Ni CCC G 143 ENGOTGYN 1 A Randomised

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Ni. CCC (G 143) (ENGOT-GYN 1) A Randomised Phase II study Of Nintedanib (BIBF

Ni. CCC (G 143) (ENGOT-GYN 1) A Randomised Phase II study Of Nintedanib (BIBF 1120) Compared To Chemotherapy in Patients With Recurrent Clear Cell Carcinoma Of The Ovary Or Endometrium Eudra. CT Number: 2013 -002109 -73 ISRCTN 50772895 INITIATION SLIDES (Version 1. 0, 15 th July 2014)

Trial Details • The trial is an NCRN/Boehringer Ingelheim (BI), collaboration • The trial

Trial Details • The trial is an NCRN/Boehringer Ingelheim (BI), collaboration • The trial is being co-ordinated via the Cancer Research UK Clinical Trials Unit, Glasgow • Sponsor of the trial is Greater Glasgow Health Board (GGHB) • The trial will also open across Europe via collaborations with the EORTC, the NSGO and ARCAGY-GINECO • The Chief Investigator is Dr Ros Glasspool of the Beatson West of Scotland Cancer Centre. The International Chief Investigator is Dr Mansoor Mizra of Copenhagen University Hospital • The trial is being funded by an educational grant from Boehringer Ingelheim (who are also providing drug supply of Nintedanib) and is endorsed by CTAAC (Cancer Research UK) ********************************** Please note this presentation has been prepared as part of your site initiation training. These slides are a compliment to the protocol, all site staff must have read and understood the protocol and the trial requirements prior to signing off the initiation acknowledgment sheet ********************************** Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 2

Trial Team • Chief Investigator : Dr Ros Glasspool • International Chief Investigator: Dr

Trial Team • Chief Investigator : Dr Ros Glasspool • International Chief Investigator: Dr Mansoor Mizra • Co-Investigator/ Translational Research Co-ordinator: Professor Ian Mc. Neish • trial Statistician: Jim Paul • Project Manager: Claire Lawless • Pharmacovigilance: Lindsey Connery / Susannah Redford • Clinical Trial Coordinator: Laura Douglas • Clinical Trial Monitor: Calum Innes Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 3

Trial Design A multi-centre, randomised, open label phase II trial 90 patients with progressive

Trial Design A multi-centre, randomised, open label phase II trial 90 patients with progressive or recurrent clear cell ovarian and up to 30 patients with clear cell endometrial cancer Registration Central Pathology Review Criteria and Eligibility Criteria met Randomisation Control Arm Experimental Arm Physicians choice of standard chemotherapy, from list below*. Nintedanib 200 mg BD continuously until progression or withdrawal from trial Assessments Clinical: At screening, Day 1 of each course of chemotherapy CA 125: At screening and day 1 of each cycle during treatment then every 8 weeks until progression CT Scans Screening, and every 8 weeks until week 48 or until progression Clinical: At screening, Day 1 and then every 4 weeks until week 24 and then every 8 weeks. CA 125: At screening, day 1 and every 4 weeks until week 24 then every 8 weeks until progression CT Scans Screening, and every 8 weeks until week 48 or until progression Primary Endpoint: PFS Secondary Endpoints: OS, Qo. L, QTWIST, ORR, & DCR at 12 weeks Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 4

Control Arm • Chemotherapy options – Investigator decision Standard Chemotherapy choice: Ovarian Cancer Patients

Control Arm • Chemotherapy options – Investigator decision Standard Chemotherapy choice: Ovarian Cancer Patients (all chemotherapy regimens are 4 -weekly): Paclitaxel (80 mg/m 2) IV Day 1, 8, 15 every 28 days, up to 6 cycles PLD (40 mg/m 2) IV every 28 days, up to 6 cycles Topotecan 4 mg/m 2 IV Day 1, 8, 15 every 28 days, up to 6 cycles Endometrial Cancer Patients (all chemotherapy regimens are 3 -weekly): Carboplatin (AUC 5) and Paclitaxel (175 mg/m 2) IV q 21, up to 6 cycles Doxorubicin IV 60 mg. m 2 every 21 days, up to 6 cycles Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 5

Population and Aims Trial population • 120 patients with progressive or recurrent ovarian clear

Population and Aims Trial population • 120 patients with progressive or recurrent ovarian clear cell carcinoma, or progressive or recurrent endometrial clear cell carcinoma. The primary diagnosis must be histologically confirmed and central pathological review of the presenting tumour or biopsy of relapsed disease must find at least 50% clear cell carcinoma with no serous differentiation Trial Aims Primary Objective: • The primary endpoint for efficacy is progression free survival as defined by RECIST 1. 1 criteria. Progression free survival (PFS) is defined as the duration of time from date of randomisation to date of progression or death, which ever occurs earlier Secondary Objectives: • Overall survival (OS) Patients will be followed up to the end of the trial period. • Overall Response Rate (ORR). Best response rate will be determined according to combined GCIG criteria • Disease Control Rate (DCR = Complete Response, Partial Response and Stable Disease) at 12 weeks • Toxicity. Adverse event data will be collected during the treatment phase of the trial • Quality of Life. Patients will be asked to complete 4 questionnaires (EORTC QLQ C 30, OV 28, MOST and EQ-5 D). • Q-TWi. ST (Quality-Adjusted Time Without Symptoms of Disease or Toxicity of Treatment) will balance quality and quantity of time by combining survival data with EQ-5 D quality of life data Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 6

Trial Eligibility Inclusion Criteria: 1. Progressive or recurrent ovarian clear cell carcinoma, or progressive

Trial Eligibility Inclusion Criteria: 1. Progressive or recurrent ovarian clear cell carcinoma, or progressive or recurrent endometrial clear cell carcinoma. The primary diagnosis must be histologically confirmed and central pathological review of the presenting tumour or biopsy of relapsed disease must find at least 50% clear cell carcinoma with no serous differentiation. Progressive disease as defined by RECIST 1. 1 2. Failure after ≥ 1 prior platinum containing regimen which may have been given in the adjuvant setting. For patients with ovarian clear cell carcinoma, progression must have occurred within 6 months of their last platinum dose 3. ECOG Performance status of ≤ 2 4. Life expectancy of >3 months 5. Adequate hepatic, bone marrow coagulation and renal function -Hepatic function: total bilirubin within normal limits; ALT and AST < 2. 5 x ULN -Coagulation parameters: INR <2 x ULN and prothrombin time and activated partial thromboplastin time < 1. 5 x ULN in the absence of therapeutic anticoagulation -Absolute neutrophil count (ANC) ≥ 1. 5 x 109/L -Platelets ≥ 100 x 109 L -Haemoglobin ≥ 9. 0 g/d. L -Proteinuria < grade 2 (CTCAE version 4) -Glomerular Filtration Rate ≥ 40 ml/min. (calculated using Cockroft & Gault equation or measured by EDTA clearance) 6. Female and > 18 years of age 7. Signed and dated written informed consent prior to admission to the trial in accordance with ICH-GCP guidelines and local legislation. 8. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 7

Trial Eligibility Exclusion Criteria: 1. Prior treatment with Nintedanib or other angiogenesis inhibitor/VEGF targeted

Trial Eligibility Exclusion Criteria: 1. Prior treatment with Nintedanib or other angiogenesis inhibitor/VEGF targeted therapy, except for prior treatment with bevacizumab which is permitted 2. Treatment within 28 days prior to randomisation with any investigational drug, radiotherapy, immunotherapy, chemotherapy, hormonal therapy or biological therapy Palliative radiotherapy may be permitted for symptomatic control of pain from bone metastases in extremities, provided that the radiotherapy does not affect target lesions, and the reason for the radiotherapy does not reflect progressive disease 3. Previous treatment with the chemotherapy regimen selected as the control arm by the investigator. (Prior therapy with paclitaxel given on a three weekly regimen is permitted for patients receiving weekly Paclitaxel) 4. Other malignancy diagnosed within 5 years of enrolment except for: a) Non-melanomatous skin cancer (if adequately treated) b) Cervical carcinoma in situ (if adequately treated) c) Carcinoma in situ of the breast (if adequately treated) d) For patients with ovarian clear cell cancer, prior or synchronous endometrial cancer (if adequately treated), provided all of the following criteria are met: • Disease stage FIGO Stage 1 a (tumour invades less than one half of myometrium) • Grade 1 or 2 5. Patients with any other severe concurrent disease, which may increase the risk associated with trial participation or trial drug administration and, in the judgement of the investigator, would make the patient inappropriate for entry into this trial, including significant neurologi c, psychiatric, infectious, hepatic, renal, or gastrointestinal diseases or laboratory abnormality 6. Symptoms or signs of gastrointestinal obstruction requiring parenteral nutrition or hydration or any other gastro-intestinal disorders or abnormalities, including difficulty swallowing, that would interfere with drug absorption 7. Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal) or antiviral therapy, including known hepatitis B and/or C infection and HIV-infection 8. Symptomatic CNS metastasis or leptomeningeal carcinomatosis Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 8

Trial Eligibility Exclusion Criteria continued: 9. Known, uncontrolled hypersensitivity to the investigational drugs or

Trial Eligibility Exclusion Criteria continued: 9. Known, uncontrolled hypersensitivity to the investigational drugs or their excipients 10. Significant cardiovascular diseases, including uncontrolled hypertension, clinically relevant cardiac arrhythmia, unstable angina or myocardial infarction within 6 months prior to randomisation, congestive heart failure > NYHA III, severe peripheral vascular disease or clinically significant pericardial effusion 11. History of major thromboembolic event defined as: • pulmonary embolism (PE) within six months prior to randomisation • recurrent pulmonary embolism (history of at least 2 events) • history of at least 2 unprovoked (=without a transient reversible risk factor) events of proximal deep venous thrombosis • history of a provoked (=with transient or reversible risk factor, such as surgery) thrombosis of proximal deep veins or visceral vessels within 6 months prior to randomisation if not on stable therapeutic anticoagulation 12. Prior thrombosis or thromboembolic event in the presence of an inherited coagulopathy (including deficiency of antithrombin, deficiency of protein C or protein S, Factor V Leiden mutation or prothrombin G 20210 A mutation) 13. Known inherited predisposition to bleeding or thrombosis 14. History of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the past 6 months 15. History of clinically significant haemorrhage in the past 6 months 16. Major injuries or surgery within the past 28 days prior to start of trial treatment with incomplete wound healing and/or planned surgery during the on-treatment trial period 17. Pregnancy or breastfeeding. Patients with preserved reproductive capacity must have a negative pregnancy test (β-HCG test in urine or serum) prior to commencing trial treatment 18. Patients with preserved reproductive capacity, unwilling to use a medically acceptable method of contraception for the duration of the trial and for 3 months afterwards 19. Radiographic evidence of cavitating or necrotic tumours with invasion of adjacent major blood vessels 20. Any psychological, familial, sociological or geographical consideration potentially hampering compliance with the trial protocol and follow up schedule; those considerations should be discussed with the patient 9 before registration in the trial Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014

Site Set Up CTU GLASGOW Main REC approval - MHRA approval - Site Initiation

Site Set Up CTU GLASGOW Main REC approval - MHRA approval - Site Initiation Slides - Investigator File - Pharmacy File SITE Delegation Log – SSI - R&D Approval - CVs and GCP certificates for PI and Lead Pharmacist - Clinical Trial Agreement - PIS, Consent, GP Letter etc on Trust Headed paper - Lab normal ranges (Haem + Biochem), Accreditation certificates. INITIATION PROCESS DRUG SUPPLY OF NINTEDANIB SITE ACTIVATED Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 10

Informed Consent Process Informed consent process: • Two original Consent Forms must be completed

Informed Consent Process Informed consent process: • Two original Consent Forms must be completed by a clinician (or deputy listed on delegation log) • Two originals signed and completed by the patient • Date must be prior to registration/ randomisation. • Make one photocopy - Original to be filed in Investigator File - Original to be given to patient (+PIS) - Photocopy to be filed in hospital notes • Consent Form must not be sent to the Clinical Trials Unit FOR ERRORS NOTED AFTER CONSENT • Add explanatory note/file note • New version of Patient Information Sheet must be provided to patients consented with previous version. This must be given to all patients regardless of treatment stage, during next possible clinic visit. • Patients who are still on active treatment will be required to repeat the consent process using the updated form. If it is not appropriate to re-consent patient (i. e. patient terminally ill) please make a note regarding this in the patients case notes and on re- consent log which is filed in your trial site file. CONSENT WITHDRAWAL When the patient specifically asks to withdraw their consent at any point in the trial. If this occurs: • • Document clearly in the patient notes that the patient has withdrawn consent, the level of consent withdrawal and the reason (if the patient has given any) Complete the consent withdrawal notification form ; Send the consent withdrawal notification form to the CRUK CTU No further follow-up should be collected on the patient from that point onwards. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 11

Registration Process • All patients must be registered onto the trial prior to commencement

Registration Process • All patients must be registered onto the trial prior to commencement of any trial procedures, and central pathological review to confirm patient’s eligibility • Check that patient has given written informed consent as per the informed consent process. • Complete Registration Form. • Site staff must contact the Cancer Research Clinical Trials Unit, Glasgow to register the patient. Registration to the trial can be done by either telephone or fax on the following numbers: Tel no: ++ 44 141 301 7215 Fax no: ++ 44 141 301 7219* 08. 30 -17. 00 Monday - Thursday 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 3 digit sequential patient ID number for the trial. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 12

Process for UK Central Pathology Review • Once patients are identified and have given

Process for UK Central Pathology Review • Once patients are identified and have given informed consent, a central pathology review will be performed in order to confirm patient eligibility. Patients must first be registered for the trial to allow central pathology review to be performed • The information collected on Registration Form will be passed to lead Pathologist for trial in UK, who will contact the local pathologist and discuss the case and ascertain if the basic criteria are reached • If the basic criteria are reached a request for 3 sets of the 3 most representative slides should be scanned as digital images and sent via email to the 3 reviewing pathologists for the trial. A scanned copy of the completed patient Registration Form should also be provided. If it is not possible to provide digital images of the slides, alternatively a single set of representative slides can be sent • The slides will be reviewed and agreement reached as to whether the accepted criteria is met. A majority decision will be acceptable • The review decision will be emailed to the CRUK UK Clinical Trials Unit, Glasgow who will subsequently inform the site • Patients who meet the accepted criteria will then be able to be randomised to the trial, following completion of randomisation form Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 13

Randomisation Process • Check that central pathology review has confirmed patient as eligible •

Randomisation Process • Check that central pathology review has confirmed patient as eligible • Check that patient fulfils all additional eligibility criteria as per trial protocol • Complete Randomisation Form • Site staff must contact the Clinical Trials Unit, Glasgow to randomise the patient. Randomisation to the trial can be done by either telephone or fax on the following numbers: Tel no: ++ 44 141 301 7215 Fax no: ++ 44 141 301 7219* 08. 30 -17. 00 Monday - Thursday 08. 30 -16. 30 Friday, except public holidays * Faxes received outside of office hours will be processed the next working day • Each patient randomised will be allocated a unique 4 digit sequential patient ID number for the trial Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 14

Pre Randomisation Evaluations Prior to commencing any trial related procedures, all participants will be

Pre Randomisation Evaluations Prior to commencing any trial related procedures, all participants will be fully informed about the risks, benefits and procedures involved in trial participation, and will sign a consent form confirming this process. All patients will then undergo a period of screening during the 28 days prior to initiation of trial treatment. Screening will consist of: • • • Complete medical history Concomitant medication Physical examination including weight, height and performance status Baseline symptoms and toxicity assessment Disease evaluation - CT or MRI of chest pelvis and abdomen reported to RECIST v 1. 1 and CA 125 Central Pathology review In addition, during the 14 days prior to initiation of trial treatment all patients will undergo the following evaluations: • • • Vital signs: Blood pressure , Pulse ECG Urinalysis (Dipstick) ECOG Performance Status Pregnancy test (only in those with preserved reproductive capacity) Translational blood samples* Qo. L assessments Serum biochemistry Haematology, including FBC and COAG Protocol treatment must commence within 14 days of registration. * Only applicable for patients participating in the translational component of the trial. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 15

Treatment and Duration • Control Arm The chemotherapy regimen will be physician’s choice from

Treatment and Duration • Control Arm The chemotherapy regimen will be physician’s choice from the list below. The planned regimen (if allocated to the control arm) must be declared prior to randomisation: • Ovarian Cancer Patients: Paclitaxel (80 mg/m 2) IV Day 1, 8, 15 every 28 days, x 6 cycles Pegylated Liposomal Doxorubicin (PLD) (40 mg/m 2) IV every 28 days, x 6 cycles Topotecan (4 mg/m 2) IV Day 1, 8, 15 every 28 days, x 6 cycles • Endometrial Cancer Patients: Carboplatin (AUC 5) and Paclitaxel (175 mg/m 2) IV every 21 days, x 6 cycles Doxorubicin IV (60 mg/m 2) every 21 days x 6 cycles • Experimental Arm Nintedanib (BIBF 1120) 200 mg twice daily PO, continuously, until progression or withdrawal from the treatment. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 16

Nintedanib Dose Delays • Treatment with Nintedanib has to be interrupted if any of

Nintedanib Dose Delays • Treatment with Nintedanib has to be interrupted if any of the criteria listed below are fulfilled: Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 17

Nintedanib Dose Reductions • After interruption of Nintedanib the following criteria must be met

Nintedanib Dose Reductions • After interruption of Nintedanib the following criteria must be met to restart Nintedanib: • GI adverse events: -nausea CTCAE grade ≤ 1 -vomiting CTCAE grade 0 -diarrhoea CTCAE grade ≤ 1 • Liver enzyme elevations: -bilirubin values CTCAE grade 0 -AST and ALT CTCAE grade ≤ 1 • • Neuropathy: -neuropathy CTCAE grade ≤ 2 Other non-haematological adverse events: -other non-haematological adverse which are considered drug-related have recovered to less than or equal to the patient's pre-therapy value at trial enrolment • Nintedanib - Dose Modification for Toxicity Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 18

Nintedanib Compliance • Empty Nintedanib bottles and any remaining medication is to be returned

Nintedanib Compliance • Empty Nintedanib bottles and any remaining medication is to be returned at each patient visit • These are then returned to pharmacy where a count takes place • Sites will need to have a local process where pharmacy and research staff review patient returns in a timely manner in order to assess patient compliance • Over or under compliance should be escalated to the trial team • Patients will be provided with Nintedanib Diary Card to record their compliance Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 19

Trial Restrictions • • • Additional chemo-, immuno-, hormone- or radiotherapies are not allowed

Trial Restrictions • • • Additional chemo-, immuno-, hormone- or radiotherapies are not allowed during except for palliative radiotherapy for symptomatic control of pain from bone metastases in extremities. To be discussed with CI. Treatment < 28 days prior to randomisation with any investigational drug is not permitted. Patients must not be recruited to any IMP trials that involve an IMP while on Ni. CCC protocol treatment, and during the follow up period prior to recurrence. Debulking surgery is not permitted on the trial prior to progression. Any invasive procedures such as minor or major surgery should be postponed to at least 4 weeks after the end of treatment with Nintedanib. For urgent interventions, Nintedanib should be interrupted 2 weeks prior to the procedure and not be started before wound healing is complete. If patients require emergency surgery, Nintedanib should be stopped as soon as the procedure is planned and, if possible, at least 48 hours prior to the procedure. Concomitant therapy with the 5 -HT 3 receptor antagonists tropisetron and/or dolasetron which are metabolized by cytochrome 2 D 6 should be avoided in patients on Nintedanib since they may lack efficacy in patients who are ‘fast metabolizers’. During treatment with Nintedanib, all trial patients will be advised to avoid sun exposure or artificial UVA/UVB radiation in solaria or tanning booths. If exposure to sunlight cannot be avoided, protective clothing and broad spectrum (UVA/UVB) sunscreens should be used. After discontinuation of Nintedanib treatment all protective measures should be continued for at least 2 weeks Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 20

Contraception • Patients will be considered to be of childbearing potential unless surgically sterilised

Contraception • Patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years. • Patients of child bearing potential who are sexually active must consent to use a highly effective method of birth control for the duration of the trial and for at least 3 months after the end of active therapy. • A highly effective method of birth control is defined as one which results in a low failure rate (i. e. less than 1% per year) when used consistently and correctly, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner. • Hormonal contraceptives should not be used for this trial. Intrauterine systems (IUS) that release hormones are not allowed. The methods of contraception used must be stated in the patient’s medical notes and CRFs. • If a patient becomes pregnant during the trial, the CRUK CTU must be informed immediately. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 21

Pregnancy Reporting • In the event of a pregnancy, a Pregnancy Notification Form (PNF)

Pregnancy Reporting • In the event of a pregnancy, a Pregnancy Notification Form (PNF) must sent to CRUK Clinical Trials Unit CTC within 24 hours • The pregnancy should be followed by site to follow pregnancy until term • Any changes in pregnancy such as miscarriage, termination, or birth should be added to the PNF and sent to CRUK Pharmacovigilance as soon as possible • If at birth, there is found to be a defect or congenital anomaly then this will also require immediate reporting to CRUK CTU Pharmacovigilance as a SAE Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 22

Translational Research Translational research will be conducted at 3 levels; centres will select their

Translational Research Translational research will be conducted at 3 levels; centres will select their level of participation. • Level 1 Research: Formalin Fixed Paraffin Embedded Tissue Blocks from original primary surgery Archival formalin-fixed, paraffin-embedded surgical/biopsy specimens of the original primary tumour will be collected. Only ‘surplus’ tissue will be collected, i. e. surplus to diagnostic requirements. Blood Samples for Circulating Endothelial Cells A sample will be collected at screening or day 1 of cycle 1, on day 1 of cycle 2, and at the end of treatment visit. • Level 2 Research: Level 1 samples plus the following: Plasma Samples A sample will be collected at baseline, on day 1 of each cycle, end of treatment visit, follow-up visits and at progression. Plasma Samples for Circulating Tumour DNA A sample will be collected at baseline, on day 1 of each cycle, end of treatment visit, follow-up visits and at progression. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 23

Translational Research • Level 3 Research: Level 2 samples plus the following: Tumour Biopsies

Translational Research • Level 3 Research: Level 2 samples plus the following: Tumour Biopsies Women who consent to additional biopsies will undergo an image-guided tumour biopsy after giving informed consent at least one week prior to starting trial treatment. With continued consent they will have a further biopsy at disease progression. • Baseline blood samples may be taken at screening or on day 1 of cycle 1 prior to treatment. • Samples for circulating endothelial cells will be sent on the day of sampling to the Laboratory of Translational Tumour Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. • All other samples will be processed and stored at site and shipped in batches. • The samples must be collected for all patients who have consented to the translational aspects of the trial on the consent form, please ensure all samples are taken for all consenting patients Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 24

Drug Induced Liver Injuries (DILIs) • • • Detection of Drug-induced liver injury (DILI)

Drug Induced Liver Injuries (DILIs) • • • Detection of Drug-induced liver injury (DILI) has become an important aspect of patients’ safety guarding in drug development Any potential DILI has to be reported in an expedited manner to the FDA and be followed-up appropriately, by Boehringer Ingelheim (BI). The follow-up includes a detailed clinical evaluation and identification of possible alternative diseases (e. g. Hepatitis B) and/or other concomitant therapies that might potentially be hepatotoxic. Although rare, a potential for drug-induced liver injury is under constant surveillance by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and follow-up of laboratory alterations of selected liver laboratory parameters to ensure patients´ safety The concept below has been worked out by BI in order to guard patient´s safety and to respond to regulatory requirements: Definition The following changes in the laboratory values are considered to be a protocol-specific significant adverse event for all patients with: Ø an elevation of ALT and / or AST > 5 x ULN without bilirubin elevation measured in the same blood draw sample Ø an elevation of AST and/or ALT >2. 5 fold ULN combined with an elevation of bilirubin to >1. 5 fold ULN measured in the same blood draw sample Patients showing these laboratory abnormalities need to be followed up until the protocol specific retreatment criteria have been met Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 25

Potential DILI Evaluation & Follow Up Procedures - 1 Procedures • Stop Nintedanib •

Potential DILI Evaluation & Follow Up Procedures - 1 Procedures • Stop Nintedanib • Protocol specified significant events are to be reported in an expedited manner similar to Serious Adverse Events, even if they do not meet any of the seriousness criteria and documented in the CRF • Repeat the following laboratory tests for confirmation within 48 hours: – AST and ALT, bilirubin measurement (total and direct bilirubin), Alkaline Phosphatase, Haptoglobin assay, complete blood count and cell morphology, reticulocyte count, CK, LDH • The results of these repeated laboratory tests must be documented on the DILI Checklist Form (Part 1) and reported to CRUK CTU Pharmacovigilance as soon as they are available. • An evaluation of the patient within 48 hours with respect to but not limited to: – Abdominal ultrasound or clinically appropriate other imaging and investigations adequate to rule out biliary tract, pancreatic, intra- or extrahepatic pathology, e. g. bile duct stones, neoplasm, hepatic tumour involvement, biliary tract, pancreatic or intrahepatic pathology, vascular hepatic conditions such as portal vein thrombosis or right heart failure. – detailed history of current symptoms and concurrent diagnoses and medical history of concomitant drug use (including non-prescription medications, herbal and dietary supplement preparations and eg steroids as concomitant supportive treatment), alcohol use, recreational drug use, and special diets detailed history of exposure to environmental chemical agents Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 26

Potential DILI Evaluation & Follow Up Procedures - 2 • • If neither imaging

Potential DILI Evaluation & Follow Up Procedures - 2 • • If neither imaging nor laboratory values suggest that cholestasis is the reason for ALT / AST increase, and in particular if Alk. Phos < 2 x ULN, the following laboratory tests should be performed within 7 days of the DILI first being reported, and results should be recorded on the DILI Checklist Part 2: Clinical chemistry – – Alkaline phosphatase, cholinesterase (either plasma or red blood cell), albumin, PT or INR, CKMB, transferrin, ferritin, cholesterol, triglycerides Serology Hepatitis A (Anti-Ig. M, Anti-Ig. G), Hepatitis B (Hbs. Ag, Anti-HBs, DNA), Hepatitis C (Anti-HCV, RNA if Anti-HCV positive), Epstein Barr Virus (VCA Ig. G, VCA Ig. M), cytomegalovirus (Ig. G, Ig. M), herpes simplex virus (Ig. G, Ig. M), varicella (Ig. G, Ig. M), parvovirus (Ig. G, Ig. M) Perform repeat testing of ALT, AST, bilirubin (with fractionation into total and direct) and Alk Phos at least weekly until the laboratory values return to normal or to the values as defined in the protocol. • If, despite stopping Nintedanib, the ALT, AST and bilirubin are NOT returning to normal levels at the first weekly retest, and if all other liver tests are normal – i. e. no other cause for liver dysfunction identified then perform: coeruloplasmin, α-1 antitrypsin, amylase, lipase, fasting glucose, Hepatitis D (Anti-Ig. M, Anti-Ig. G), Hepatitis E (Anti-HEV, Anti-HEV Ig. M, RNA if Anti. HEV Ig. M positive), Anti-Smooth Muscle antibody (titer), Anti-nuclear antibody (titer), Anti. LKM (liver-kidney microsomes) antibody, Anti-mitochondrial antibody, TSH, Thrombocytes, eosinophils Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 27

Potential DILI Evaluation & Follow Up Procedures - 3 • If transaminases and/or bilirubin

Potential DILI Evaluation & Follow Up Procedures - 3 • If transaminases and/or bilirubin increase despite cessation of the experimental therapy, more frequent intervals of testing will be required (as per local practice guidelines) • Depending on further laboratory changes, additional parameters identified e. g. by reflex testing will be followed up based on medical judgement and Good Clinical Practices • Nintedanib should only be restarted if all liver function tests return to levels specified for the treatment specified in the protocol. If a patient’s liver function tests recover and another cause of their liver dysfunction is found, i. e. DILI is excluded, and the investigator wishes to restart Nintedanib, this should be discussed with the chief investigator first who will also discuss with the BI medical advisor Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 28

Reporting radiological investigations to RECIST Criteria • All radiological investigations must be reported as

Reporting radiological investigations to RECIST Criteria • All radiological investigations must be reported as per protocol / RECIST version 1. 1 • Source documentation of this must be available for review if the original report has had to be supplemented to bring it in line with protocol requirements • CTU, Glasgow have produced a worksheet to assist with the documentation of trial specific reporting and will make this available to any participating site upon request to the trial monitor Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 29

Qo. L Questionnaires • Patients will be asked to complete 4 questionnaires: EORTC QLQ

Qo. L Questionnaires • Patients will be asked to complete 4 questionnaires: EORTC QLQ C 30, OV 28, MOST and EQ 5 D • Qo. L assessments will be performed at screening, and on day 1 of cycle 2, 4 and 6 • For patients on the chemotherapy arm, Qo. L assessments will be performed at the end of treatment visit and every 8 weeks on follow up • For patients on Nintedanib arm, Qo. L assessments will be performed at day 1 of every cycle from cycle 7 onwards, at the end of treatment visit and every 8 weeks on follow up • Qo. L assessments will continue every 2 months post progression as long as the PI considers it appropriate and the patient continues to consent Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 30

Patient Alert Cards • A template Patient Alert Card will be provided for use,

Patient Alert Cards • A template Patient Alert Card will be provided for use, to be given to all patients • Patients should be encouraged to carry the card on their person throughout their participation in the trial and for at least 30 days after the last dose of trial drug • The patient should present the card to any healthcare provider she sees and should advise her family that she is carrying the card so that in the event that the patient is seriously ill they can present the card to the healthcare provider on the patient’s behalf • The card will be provided by the recruiting site and will contain local contact details • The patient should be requested to return their Patient Alert Card to site staff during follow up once they are 30 days post treatment completion/discontinuation. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 31

Patient Diary Cards • A template Patient Diary Card will be provided for use,

Patient Diary Cards • A template Patient Diary Card will be provided for use, to be given to all patients randomised to receive Nintedanib • The patient should be given a Diary Card at the beginning of each treatment cycle, and instructed to use this to record at what time each day they took their Nintedanib capsules, or if they took an in correct doses or missed any doses. • The Diary Card should be returned to site staff at the next visit and retained as source documentation for Nintedanib compliance • The card will be provided by the recruiting site and will contain local contact details Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 32

CRFs • • • • • Consent Notification Form Registration Randomisation Form Baseline Form

CRFs • • • • • Consent Notification Form Registration Randomisation Form Baseline Form QLQ C 30 and OV 28 Qo. L Form EQ-5 D Qo. L Form MOST Qo. L Form Treatment Form – Chemotherapy Treatment Form – Nintedanib Response Form Follow–up Form Concomitant Medication Form Consent Withdrawal Notification Form DILI Checklist Form Part 1 DILI Checklist Form Part 2 Pregnancy Notification Form SAE Form Please note the SAE form is faxed to Pharmacovigilance at CTU and the original SAE report is kept at site. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 33

CRF Completion • • CRF completion guidelines for the trial are currently being developed

CRF Completion • • CRF completion guidelines for the trial are currently being developed and will provided to sites when available Entries to the CRFs will be made in black ball-point pen and must be legible Correction fluid etc. must not be used Any errors must be crossed out with a single stroke, correction inserted and change initialled and dated An explanation can be written next to amendment if necessary Date format: DD/ MON/ YYYY Please ensure all data submitted on the CRFs is verifiable in source documents Take photocopy of all completed CRFs. Originals to be sent to CRUK CTU Glasgow CRF completion timelines: Timelines for entry of required data in the CRF Timelines for resolution of data queries Timelines for receipt of CRFs at CRUK CTU, Glasgow Within 4 weeks of patient visit Within 4 weeks of receipt Within 2 weeks of form completion Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 34

Pharmacovigilance Clinical Trial Regulations require: • Investigators document Adverse Events (AEs) in patient notes

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) • Expedited reports of Suspected Unexpected Serious Adverse Reactions (SUSARs) are reported to the Regulatory Authority in the occurrence country (the CTU, on behalf of the Sponsor, will submit SUSAR reports to the appropriate Regulatory Authority and with the assistance of collaborating groups, submit as per local requirements to the Regulatory Authorities of non-occurrence countries, RECs and Investigators. Additionally BI & the overall trial Sponsor will also receive a copy of any SUSAR reports) • A Development Safety Update Report (DSUR) is prepared and submitted annually to the Regulatory Authorities and RECs of the countries in which the trial is being conducted (the CTU will produce a DSUR on behalf of the Sponsor and circulate it to the collaborative groups for onward transmission to Regulatory Authorities, RECs and investigators as per local requirements. BI will also receive a copy of the DSUR) Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 35

Adverse Event Reporting • All AEs must be followed: - until resolution, - or

Adverse Event Reporting • All AEs must be followed: - until resolution, - or for at least 30 days after discontinuation of trial 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 • Any AEs that are related to disease progression should be reported as unrelated to the trial drugs (chemotherapy/Nintedanib). AEs that appear as related to disease progression that are recorded as related to the trial drugs will be queried by CRUK CTU Pharmacovigilance Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 36

Definition of a SERIOUS ADVERSE EVENT A Serious Adverse Event (SAE) is defined as

Definition of a SERIOUS ADVERSE EVENT A Serious Adverse Event (SAE) is defined as any untoward medical occurrence, not necessarily related to protocol treatment, that: • • Results in death Is life-threatening Requires hospitalisation or prolongation of existing hospitalisation Results in persistent or significant disability or incapacity Consists of a congenital anomaly or birth defect Is considered medically significant by the Investigator Additionally for the Ni. CCC trial, any event which meets the criteria of a AE of special interest (AESI) must also be reported within 24 hours on a SAE report form. Some AESIs will also meet the criteria of a SAE as noted above and will be processed as a SAE. However all AESI must be reported within 24 hours on a SAE report form whether the SAE criteria is met or not. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 37

Definition of a SERIOUS ADVERSE EVENT Life threatening: • The patient is at immediate

Definition of a SERIOUS ADVERSE EVENT Life threatening: • The patient is at immediate risk of death from the event as it occurred. It does not include an event that, had it occurred in a more serious form, might have caused death Requires in-patient hospitalisation: • Is as a hospital admission required for treatment of an adverse event even when the adverse event is not related to the protocol treatment Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 38

AEs of Special Interest • • Although not necessarily meeting the definition of a

AEs of Special Interest • • Although not necessarily meeting the definition of a SAE, the following AEs of special interest (AESIs) must be reported on both the CTU and BI SAE Report within 24 hours according to the SAE reporting procedures specified above: Any gastrointestinal and non gastrointestinal perforation, leakage, fistula formation, abscess. In such a case the following additional information must be collected, documented in the respective comment field of the CRF page and the respective narratives of the SAE – – – – • • • Location of perforation, leakage, fistula, abscess Location/extent of abdominal tumour manifestations, Imaging & reports (CT, ultrasound, endoscopy, pathology, etc. ) Prior surgery (location, wound healing complications) Concomitant diseases with GI involvement (eg, Crohn’s, vasculitis, tuberculosis, diverticulitis) Thromboembolic events (or predisposition) At least two elevated liver enzymes within a 2 week period, based on laboratory values ALT and/or AST >5 x ULN without bilirubin elevation measured in the same blood draw sample* ALT and/or AST >2. 5 x ULN combined with bilirubin >1. 5 x ULN measured in the same blood sample* *Where this occurs, patients should be followed up for potential drug-induced liver injury (DILI), and the DILI Checklist Form(s) completed Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 39

Reporting SAEs and AESIs • • • Serious Adverse Events (SAEs) and Adverse Events

Reporting SAEs and AESIs • • • Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) must be reported immediately (within 24 hours of knowledge of the event) AESIs only require to be reported for patients randomised to receive Nintedanib SAEs and AESIs are reported using the CTU SAE report form (and BI SAE report form for patients receiving Nintedanib) Sites must complete the SAE report form(s) and fax the report(s) to Pharmacovigilance at the Glasgow CTU fax number +44 (0)141 301 7213 The CTU will create a SAE reference number and will send an acknowledgement fax to confirm receipt (no reference number will be generated for AESIs) The CTU will request additional information if the SAE is unexpected CTU will raise queries for any inconsistent or missing information (but not for AESIs) If the AESI is a potential drug-induced liver injury (DILI), the DILI Checklist Form(s) must also be completed and submitted to Pharmacovigilance at the Glasgow CTU fax number 0141 301 7213 SAEs must be reported locally by the PI at each site in accordance with the local practice at their site (i. e. R&D Office) SAEs and AESIs are required to be reported for up to 30 days after discontinuation of trial 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 Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 40

Reporting Potential DILIs • • • A DILI is a particular criteria of Adverse

Reporting Potential DILIs • • • A DILI is a particular criteria of Adverse Event of Special Interest (AESI) that requires additional reporting for patients receiving Nintedanib. Not all AESIs will be DILIs must be reported immediately (within 24 hours of knowledge of the event) DILIs are reported using the CTU SAE report form, BI SAE report form and the DILI Checklist Form(s) Sites must complete the SAE report form and fax the report to Pharmacovigilance at the Glasgow CTU fax number +44 (0)141 301 7213 The CTU will send an acknowledgement fax to confirm receipt (no reference number will be generated for DILIs) The CTU will may request additional information on the SAE report form CTU will raise queries for any inconsistent or missing information on the SAE report form, only if the DILI event also meets the criteria for being a SAE DILI Checklist Forms If the AESI is a potential drug-induced liver injury (DILI), the DILI Checklist Form(s) should also be completed and these should be submitted to the CRUK CTU Trials Unit , Fax no: ++ 44 141 301 7213 The DILI Checklist Form(s) will be forwarded by the CRUK CTU Trials Unit to Boehringer Ingelheim Pharmacovigilance Department Boehringer Ingelheim Pharmacovigilance may request additional information on the DILI Checklist Form directly with sites Boehringer Ingelheim Pharmacovigilance will raise queries for any inconsistent or missing information on the DILI Checklist form directly with sites Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 41

Procedure for Reporting SAEs and SAE Report Processing Data Flow For SAE Reports CTU

Procedure for Reporting SAEs and SAE Report Processing Data Flow For SAE Reports CTU generates Patient SAE and DCF SAE queries form completed Site complete Patient SAE and. SAE report form(s) form completed CTU faxes DCFs to site/ Patient SAE and SAE form Centre (for faxing to country site) completed Fax +44 0141 301 7213 Site/ Country Centre fax Patient SAE and SAE form SAE report(s) to CTU fax completed (+44) 0141 301 7213 Site resolves queries Patient SAE and SAE within 2 weeks form completed CTU fax. SAE report Patient and SAE acknowledgment form completed receipt to site/centre Site queries to be signed Patient SAE and SAE form by Principal Investigator completed or delegated doctor CTU generate SAE Patient SAE and SAE form reference number (not for completed AESIs) Yes CTU data. SAE entry SAE Patient andof. SAE report ( not for AESIs ) form completed onto trial database Is SAE CTUrelated to IMA? DCF queries required? No CTU Data. SAE checked final Patient and SAE dataform check generated completed CTU edit SAE check SAE Patient andof. SAE report data (Not AESIs) form completed Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 SAE Data Flow Version 3 31 Mar 2014 Site faxes DCFs CTU Patient SAE and to SAE form or to Centre (for faxing to CTU) completed Fax +44 0141 301 7213 CTU queries entered Patient SAE and SAE onto trialcompleted database form CTU checks Patient SAESAE and report SAE data form completed 42

Procedure for Identifying Suspected Unexpected Serious Adverse Reactions (SUSARs) • A checklist will be

Procedure for Identifying Suspected Unexpected Serious Adverse Reactions (SUSARs) • A checklist will be used to identify SUSARs that require expedited reporting to the Regulatory Authority, Main REC and Sponsor • The checklist is a list of the events expected to occur in patients receiving the protocol treatment (Chemotherapy & Nintedanib) taken from the section of the Investigator Brochure (IB) and Summary of product Characteristics (Sm. PCs) that have regulatory approval when the SAE is reported. For any SAE that is documented as related to protocol treatment (SAR) and is not listed on the checklist, the Chief Investigator (CI) will be contacted for an opinion of SUSAR status (unexpectedness) • The CI is responsible for deciding if a SAR requires expedited reporting • BI will be informed of the decision to report a SAR as a SUSAR and receive a copy of the SUSAR report Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 43

Expedited Reporting SAEs that meet the criteria for SUSARs will be reported to the

Expedited Reporting SAEs that meet the criteria for SUSARs will be reported to the Regulatory Authority, REC, BI and Sponsor where in the opinion of the CI the event was: • Related – that is, resulted from administration of any of the trial drugs And • Unexpected – that is the type of event is not listed in the regulatory approved IB or Sm. PCs as an expected occurrence SUSAR reports will be submitted using Eudravigilance within 7 days for fatal/life threatening events and 15 days for all other events Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 44

Development Safety Update Reports • A Development Safety Update Report (DSUR) covering the safety

Development Safety Update Reports • A Development Safety Update Report (DSUR) covering the safety of all trial participants will be prepared by the CRUK, CTU and submitted annually to the Regulatory Authority in the UK, REC BI, Sponsor & UK trial Investigators. • The DSUR will also be submitted to the European Coordinating Centres for submitting to the Regulatory Authorities, RECs and Investigators following the requirements of the countries they are coordinating. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 45

Ni. CCC – MONITORING UK SITES (1) Central Monitoring • trial sites will be

Ni. CCC – MONITORING UK SITES (1) Central Monitoring • trial sites will be monitored centrally by checking incoming forms for compliance with the protocol, data consistency, missing data and timing. trial 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 1 st visit will take the form of a remote telephone monitoring visit when the first patient at site has completed two cycles of treatment • A 2 nd telephone monitoring visit will be conducted six months after the randomisation of the 1 st patient at site • The time & date will be agreed with a member of the Site trial 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 agreed date • Please set aside 50 to 70 minutes for this call. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 46

MONITORING UK SITES (2) The 3 rd visit will take the form of an

MONITORING UK SITES (2) The 3 rd visit will take the form of an on site monitoring visit 12 months after randomisation of the first patient at a site : • • Investigators and site staff will be notified in advance about forthcoming pre arranged monitoring visits. All patient source documentation should be made available to enable Source Document Verification by the Clinical Trial Monitor. • A full working day is required for on-site visits & arrangements should be in place to facilitate the monitor access on the agreed date. • If sites are able to provide printed results/reports these must be filed in the source documents. • If a site is using electronic data reporting systems or electronic records & hard copies are not available the clinical trial monitor must be permitted access to the system either by being issued with a temporary login or a member of staff available for the duration of the visit to facilitate electronic access to authorised reports/results. • The pharmacy department responsible for the trial will be visited to allow monitoring of the pharmacy site file and review of security, storage and accountability of trial drugs. • All findings will be discussed at an end of visit and any unresolved issues raised as Action Points. • Action Points will be followed up by the monitor until resolved. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 47

Investigator Responsibilities The following principles are from ICH GCP Topic E 6 and apply

Investigator Responsibilities The following principles are from ICH GCP Topic E 6 and apply to clinical trials of Investigational Medicinal Products: • • Qualifications & Agreements: -The Investigator should be qualified by education, training & experience. -Thoroughly familiar with protocol & medicinal products. -Comply with GCP and applicable regulations. -Permit – monitoring and audit by the sponsor and inspection by regulatory authorities. -Maintain a delegation logs of staff involved in the clinical trial at the trial site. -Ensure that all persons assisting with the trial are adequately informed about the protocol, IMP and their duties and functions. Resources: -The Investigator should have sufficient time to properly conduct and complete the trial within the agreed period. -Have available adequate facilities and qualified staff to conduct the trial properly and safely. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 48

Investigator Responsibilities • • • Medical Care of Trial Subjects: - A qualified physician

Investigator Responsibilities • • • Medical Care of Trial Subjects: - A qualified physician who is an Investigator (or co-investigator) should be responsible for all trial related medical decisions. During and following participation the Investigator should ensure adequate medical care for any adverse events (AEs). The Investigator should make as reasonable effort to ascertain reasons for withdrawal from the trial (although a subject is not obliged to give reasons) Ethics: Before initiating the trial there should be written and dated approval/favourable opinion from the Ethics Committee for the protocol, patient information sheet/consent form and any amendments. Compliance with Protocol: The Investigator should conduct the trial in compliance with the protocol. Not implement any deviation from the protocol without prior approval/favourable opinion of the IEC and the sponsor. The Investigator should document and explain any deviation from the protocol. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 49

Investigator Responsibilities • The IMP : Investigator has responsibility for IMP accountability at trial

Investigator Responsibilities • The IMP : Investigator has responsibility for IMP accountability at trial site Some/all IMP duties at the trial site may be assigned to suitably qualified pharmacist. Records must be maintained: delivery, inventory, use and destruction - Storage of the IMP should be as specified by the sponsor/regulatory requirements. The IMP should only be used in accordance with the protocol. The Investigator (or designee) should explain the correct use of the IMP to each patient. • Registration & Randomisation: The Investigator should follow the trial’s registration and 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. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 50

Investigator Responsibilities • Reports & records – The investigator is responsible for accuracy, completeness,

Investigator Responsibilities • Reports & records – The investigator is responsible for accuracy, completeness, legibility and timeliness of the data reported to the sponsor. Data reported on CRFS, from source documents should be consistent with source documents or discrepancies explained. Corrections should be : dated, initialled, explained (if necessary) and should not obscure the original entry. All trial documents should be maintained as specified in ICH GCP E 6, 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. Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 51

Other Site Staff The Principal Investigator has overall responsibility for the conduct of the

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 Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 52

CONTACT DETAILS FOR CRUK CTU Project Manager Claire Lawless Tel: 0141 301 7947 Fax:

CONTACT DETAILS FOR CRUK CTU Project Manager Claire Lawless Tel: 0141 301 7947 Fax: 0141 301 7946 E-mail: claire. [email protected] ac. uk Pharmacovigilance Manager Lindsey Connery Tel: 0141 301 7209 Fax: 0141 301 7213 E-mail: lindsey. [email protected] ac. uk Pharmacovigilance CTC Susannah Radford Tel: 0141 301 7211 Fax: 0141 301 7213 E-mail: susannah. [email protected] ac. uk Clinical Trial Monitor Calum Innes Tel: 0141 301 7948 Fax: 0141 301 7187 Mobile : 07825 030 429 E-mail: calum. [email protected] ac. uk Postal Address Cancer Research UK Clinical Trials Unit Level 0, Beatson West of Scotland Cancer Centre 1053 Great Western Road Glasgow, G 12 0 YN Clinical Trial Coordinator Laura Douglas Tel: 0141 301 7215 Fax: 0141 301 7219 E-mail: laura. [email protected] ac. uk Ni. CCC - Initiation Slides V 1. 0, 21 Jul 2014 53