SAE
data completed
entered
form
CTU identifies any
Patient SAE and SAE form
missing or inconsistent
completed
data
Is SAE
CTUrelated
to IMA?
DCF queries
required?
No
Site
fax queries
toSAE
CTU
Patient
SAE and
Faxform
0141
232
9429
completed
Site
updates
Patient
SAEelectronic
and SAE
SAE report
with queries
form completed
CTU records
Patient
SAE andSAE
SAE
report
complete
formiscompleted
CTU checks
SAE
Patient
SAE and
SAE
electronic
report
data
form completed
SAE Data Flow Version 3 10 Apr 2012
PLUTO - Procedure for Identifying Unexpected and
Related Events
• A checklist will be used to identify SUSARs that require expedited
reporting to the Regulatory Authority, Main REC and Sponsor
• The checklist is a list of the events expected to occur in patients
receiving the protocol treatment (Paclitaxel and Pazopanib). For any
SAE that is documented as related to protocol treatment (SAR) and is
not listed on the checklist, the Chief Investigator will be contacted for
an opinion of SUSAR status (unexpectedness)
• The Chief Investigator is responsible for deciding if a SAR requires
expedited reporting
• GSK will be informed of the decision to report a SAR as a SUSAR and
receive a copy of the SUSAR report
PLUTO - Expedited Reporting
SAEs that meet the criteria for SUSARs will be reported to the
MHRA, Main REC, GSK and Sponsor where in the opinion
of the Chief Investigator the event was:
• Related – that is, resulted from administration of any of the research
procedures
And
• Unexpected – that is the type of event is not listed in the Investigator
Brochure or Summary of Product Characteristics (SmPC) as an expected
occurrence
Reports of related and unexpected SAEs will be submitted
within 7 days for fatal/life threatening events and 15 days for
all other events
PLUTO - Development Safety Update Reports
A Development Safety Update Report (DSUR)
covering the safety of all trial participants will be
prepared by the CR-UK CTU and submitted to the
MHRA, Main REC, GSK, Sponsor & trial
Investigators annually
MONITORING (1)
Central Monitoring
Study sites will be monitored centrally by checking incoming forms for compliance with the
protocol, data consistency, missing data and timing. Study staff will be in regular contact with site
personnel (by phone/fax/email/letter) to check on progress and deal with any queries that they
may have.
On-site and Remote Telephone Monitoring
The 1st visit will take the form of a remote telephone monitoring visit:
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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
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A pro forma covering the questions which will be covered during the telephone monitoring
visit will be sent with confirmation of the confirmation of the agreed date
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Please set aside 50 to 70 minutes for this call.
MONITORING (2)
The 2nd visit will take the form of an on site monitoring visit:
•
Investigators and site staff will be notified in advance about forthcoming pre arranged monitoring
visits
•
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
•
The pharmacy department responsible for the trial will be visited to allow monitoring of the pharmacy
site file and review of security, storage and accountability of trial drugs.
•
All findings will be discussed at an end of visit and any unresolved issues raised as Action Points
•
Action Points will be followed up by the monitor until resolved
PLUTO – Ethical and Regulatory Standards
•
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
PLUTO – Investigator Responsibilities
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.
PLUTO – Investigator Responsibilities
•
•
•
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)
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.
PLUTO – Investigator Responsibilities
•
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 trial’s randomisation procedures as detailed in the protocol.
•
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.
PLUTO – Investigator Responsibilities
•
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 as soon as they
become aware of the event.
PLUTO – Other Site 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
PLUTO - CONTACT DETAILS FOR CR-UK CTU
Project Manager
Judith Dixon
Tel: 0141 301 7540
Fax: 0141 301 724
E-mail: [email protected]
Trial Coordinator
Anna Morris
Tel: 0141 301 7232
Fax: 0141 301 7228
E-mail: [email protected]
Pharmacovigilance
Pharmacovigilance Manager
Lindsey Connery
Tel:
0141 301 7209
Fax:
0141 301 7213
E-mail: [email protected]
Pharmacovigilance CTC
Susannah Radford
Tel: 0141 301 7211
Fax: 0141 301 7213
E-mail: [email protected]
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