Download Initiation Slides - Clinical Trials Unit Glasgow

PIONEER
A Phase I Study of Olaparib In Combination with ChemoRadiation in Locally Advanced Pancreatic Cancer
INVESTIGATOR INITIATION PRESENTATION
Version 1, 16th April 2015
STUDY DETAILS
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Coordinated by CRUK Clinical Trials Unit, Glasgow
Sponsor - Greater Glasgow and Clyde Health Board (GGCHB) and University of Glasgow
Chief Investigator - Professor Jeff Evans
Funded by CRUK (New Agents Committee) and also by AstraZeneca as part of the ECMCCombinations Alliance
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Please note this presentation has been prepared as part of your site initiation.
These slides are a compliment to the protocol, all site staff must have read
and understood the protocol and the study requirements prior to signing off
the initiation acknowledgment sheet.
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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
STUDY TEAM
Chief Investigators:
Professor Jeff Evans
Trial Statisticians:
Jim Paul/Jamie Stobo
Project Management:
Liz-Anne Lewsley
Clinical Trial Co-ordinator:
Calum Innes
Sponsor Pharmacist:
Dr Samantha Carmichael/Paula Morrison
Pharmacovigilance:
Lindsey Connery/Pam Fergusson
Clinical Trial Monitor:
Jan Graham
Sponsor Representative:
Dr Erica Packard
STUDY DESIGN
A phase I, open-label, non-randomised, multi-centre, dose escalation trial
of the PARP inhibitor, olaparib, administered in combination with standard
capecitabine
patients
- based chemo-radiation combined modality therapy in
with
locally
advanced,
inoperable
pancreatic
ductal
adenocarcinoma. Once the recommended dose has been determined, an
additional cohort of 12 patients with “borderline” resectable pancreatic
ductal adenocarcinoma will be recruited.
STUDY OBJECTIVES
The objectives of this trial are to explore the safety and toxicity of this
regimen, to identify the dose-limiting toxicities and the maximum tolerated
dose, and to recommend a dose of olaparib for phase II clinical trials. The
objectives of the additional cohort are to determine the tolerability of this
regimen in this patient population, and to explore preliminary data on
whether or not this regimen can potentially down-stage their disease.
STUDY ENDPOINTS
Primary Endpoint
• Maximum tolerated dose of olaparib when administered in combination
with standard capecitabine-based chemo-radiation based on clinical and
laboratory toxicity (NCI-CTCAE 4.03)
Secondary Endpoints
• Safety and tolerability of olaparib in combination with capecitabine-based
chemoradiation
Research/Tertiary Endpoints
• Pharmacodynamic effects of the combination of olaparib with
capecitabine-based chemo-radiation in blood, hair follicles and, where
available, tumour samples
SLOT REQUESTS AND SLOT ALLOCATION
Please note that this applies to the dose escalation phase of the study only.
Each cohort has 6 places which can be filled using the slot request system. Ethically we cannot refuse
treatment to an eligible patient that has consented to a study so each site must ensure that they have a
slot on the current dose cohort before the patient has been approached with the patient information
sheet.
SLOT ALLOCATION
• CTU will provide a slot request form for the site that should be completed and returned to the CTU
in order for a slot to be allocated.
• Upon receipt of the slot request form, the CTU will process the form and allocate the slot if there is
one available.
• Upon confirmation of the slot allocation the site can approach the patient with the patient
information, consent (if patient agrees) and begin the screening process.
• For patients that decline participation, or fail to meet the eligibility criteria please contact the CTU
immediately in order that this slot can be re-allocated
For slot allocations and requests: Calum Innes, Tel: 0141 301 7382, Fax: 0141 301 7192
[email protected]
INFORMED CONSENT PROCESS
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Two original Consent Forms to be completed by a clinician (or designee listed on study specific training and delegation log)
Two originals signed and completed by the patient
Date must be on or prior to registration
Make one photocopy
– Original to be filed in Investigator Site File
– Original to be given to patient
– Photocopy to be filed in hospital notes
Consent Form must not be sent to the CRUK Trials Unit, Glasgow
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FOR ERRORS NOTED AFTER CONSENT
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Explanatory file note is completed and sent to CRUK CTU Glasgow with a copy remaining at site
PATIENT RECONSENT
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If the sponsor requires patients to be re-consented then the new version of the patient information sheet and consent form
must be given to the patient at the next clinic visit. The consent process should be followed as above.
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If a patient cannot re-consent (i.e. patient is terminally ill) then a file note should be written to explain this as well as this
being documented in the patient’s notes.
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The re-consent log in the Investigator Site File should be kept up to date
CONSENT WITHDRAWAL
When the patient specifically asks to withdraw consent at any point in the study. If this occurs:
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Document clearly in the patient notes that the patient has withdrawn consent, the level of consent withdrawal (e.g.
withdrawal from treatment only or complete withdrawal with no follow-up data to be collected) and the reason (if the
patient has given any);
Completed the consent withdrawal notification form (NB this is only required if patient withdraws consent completely from
the stud, e.g if patient withdraws from treatment only this does not need to be completed);
Send the consent withdrawal notification for to the CRUK CTU
No further follow-up should be collected on the patient from that point onwards (should the patient have withdrawn this
level of consent)
Please note that SAEs will continue to be collected even if a patient has withdrawn consent and this should be explained to
the patient
PATIENT REGISTRATION FOR STUDY TREATMENT
All patients must be registered onto the study prior to commencement of any treatment.
 All screening evaluations must be performed as per study protocol section 4.1 (please note that all evaluations should be
performed within 7 days of treatment administration except for CT scan Chest, Abdomen and Pelvis which should be within 28 days).
 Patients must be able to start treatment within 4 weeks of completion of induction chemotherapy.
Check that patient fulfils eligibility criteria as per study protocol section 3.3.
There will be no exceptions to the eligibility requirements at the time of registration. Queries in relation to the eligibility criteria should
be addressed prior to calling for registration. Patients are eligible for the trial if all inclusion are met and none of the exclusion criteria
applies.
 Check the patient has given written informed consent as per the informed consent process
 Complete Registration Form.
Site staff must contact the Cancer Research UK Clinical Trials Unit, Glasgow to register the patient. Registration to the study can be
done by either telephone or fax on the following numbers:
Tel no: ++ 44 141 301 7382
Fax no: ++ 44 141 301 7192*
08.30-17.00 Mon-Thurs and 08.30-16.30 Friday, except public holidays
* Faxes received outside of office hours will be processed the next working day
 Each patient registered will be allocated a unique sequential patient ID number for the study.
Treatment and Duration
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Patients will have been treated with 12 weeks of induction with the standard gemcitabine and
capecitabine chemotherapy regimen used locally. Patients with stable or responding disease,
tumour diameter of 6 cm or less, and ECOG performance status < 1 will receive escalating doses of
olaparib administered 3 days before radiotherapy and continuing on a Monday to Friday basis, in
combination with capecitabine (830 mg/m2 twice daily, Monday to Friday only) in combination
with radiation (50·4 Gy in 28 fractions, Monday to Friday).
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Patients must start chemoradiation within 4 weeks of finishing induction chemotherapy
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Olaparib will be administered orally twice daily as the tablet formulation starting 3 days prior to
chemo-radiation and then subsequently from Monday to Friday with chemo-radiation. The starting
dose will be 50 mgs PO twice daily, and with escalation to other dose levels as below, until the
maximum tolerated dose is defined. The maximum tolerated dose of olaparib when administered
in combination with capecitabine and radiation is defined as the highest dose at which 0 out of 3 or
< 1 out of 6 patients experience dose limiting toxicity.
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Expansion cohort of 12 patients with borderline resectable disease will be treated at the Olaparib
MTD.
Treatment and Duration
Planned Dose Cohorts:
Dose Level
Olaparib Dose PO (starting 3 days prior to radiotherapy)
1
50mg twice daily
2
100mg twice daily
-3*
150mg twice daily
3
200mg twice daily
-4*
250mg twice daily
4
300mg twice daily
*Intermediate dose cohorts -3 and -4 potentially could be explored based on ongoing toxicity assessment
RADIOTHERAPY QUALITY ASSURANCE
Radiotherapy Quality Assurance requires to be approved by the RTQA group as part of site
initiation/set-up.
Sites will use their QA process for the ESPAC5/SCALOP2 studies for PIONEER (there is not a standalone
QA process for this project)
On-trial QA is performed on patients who have been recruited into the trial and consists of:
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Individual case reviews: For all patients, the plan assessment form (PAF) should be reviewed by the
QA centre before the patient starts treatment
Universal data collection: Data will be collected by the QA centre for all patients treated in the
trial. This includes: planning CT images, contours, treatment plan, planned dose cubes along with
completed PAFs. All data must be appropriately anonymised, and in DICOM format where
possible. Data may be sent by secure electronic transfer (preferred) or physical media.
***Please note the QA process differs in the protocol and this will be amended to reflect the above***
DOSE LIMITING TOXICITIES (DLT) and MAXIMUM TOLERATED DOSE (MTD)
Any of the following events that occur in the period commencing with the start of olaparib dosing and
until completion of the olaparib plus chemo-radiation will be considered a DLT, in the opinion of the
Chief Investigator, the event is due to the combination of olaparib and chemo-radiation:
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Grade IV neutropenia lasting for >7 days
Grade III/IV neutropenia with sepsis or with fever > 38.5 0C
Grade IV thrombocytopenia
Grade IV diarrhoea
Grade > III other non-haematological toxicities except for alopecia, and except for nausea or
vomiting unless patients are taking optimal prophylaxis or supportive measures
Failure to deliver > 75% of the planned doses of either olaparib or capecitabine due to toxicity
(unless the toxicity is specifically due to capecitabine and is unlikely to have been exacerbated by
olaparib, e.g. DPD deficiency).
Treatment related toxicities that lead to an interruption of radiotherapy for more than 7 days or
a failure to deliver > 26 fractions of radiotherapy
In all cases of suspected DLT, clinical judgement should be the final arbiter as to whether or not the
event should be categorised as a DLT.
DOSE LIMITING TOXICITIES (DLT) and MAXIMUM TOLERATED DOSE (MTD)
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The maximum tolerated dose is defined as the dose level immediately below that which causes
dose-limiting toxicity in > 1 out of 3-6 patients.
Patients who fail to receive >=75% of the planned dose of any of the treatment components
(olaparib, XRT, capecitabine) for reasons clearly not related to olaparib (e.g. disease progression)
will be unevaluable for DLT assessment and will be replaced.
The DLT assessment period will be up to 1 week post completion of chemoradiation
***Please note sites will require to submit DLT forms weekly during the DLT
Assessment Period***
DOSE ESCALATION DECISION
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The decision to escalate to the next dose cohort will be made by a Safety Review
Committee meeting with clinical representation from each of the participating
sites.
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These meetings will take place regularly throughout dose escalation phase of the
study.
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The decision to dose escalate will be based on clinical and laboratory safety
parameters.
SUPPLY OF STUDY DRUGS
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All drugs administered in this trial are considered Investigational Medicinal Products (IMPs) for the
purposes of this protocol (this excludes the 12 week induction chemotherapy)
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Capecitabine for use in the trial (excluding the 12 weeks of induction chemotherapy) should be
taken from usual pharmacy stock; there is no provision for funding, reimbursement or discounted
stock. Shelf stock will not require IMP labelling but all IMP being dispensed to patients must be
labelled at site, at the time of dispensing, in accordance with all applicable regulatory requirements
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Olaparib is provided free of charge by AstraZeneca (this will be distributed by Fisher Clinical
Services)
***Full instructions regarding management, labelling and accountability for all study
drugs is given in a separate IMP Management Document for the study. Please also
note that there are separate Pharmacy Site Initiation Slides.***
Concomitant Medications
• Please refer to protocol section 5.4 for medications permitted/supportive
care in relation to Chemo-radiation
• Please refer to protocol section 6 for advice regarding concomitant
therapy for olaparib:
– Olaparib and CYP3A4
– Other concomitant medications (including anticoagulant therapy)
– Administration of other anti-cancer agents
– Medications that may NOT be permitted
***If there are any queries surrounding any medications that patients are taking either prior to
registration or for the duration of the trial then please contact the CRUK CTU in the first
instance***
Dose Modifications
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Once any dose reduction has been implemented, this should not be increased at a later time.
Non-haematological, non-gastrointestinal toxicity (Chemoradiation only)
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Both capecitabine and RT should be interrupted (see Olaparib recommendations on separate
slide) if patients develop grade 3 toxicity with treatment, except for grade 3 anaemia or alopecia.
Capecitabine and RT can be recommenced when toxicities resolve to grade 1 or baseline. Grade 3
aesthenia is common during CRT and treatment may be continued as long as patients are able to
do so. For management of non-haematological capecitabine related toxicity, follow guidance on
table on next slide
If the creatinine clearance decreases during treatment to a value < 30 mL/min, capecitabine
should be discontinued. Please refer to the current version of the SmPC for Capecitabine
Dose Modifications
Capecitabine Dose Reduction Schedule for Non-haematological Toxicities
(excluding gastro-intestinal)
Toxicity
During a course of therapy
Dose adjustment for next cycle (%
of starting dose)

Grade 1
Any appearance
Grade 2
1st appearance

2nd appearance
Interrupt until resolved to grade 0-1
75%
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3rd appearance
Interrupt until resolved to grade 0-1
50%
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4th appearance
Discontinue treatment permanently
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Grade 3
1st appearance
Interrupt until resolved to grade 0-1
75%
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2nd appearance
Interrupt until resolved to grade 0-1
50%

3rd appearance
Discontinue treatment permanently

Grade 4
1st appearance
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Maintain dose level
Maintain dose level
Interrupt until resolved to grade 0-1
100%
Discontinue permanently
Or
If physician deems it to be in the
participant’s best interest to continue,
interrupt until resolved to Grade 0-1 after
discussion with CI
50%
Dose Modifications
Dose Reductions for Gastro intestinal toxicity
Toxicity
Grade
Capecitabine
Olaparib
RT
Nausea/vomiting
Grade 1 / 2
Full Dose
Full Dose
Continue
Grade 2 despite
Withhold until G1.
Withhold until G1.
Withhold until G1
full anti-emetics
Restart at 100%
Restart at full dose
Comments
Maximize antiemetics
dose
Grade 3, 1st
Withhold until G1.
Withhold until G1.
episode
Restart at 75% dose Restart at 1 dose
Withhold until G1
Maximize antiemetic
level below which
has been shown to
be tolerable1
Grade 3, 2nd
Stop CRT
Stop CRT
Stop CRT
Stop CRT
Grade 4
Stop CRT
Stop CRT
Stop CRT
Stop CRT
Grade 1 / 2
Full Dose
Full Dose
Continue
Maximize anti-
Grade 2 despite
Withhold until G1.
Withhold until G1.
Withhold until G1.
full anti-diarrhoeal Restart at full dose
Restart at full dose
episode
Diarrhoea (nonpancreatic)
diarrhoeal
Maximize antidiarrhoeal
treatment
Grade 3, 1st
Withhold until G1.
Withhold until G1.
episode
Restart at 75% dose Restart at 1 dose
Withhold until G1
Maximize antidiarrhoeal
level below which
has been shown to
be tolerable1
Grade 3,
2nd
Stop CRT
Stop CRT
Stop CRT
Stop CRT
Stop CRT
Stop CRT
Stop CRT
Stop CRT
episode
Grade 4
1Shown
to have 0 DLTs in 3 patients or a maximum of 1DLT in 6 patients
Dose Modifications
Gastro-intestinal Bleeding
Any episode of gastro-intestinal bleeding during RT should
be investigated with upper GI endoscopy. Haemorrhagic
gastritis/duodenitis should be treated with maximal
proton pump inhibition and a break from CRT for one
week. If this recurs after re-starting treatment, CRT
should be abandoned.
Dose Modifications
Olaparib
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If toxicity occurs that meets the definition of a dose-limiting toxicity (DLT) – see protocol section 3.1 –
then olaparib treatment will be interrupted until recovery to baseline or grade < 1, when olaparib can
be re-introduced at the dose level immediately below that at which the DLT occurred. If toxicity does
not recover adequately to allow re-introduction of treatment within 14 days, then olaparib will be
permanently discontinued.
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Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 adverse event occurs which the
Investigator considers to be related to the administration of olaparib (other than alopecia, anaemia, or
nausea / vomiting unless the patient is taking maximal anti-emetic support).
Dose Modifications
Management of Anaemia
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Haemoglobin must be maintained above 10g/dl throughout CRT; if necessary maintain through
blood transfusion.
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Adverse events of anaemia CTCAE grade 1 or 2 (Haemoglobin (Hb) <LLN but > 8 g/dl) should be
investigated and managed as deemed appropriate by the investigator Common treatable causes
of anaemia (e.g., GI blood loss, iron, vitamin B12 or folate deficiencies and hypothyroidism)
should be excluded. In some cases management of anaemia may require blood transfusions.
However, if a patient develops anaemia CTCAE grade 3 (Hb < 8g/dl) or worse, without any
evidence of GI blood loss, then olaparib treatment should be interrupted for up to maximum of 4
weeks to allow for bone marrow recovery and the patient should be managed appropriately.
Study treatment can be restarted at the same dose if Hb has recovered to > 10 g/dl. Any
subsequently required anaemia related interruptions, considered likely to be dose related, or
coexistent with newly developed neutropenia, and or thrombocytopenia, will require dose
reductions of olaparib to the previous dose level.
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If a patient has been treated for anaemia with multiple blood transfusions without study
treatment interruptions and becomes blood transfusion dependant as judged by investigator,
olaparib treatment should be permanently discontinued.
Dose Modifications
Haematological Toxicity (neutrophil and platelet count)
Neutrophil*
X 109/l
≥1.0
≥1.0
<1.0
Platelet*
X 109/l
>100
75-100
<75
< 0.5
< 50
Capecitabine
Olaparib
100% dose
100% dose
Omit dose for the
week.
Subsequent
dose at 75%
100% dose
100% dose
Omit dose for the
week. Subsequent
dose at 1 dose level
below starting dose
which has been
shown to be
tolerable1
Omit dose until
recovery to
neutrophils > 1,
platelets > 75, then
re-start at 1 dose
level below starting
dose which has been
shown to be
tolerable1
Omit dose until
recovery
to
neutrophils > 1,
platelets > 75, then
re-start at 50% dose
RT
Continue
Continue
continue
Stop RT if neutrophil
<0.5 or platelets <50;
repeat FBC in 3 days.
Restart RT alone if
neutrophil >0.5 and
platelets >50. Restart
chemotherapy when
neutrophil >1 and
platelets >75
*If neutrophils and platelets are at different levels, adjust for the worst level
1Shown to have 0 DLTs in 3 patients or a maximum of 1DLT in 6 patients
Dose Modifications
Management of new or worsening pulmonary symptoms
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If new or worsening pulmonary symptoms (e.g. dyspnoea) or radiological abnormality occurs, an
interruption in olaparib dosing is recommended and a diagnostic workup (including a high
resolution CT scan) should be performed, to exclude pneumonitis. Following investigation, if no
evidence of abnormality is observed on CT imaging and symptoms resolve, then olaparib
treatment can be restarted, if deemed appropriate by the investigator. If significant pulmonary
abnormalities are identified, these need to be discussed with the CRUK CTU.
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All dose reductions and interruptions (including any missed doses), and the reasons for the
reductions/interruptions are to be recorded in the CRF.
Dose Modifications
Management of Nausea and Vomiting
The management of nausea and vomiting is as per standard therapy of patients
receiving chemo-radiotherapy for pancreatic cancer. For example, all patients
should receive a proton pump inhibitor or H2 blocker (starting prior to
radiotherapy and continued for at least 3 month following completion of
radiotherapy), and all patients should receive regular anti-emetics one hour prior
to each radiotherapy fraction (e.g. Metoclopramide 20mg or ondansetron 4 to 8
mg) and as needed.
Dose Modifications
Dose Delays for Radiotherapy
Delays of up to 7 days in radiotherapy are permitted once the patient has started
radiotherapy. Patients should continue taking olaparib and capecitabine until
radiotherapy is completed, unless the cause of the delay is thought to be related
to olaparib, capecitabine, or olaparib/chemoradiation combination.
Dose Modifications
Other Dose Modifications (Olaparib)
For non-haematological, non-gastrointestinal toxicities that are
considered to be related to olaparib, the dose of olaparib will be
interrupted for a grade 3 / 4 event until recovery to grade 0 or 1,
and reduced by one dose level below which has shown to be
tolerable (shown to have 0 DLTs in 3 patients or a maximum of 1
DLT in 6 patients) if a DLT occurs.
Translational Research
PK Samples (All Patients)
PK samples will be taken at the following time-points:
Day -3
First week of CRT
Pre-dose
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30 mins
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1 hour
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2 hours
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4 hours
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6 hours
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8 hours
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24 hours
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Please refer to lab manual for details on handling and shipping
Translational Research
PD/Predictive Markers – Blood and Tumour (All Patients)
• Tumour biopsies (rather than FNA) will be mandatory prior to
treatment for patients with borderline operable pancreatic
cancer who are recruited into the expansion cohort at the
optimal dose level
• These will be performed where feasible in the patients
recruited into the dose escalation part of the trial
• Blood samples can be taken up to 3 weeks prior to treatment
administration
• These samples will be used for DNA damage repair analyses
(Belfast) and genomic studies
Pre-induction chemotherapy archival tumour sample can be used
Translational Research
Blood PD Markers (All Patients)
Blood samples will be collected (CK18 analyses) and PBMCs
prepared for analysis of inhibition of PARP. 20mls of blood will
be collected at the following time-points:
Day -3
Day 8 CRT
Pre-dose
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6 hours
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
24 hours
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Please refer to lab manual for details on handling and shipping
Translational Research
Pathology Assessment of Resected Tumour Specimens
(Dose Expansion Cohort only)
In the expansion cohort of patients with “borderline” resectable
disease whose tumours are down-staged by the trial treatment
and who undergo surgery (resection or biopsy if inoperable),
tumour specimens will be processed, analysed, and reported as
per standard pathology practice. Sections will be reviewed
centrally and extent of tumour necrosis and pathological
response will be determined.
Translational Research
Hair Follicles PD Markers (Dose Expansion Cohort only)
Plucked hair follicle (eyebrow) samples will be collected for
induction of γH2AX foci (immunofluorescence assay) at the
following time-points:
Day -3
Day 8 CRT
Pre-dose


6 hours


Please refer to lab manual for details on handling and shipping
Assessments
Study specific procedures should only be performed after written informed consent. Written informed
consent must be within 42 days of study registration. Please note that treatment should start within 4 weeks
of completion of induction chemotherapy.
Evaluations prior to starting Treatment:
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Medical History (including concomitant medications)
Physical examination
Toxicity assessment (post – induction chemotherapy; NCI – CTCAE v 4.03, see Appendix 4)
Concomitant medications
Height, weight, and Body Surface Area
Vital signs – pulse, temperature and blood pressure
ECG
ECOG Performance Status
Creatinine clearance / glomerular filtration (this should be checked throughout treatment as indicated)
Full blood count
Coagulation screen (APTT and INR)
Biochemistry (urea & electrolytes, liver function tests (including AST, ALT and bilirubin), creatinine, calcium, alkaline
phosphatase, LDH, albumin, C-reactive Protein and glucose)
Pregnancy test (if appropriate)
Review of eligibility criteria
NB CT scan of chest / abdomen / pelvis will have been performed within 3 weeks of completion of induction chemotherapy
and will be the baseline pre-treatment disease assessment prior to chemo-radiation (this should be within 28 days of the
start of study treatment)
Assessments
Evaluations during Treatment:
Day -3 First Administration of Olaparib
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Toxicity assessments
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Concomitant medications
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Commence olaparib administration orally, twice daily (days -3, -2, and -1)
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Blood for olaparib PK studies: pre-dose, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dosing.
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Blood for PD studies: pre-dose, 6 and 24 hours post-dosing
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Hair follicles for PD studies: pre-dose and 6 hours after dosing (dose expansion cohort only)
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ECOG Performance Status (see Appendix 3)
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Full blood count
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Biochemistry (urea & electrolytes, liver function tests (including AST, ALT and bilirubin), creatinine, calcium, alkaline
phosphatase, LDH and albumin
Weekly during Treatment
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Toxicity assessments
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Concomitant medications
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Physical examination
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Weight
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Body Surface Area
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Vital signs – pulse, temperature and blood pressure
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ECOG performance status
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Creatinine clearance / glomerular filtration
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Full blood count (+/- 24h)
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Biochemistry (urea & electrolytes, liver function tests (including AST, ALT and bilirubin), creatinine, calcium, alkaline
phosphatase, LDH and albumin. (+/- 24h)
Follow-Up
End of Treatment/Follow up (1 week after completion of chemo-radiotherapy)
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Toxicity assessments
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DLT assessment
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Concomitant medications
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Physical examination
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Weight
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ECOG performance status (see Appendix 3)
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Full blood count (+/- 24h)
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Biochemistry (urea & electrolytes, liver function tests (including AST, ALT and bilirubin), creatinine, calcium, alkaline
phosphatase, LDH and albumin (+/- 24h)
Follow up (4 weeks after completion of chemo-radiotherapy)
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Toxicity assessments
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Concomitant medications
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Physical examination
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Weight
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ECOG performance status (see Appendix 3)
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Full blood count (+/- 24h)
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Biochemistry (urea & electrolytes, liver function tests (including AST, ALT and bilirubin), creatinine, calcium, alkaline
phosphatase, LDH and albumin (+/- 24h)
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CT scan of chest / abdomen / pelvis
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Tumour sample from surgery (if feasible) (dose expansion phase only)
Subsequent follow up will be at 3 – monthly intervals, with further investigations at the investigator’s discretion.
SITE SET-UP
CRUK CTU GLASGOW
Main REC approval
MHRA approval
Site Initiation Slides
Investigator Site File
Pharmacy Site File
Radiotherapy QA Process
Sample Collection Supplies
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SITE
Study Specific Training and Delegation Log
SSI – R&D Approval
Investigator and Lead Pharmacist CV & GCP Certificates
Clinical Trial Agreement
Summary PIS/ PIS&Consent/GP Letter/Patient Results Letter on Headed Paper
Lab normal ranges and accreditation certificates (Haem + Biochem)
Radiotherapy QA Approval
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INITATION PROCESS
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SITE ACTIVATION/DRUG SUPPLY
CRFs
CRFs for the study:
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Registration Form
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Pre-treatment Form
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Treatment Form
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PK Assessment Form
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PD Assessment Form
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End of Treatment Form (incorporating one week follow up visit)
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Response Form (incorporating four week follow up visit)
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Follow–up Form
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Consent Withdrawal Notification Form
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Pregnancy Notification Form
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SAE Form please note the SAE form is faxed to Pharmacovigilance at the CRUK CTU and the original SAE report is kept at site
Other Study Pro Formas
•
Slot Allocation Form
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Dose Limiting Toxicity (DLT Form)
CRF Completion:
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CRF completion guidelines for the study are currently being developed and will be provided to sites when available
•
Entries to the CRF 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 an amendment if necessary
•
Please ensure all data submitted on the CRFs is verifiable in source documents
•
Take photocopy of all completed CRFs. Originals to be sent to CRUK CTU Glasgow
CRF Completion Timelines
•
Data entry – within four weeks of the patient visit Please note that during the dose escalation phase frequent data requests will
be made regarding patients on treatment with regard to adverse events, laboratory results and concomitant medications
•
Resolution of queries – within 4 weeks of receipt
•
All data should be returned to the CRUK CTU within 1 week of sign off
PHARMACOVIGILANCE
Clinical Trial Regulations require:
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Investigators document Adverse Events (AEs) in patient notes and the CRF
Investigators report Serious Adverse Events (SAEs) immediately to the CRUK Clinical Trials Unit, Glasgow (CTU)
The CTU (on behalf of the Sponsor) make expedited reports of Suspected Unexpected Serious Adverse Reactions (SUSARs) to the
Regulatory Authority (MHRA), REC, Sponsor and AstraZeneca
The CTU will produce the Development Safety Update Reports (DSURs)
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
•
All AEs must be recorded in full in the patients notes with the nature of the event, start and stop dates, severity, seriousness and causality
to each study drug and outcome
DEFINITION OF A SERIOUS ADVERSE EVENT
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that is not necessarily
related to protocol treatment that:
•
•
•
•
•
•
Results in death
Is life-threatening (patient is at immediate risk of death from the event as it occurred)
Requires hospitalisation or prolongation of existing hospitalisation (hospital admission is required
for treatment of that adverse event, even with the adverse event is not related to protocol
treatment)
Results in persistent or significant disability or incapacity
Consists of a congenital anomaly or birth defect
Is considered medically significant by the Investigator
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
Required in-patient hospitalisation:
• Is a hospital admission required for treatment of an adverse event even when the adverse event is
not related to the protocol treatment
REPORTING SAEs
•
SAEs must be reported immediately (within a maximum of 24 hours of knowledge of the event)
•
SAEs are reported using the CRUK CTU SAE report form
•
Sites must complete the SAE report form and fax to Pharmacovigilance at the CRUK CTU, Fax
number 0141 301 7213
•
The CTU will create a SAE reference number and will send an acknowledgement fax to confirm
receipt
•
CTU will raise queries for any inconsistent or missing information
•
SAEs to be reported locally by the PI at each site in accordance with the local practice (i.e. to ethics
committee, local R&D)
•
SAEs are required to be reported for up to 30 days after discontinuation of study medication
•
Any SAE that occurs after 30 days post treatment is also required to be reported if the PI thinks
that the SAE is related to the protocol treatment, and is medically important
Procedure for Reporting SAEs and SAE Report Processing
SAE Data Flow Version 24 Oct 2014
Procedure for Identifying Unexpected and Related Events
A checklist will be used to identify SUSARs that require expedited reporting to the Regulatory Authority, REC and
Sponsor.
The checklist is a list of the events expected to occur in patients receiving the study drugs. 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.
SAEs that meet the criteria for SUSARs will be reported to the MHRA, REC, AstraZeneca and Sponsor where in
the opinion of the Chief Investigator the event was:
•
•
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Related (resulted from administration of any of the research procedures)
AND
Unexpected (type of event is not listed in the IB for olaparib or SmPC for capecitabine as an expected
occurrence)
AND
Is an interaction between Olaparib and chemo-radiation
Reports of related and unexpected SAEs will be submitted within 7 days for fatal/life threatening events and 15
days for all other events. We will require sites assistance with gathering information for SUSAR reports.
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:

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

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

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
•
Generally, one 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
Investigator Responsibilities (1)
The following principles are from ICH GCP Topic E6 and apply to clinical trials of Investigational Medicinal
Products:
•
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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 log 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.
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)
Investigator Responsibilities (2)
•
•
•
•
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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.
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
Storage of the IMP should be as specified by the regulatory requirements.
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.
Investigator Responsibilities (3)
•
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.
Other Site Staff
The Principal Investigator has overall responsibility for the conduct of the clinical trial
at the trial site.
BUT
•
•
•
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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
CONTACT DETAILS FOR CRUK CTU Glasgow
Project Manager
Liz-Anne Lewsley
Tel: 0141 301 7193
Fax: 0141 301 7244
E-mail: [email protected]
Trial Coordinator
Calum Innes
Tel: 0141 301 7382
Fax: 0141 301 7192
E-mail: [email protected]
Pharmacovigilance Manager
Lindsey Connery
Tel:
0141 301 7209
Fax:
0141 301 7213
E-mail: [email protected]
Pharmacovigilance CTC
Pam Fergusson
Tel: 0141 301 7953
Fax: 0141 301 7213
E-mail: [email protected]
Clinical Trial Monitor
Jan Graham
Tel:
0141 301 7956
Fax:
0141 301 7187
CRUK CTU, Glasgow
Cancer Research UK Clinical Trials Office
Level 0, Beatson West of Scotland Cancer Centre
1053 Great Western Road, Glasgow, G12 0YN