PIONEERA Phase I Study of Olaparib In Combination with Chemo-

Radiation in Locally Advanced Pancreatic Cancer

INVESTIGATOR INITIATION PRESENTATION

Version 1.1, 21st April 2015

STUDY DETAILS

• 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 ECMC-

Combinations Alliance_______________________________________________________________________

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.

_______________________________________________________________________

• 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 - based chemo-radiation combined modality therapy in

patients 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 7192calum.innes@glasgow.ac.uk

INFORMED CONSENT PROCESS• 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

FOR ERRORS NOTED AFTER CONSENT• Explanatory file note is completed and sent to CRUK CTU Glasgow with a copy remaining at site

PATIENT RECONSENT• 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.

• 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.

• The re-consent log in the Investigator Site File should be kept up to date

CONSENT WITHDRAWALWhen the patient specifically asks to withdraw consent at any point in the study. If this occurs:

•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 TREATMENTAll 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• 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).

• Patients must start chemoradiation within 4 weeks of finishing induction chemotherapy

• 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.

• Expansion cohort of 12 patients with borderline resectable disease will be treated at the Olaparib MTD.

Treatment and Duration

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

Planned Dose Cohorts:

*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:

•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:

•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)

• 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

• 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.

• These meetings will take place regularly throughout dose escalation phase of the study.

• The decision to dose escalate will be based on clinical and laboratory safety parameters.

SUPPLY OF STUDY DRUGS

• 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)

• 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

• 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• Once any dose reduction has been implemented, this should not be increased at a later time.

Non-haematological, non-gastrointestinal toxicity (Chemoradiation only)

• 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 ModificationsCapecitabine 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 Maintain dose level Maintain dose level

Grade 2 1st appearance Interrupt until resolved to grade 0-1 100%

2nd appearance Interrupt until resolved to grade 0-1 75%

3rd appearance Interrupt until resolved to grade 0-1 50%

4th appearance Discontinue treatment permanently

Grade 3 1st appearance Interrupt until resolved to grade 0-1 75%

2nd appearance Interrupt until resolved to grade 0-1 50%

3rd appearance Discontinue treatment permanently

Grade 4 1st appearance Discontinue permanently

OrIf 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 ModificationsDose Reductions for Gastro intestinal toxicity

Toxicity Grade Capecitabine Olaparib RT Comments

Nausea/vomiting Grade 1 / 2 Full Dose Full Dose Continue

Maximiz

e anti-emeticsGrade 2 despite

full anti-emetics

Withhold until G1.

Restart at 100%

dose

Withhold until G1.

Restart at full dose

Withhold until G1

Grade 3, 1st

episode

Withhold until G1.

Restart at 75% dose

Withhold until G1.

Restart at 1 dose

level below which

has been shown to

be tolerable1

Withhold until G1 Maximize anti-

emetic

Grade 3, 2nd

episode

Stop CRT Stop CRT Stop CRT Stop CRT

Grade 4 Stop CRT Stop CRT Stop CRT Stop CRT

Diarrhoea (non-

pancreatic)

Grade 1 / 2 Full Dose Full Dose Continue Maximize anti-

diarrhoeal

Grade 2 despite

full anti-diarrhoeal

treatment

Withhold until G1.

Restart at full dose

Withhold until G1.

Restart at full dose

Withhold until G1. Maximize anti-

diarrhoeal

Grade 3, 1st

episode

Withhold until G1.

Restart at 75% dose

Withhold until G1.

Restart at 1 dose

level below which

has been shown to

be tolerable1

Withhold until G1 Maximize anti-

diarrhoeal

Grade 3, 2nd

episode

Stop CRT Stop CRT Stop CRT Stop CRT

Grade 4 Stop CRT Stop CRT Stop CRT Stop CRT

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 ModificationsOlaparib

• 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.

• 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 ModificationsManagement of Anaemia

Dose ModificationsHaematological Toxicity (neutrophil and platelet count)

Neutrophil*X 109/l

Platelet*X 109/l

Capecitabine Olaparib RT

≥1.0 >100 100% dose 100% dose Continue≥1.0 75-100 100% dose 100% dose Continue<1.0 <75 Omit dose for the

week. Subsequent dose at 75%

Omit dose for the week. Subsequent dose at 1 dose level below starting dose which has been shown to be tolerable1

continue

< 0.5 < 50 Omit dose until recovery to neutrophils > 1, platelets > 75, then re-start at 50% dose

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

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

***For management of prolonged haematological toxicities while on study treatment (olaparib only) please refer to protocol section 5.10.5***

Dose ModificationsManagement of new or worsening pulmonary symptoms

• 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.

• All dose reductions and interruptions (including any missed doses), and the reasons for the reductions/interruptions are to be recorded in the CRF.

Dose ModificationsManagement 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 ModificationsDose 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 ModificationsOther 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 ResearchPK Samples (All Patients)

PK samples will be taken at the following time-points:

Please refer to lab manual for details on handling and shipping

Day -3 First week of CRT

Pre-dose

30 mins

1 hour

2 hours

4 hours

6 hours

8 hours

24 hours

Translational ResearchPD/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 studiesPre-induction chemotherapy archival tumour sample can be used

Translational ResearchBlood 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:

Please refer to lab manual for details on handling and shipping

Day -3 Day 8 CRT

Pre-dose

6 hours

24 hours

Translational ResearchPathology 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 ResearchHair 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:

Please refer to lab manual for details on handling and shipping

Day -3 Day 8 CRT

Pre-dose

6 hours

AssessmentsStudy 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:• 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)

AssessmentsEvaluations during Treatment:

Day -3 First Administration of Olaparib• Toxicity assessments• Concomitant medications• Commence olaparib administration orally, twice daily (days -3, -2, and -1)• Blood for olaparib PK studies: pre-dose, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dosing.• Blood for PD studies: pre-dose, 6 and 24 hours post-dosing• Hair follicles for PD studies: pre-dose and 6 hours after dosing (dose expansion cohort only)• ECOG Performance Status (see Appendix 3)• Full blood count• Biochemistry (urea & electrolytes, liver function tests (including AST, ALT and bilirubin), creatinine, calcium, alkaline

phosphatase, LDH and albumin

Weekly during Treatment• Toxicity assessments• Concomitant medications• Physical examination• Weight• Body Surface Area• Vital signs – pulse, temperature and blood pressure• ECOG performance status• Creatinine clearance / glomerular filtration• Full blood count (+/- 24h)• Biochemistry (urea & electrolytes, liver function tests (including AST, ALT and bilirubin), creatinine, calcium, alkaline

phosphatase, LDH and albumin. (+/- 24h)

Follow-UpEnd of Treatment/Follow up (1 week after completion of chemo-radiotherapy)• Toxicity assessments• DLT assessment• Concomitant medications• Physical examination• Weight• ECOG performance status (see Appendix 3)• Full blood count (+/- 24h)• 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)• Toxicity assessments• Concomitant medications• Physical examination• Weight• ECOG performance status (see Appendix 3)• Full blood count (+/- 24h)• Biochemistry (urea & electrolytes, liver function tests (including AST, ALT and bilirubin), creatinine, calcium, alkaline

phosphatase, LDH and albumin (+/- 24h) • CT scan of chest / abdomen / pelvis• 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 GLASGOWMain REC approval

MHRA approvalSite Initiation SlidesInvestigator Site FilePharmacy Site File

Radiotherapy QA ProcessSample Collection Supplies

SITEStudy Specific Training and Delegation Log

SSI – R&D ApprovalInvestigator and Lead Pharmacist CV & GCP Certificates

Clinical Trial AgreementSummary PIS/ PIS&Consent/GP Letter/Patient Results Letter on Headed Paper

Lab normal ranges and accreditation certificates (Haem + Biochem)Radiotherapy QA Approval

INITATION PROCESS

SITE ACTIVATION/DRUG SUPPLY

CRFsCRFs for the study:•Registration Form•Pre-treatment Form•Treatment Form•PK Assessment Form•PD Assessment Form•End of Treatment Form (incorporating one week follow up visit)•Response Form (incorporating four week follow up visit)•Follow–up Form•Concomitant Medication Form please note that this will require to be submitted periodically during the treatment period•Consent Withdrawal Notification Form•Pregnancy Notification Form•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•Dose Limiting Toxicity (DLT Form)

CRF Completion:•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:

• 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

SAE Data Flow Version 24 Oct 2014

Procedure for Reporting SAEs and SAE Report Processing

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:

•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 MonitoringStudy sites will be monitored centrally by checking incoming forms for compliance with theprotocol, data consistency, missing data and timing. Study staff will be in regular contact with sitepersonnel (by phone/fax/email/letter) to check on progress and deal with any queries that theymay 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:

•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)• 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 trialat 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

CONTACT DETAILS FOR CRUK CTU Glasgow

Project Manager Trial CoordinatorLiz-Anne Lewsley Calum Innes

Tel: 0141 301 7193 Tel: 0141 301 7382Fax: 0141 301 7244 Fax: 0141 301 7192E-mail: liz-anne.lewsley@glasgow.ac.uk E-mail: calum.innes@glasgow.ac.uk

Pharmacovigilance Manager Pharmacovigilance CTCLindsey Connery Pam FergussonTel: 0141 301 7209 Tel: 0141 301 7953 Fax: 0141 301 7213 Fax: 0141 301 7213E-mail: lindsey.connery@glasgow.ac.uk E-mail: pam.fergusson@glasgow.ac.uk

Clinical Trial MonitorJan GrahamTel: 0141 301 7956Fax: 0141 301 7187

CRUK CTU, Glasgow Cancer Research UK Clinical Trials Office

Level 0, Beatson West of Scotland Cancer Centre1053 Great Western Road, Glasgow, G12 0YN