PIONEER A Phase I Study of Olaparib In Combination with Chemo-Radiation in Locally Advanced Pancreatic Cancer

1
PIONEERA Phase I Study of Olaparib In
Combination with Chemo-Radiation in Locally
Advanced Pancreatic Cancer

• INVESTIGATOR INITIATION PRESENTATION
• Version 1, 16th April 2015

2
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

3
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

4
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.

5
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.

6
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

7
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 [phone], Fax [phone]
• calum.innes_at_glasgow.ac.uk

8
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 patients notes.
• 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
• 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

9
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

10
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 lt 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 (504 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 lt 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.

11
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

12
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

13
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 gt7 days
• Grade III/IV neutropenia with sepsis or with
  fever gt 38.5 0C
• Grade IV thrombocytopenia
• Grade IV diarrhoea
• Grade gt 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 gt 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 gt 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.

14
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 gt 1 out of 3-6
  patients.
• Patients who fail to receive gt75 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

15
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.

16
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.

17
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

18
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 lt 30 mL/min, capecitabine
  should be discontinued. Please refer to the
  current version of the SmPC for Capecitabine

19
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 Grade 1 Grade 1
Any appearance Maintain dose level Maintain dose level
Grade 2 Grade 2 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 Grade 3 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 Grade 4 Grade 4
1st appearance Discontinue permanently Or If physician deems it to be in the participants best interest to continue, interrupt until resolved to Grade 0-1 after discussion with CI 50
20
Dose ModificationsDose Reductions for Gastro
intestinal toxicity
Toxicity Grade Capecitabine Olaparib RT Comments
Nausea/vomiting Grade 1 / 2 Full Dose Full Dose Continue   Maximize anti-emetics
Nausea/vomiting Grade 2 despite full anti-emetics Withhold until G1. Restart at 100 dose Withhold until G1. Restart at full dose Withhold until G1   Maximize anti-emetics
Nausea/vomiting 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
Nausea/vomiting Grade 3, 2nd episode Stop CRT Stop CRT Stop CRT Stop CRT
Nausea/vomiting Grade 4 Stop CRT Stop CRT Stop CRT Stop CRT
Diarrhoea (non-pancreatic) Grade 1 / 2 Full Dose Full Dose Continue Maximize anti-diarrhoeal
Diarrhoea (non-pancreatic) 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
Diarrhoea (non-pancreatic) 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
Diarrhoea (non-pancreatic) Grade 3, 2nd episode Stop CRT Stop CRT Stop CRT Stop CRT
Diarrhoea (non-pancreatic) 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
21
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.

22
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 lt
  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).

23
Dose ModificationsManagement of Anaemia

• Haemoglobin must be maintained above 10g/dl
  throughout CRT if necessary maintain through
  blood transfusion.
•  
• Adverse events of anaemia CTCAE grade 1 or 2
  (Haemoglobin (Hb) ltLLN but gt 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 lt
  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
  gt 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.
• 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.

24
Dose ModificationsHaematological Toxicity
(neutrophil and platelet count)
Neutrophil X 109/l Platelet X 109/l Capecitabine Olaparib RT
1.0 gt100 100 dose 100 dose Continue
1.0 75-100 100 dose 100 dose Continue
lt1.0 lt75 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
lt 0.5 lt 50 Omit dose until recovery to neutrophils gt 1, platelets gt 75, then re-start at 50 dose Omit dose until recovery to neutrophils gt 1, platelets gt 75, then re-start at 1 dose level below starting dose which has been shown to be tolerable1 Stop RT if neutrophil lt0.5 or platelets lt50 repeat FBC in 3 days. Restart RT alone if neutrophil gt0.5 and platelets gt50. Restart chemotherapy when neutrophil gt1 and platelets gt75
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
25
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.

26
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.

27
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.

28
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.

29
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 ? ?
30
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 studies
• Pre-induction chemotherapy archival tumour sample
  can be used

31
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 ? ?
32
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.

33
Translational ResearchHair Follicles PD Markers
(Dose Expansion Cohort only)

• Plucked hair follicle (eyebrow) samples will be
  collected for induction of ?H2AX 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 ? ?
34
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
• 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)

35
Assessments

• Evaluations 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

36
Follow-Up

• End 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)

37
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
• ?
• SITE
• Study Specific Training and Delegation Log
• SSI RD Approval
• Investigator and Lead Pharmacist CV GCP
  Certificates
• Clinical Trial Agreement
• Summary PIS/ PISConsent/GP Letter/Patient
  Results Letter on Headed Paper
• Lab normal ranges and accreditation certificates
  (Haem Biochem)
• Radiotherapy QA Approval

38
CRFs

• CRFs 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)
• Followup Form
• 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

39
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 lt 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

40
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

41
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 RD)
• 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

42
Procedure for Reporting SAEs and SAE Report
Processing
SAE Data Flow Version 24 Oct 2014
43
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.

44
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.

45
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

46
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)

47
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 trials
  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.

48
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.

49
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

50
CONTACT DETAILS FOR CRUK CTU Glasgow

• Project Manager Trial Coordinator
• Liz-Anne Lewsley Calum Innes
• Tel [phone]
  Tel [phone]
• Fax [phone] Fax
  0141 301 7192
• E-mail liz-anne.lewsley_at_glasgow.ac.uk E-mail
  calum.innes_at_glasgow.ac.uk
• Pharmacovigilance Manager Pharmacovigilance
  CTC
• Lindsey Connery Pam Fergusson
• Tel [phone] Tel [phone]
• Fax [phone] Fax [phone]
• E-mail lindsey.connery_at_glasgow.ac.uk E-mail
  pam.fergusson_at_glasgow.ac.uk
• Clinical Trial Monitor
• Jan Graham
• Tel [phone]
• Fax [phone]
• CRUK CTU, Glasgow
• Cancer Research UK Clinical Trials Office