Ni CCC G 143 ENGOTGYN 1 A Randomised

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 Protocol Number: Ni. CCC 2013 ISRCTN 50772895 PHARMACY INITIATION SLIDES (Version 2. 0 24 th Feb 2015)

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 – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 2

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 • Sponsor Pharmacist Dr Samantha Carmichael / Paula Morrison Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 3

Pharmacy Initiation • Protocol and treatment overview • IMP presentation and management • Ni. CCC IMP Stock Control Application • Site initiation process • Post site activation and monitoring arrangements Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 4

PROTOCOL & TREATMENT OVERVIEW Ni. CCC – Pharmacy Site Initiation Slides v 2. 0, 24 Feb 2015 5

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: • Includes: – Overall survival (OS) – Disease Control Rate – Toxicity – Quality of Life. – Q-TWi. ST (Quality-Adjusted Time Without Symptoms of Disease or Toxicity of Treatment) Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 6

Trial Eligibility (1) Key Inclusion Criteria: • • • 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 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 calendar months of their last platinum dose ECOG Performance status of ≤ 2 Life expectancy of >3 months Adequate hepatic, bone marrow coagulation and renal function Female and > 18 years of age See study protocol for full inclusion/exclusion criteria Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 7

Trial Eligibility (2) Key Exclusion Criteria: • • Prior treatment with Nintedanib or other angiogenesis inhibitor/VEGF targeted therapy, except for prior treatment with bevacizumab which is permitted 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 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. Prior therapy with weekly paclitaxel is permitted where this has been used as part of first line therapy and it is greater than 6 months since the last dose of weekly paclitaxel. Prior weekly paclitaxel for relapsed disease is not permitted). Other malignancy diagnosed within 5 years of enrolment with exceptions Patients with any other severe concurrent disease, which may increase the risk associated with study participation or study drug administration and, in the judgement of the investigator, would make the patient inappropriate for entry into this trial. Symptoms or signs of gastrointestinal obstruction or any other gastro-intestinal disorders or abnormalities, including difficulty swallowing, that would interfere with drug absorption. Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal) or antiviral therapy, including known hepatitis B and/or C infection and HIV-infection Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 8

Trial Eligibility (3) Key Exclusion Criteria continued: • • • Symptomatic CNS metastasis or leptomeningeal carcinomatosis Known, uncontrolled hypersensitivity to the investigational drugs or their excipients Significant cardiovascular disease History of major thromboembolic event unless on stable therapeutic anticoagulation History of CVA, TIA or subarachnoid haemorrhage or clinically significant haemorrhage in past 6 months 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 Pregnancy or breastfeeding. Patients with preserved reproductive capacity must have a negative pregnancy test (β-HCG test in urine or serum) prior to commencing study treatment 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 Radiographic evidence of cavitating or necrotic tumours with invasion of adjacent major blood vessels 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 before registration in the trial See study protocol for full inclusion/exclusion criteria Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 9

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 – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 10

Treatment and Duration • Experimental Arm Nintedanib (BIBF 1120) 200 mg twice daily PO, continuously, until progression or withdrawal from the treatment. • 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 Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 11

Nintedanib Dose Delays • Treatment with Nintedanib has to be interrupted if any of the criteria listed below are fulfilled: Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 12

Nintedanib Dose Reductions • After interruption of Nintedanib the following criteria must be met to restart Nintedanib: • GI adverse events: • Liver enzyme elevations: -bilirubin values CTCAE grade 0 -AST and ALT CTCAE grade ≤ 1 • Neuropathy: • 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 -nausea CTCAE grade ≤ 1 -vomiting CTCAE grade 0 -diarrhoea CTCAE grade ≤ 1 -neuropathy CTCAE grade ≤ 2 Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 13

Nintedanib Compliance • Empty Nintedanib bottles and any remaining medication to be returned at each patient visit • Pharmacy to perform tablet count (information on handling in IMP manual) • 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 a Nintedanib Diary Card to record their compliance • Patients given an alert card to carry for duration of clinical trial Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 14

Detailed information on control arm dosing • Protocol lists criteria for: – initiation and retreatment - should be assessed for all chemotherapy regimens for each cycle. – regimen specific information – dose modification for toxicity – dose delays – dose limiting toxicity Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 15

IMP PRESENTATION AND MANAGEMENT Ni. CCC – Pharmacy Site Initiation Slides v 2. 0, 24 Feb 2015 16

Investigational Medicinal Products - Summary • Provided by sponsor – Nintendanib – Store at 15 -30 o. C • Provided free of charge • Shipped from Almac • Full accountability required using – Ni. CCC IMP Stock Control Application and – Ni. CCC Master Site Accountability Log • Hospital own stock – – – Paclitaxel Pegylated liposomal doxorubicin Topotecan Carboplatin Doxorubicin • Accountability for traceability purposes – Use Ni. CCC Control Arm Accountability log – Retain aseptic worksheets – Dose banding permitted Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015

Prescribing Arrangements • Study specific prescriptions must be used • Sites to develop own prescription. Must include following minimum details in addition to standard prescribing information: – clearly identified as Ni. CCC study. Include Protocol No: /Eudra. CT No – Ni. CCC Subject No • Electronic prescriptions can be used • Prescriptions must be version controlled or subject to validation process • Copy of final prescription and any updated versions should be retained in the pharmacy file and a copy sent to investigator for insertion into investigator site file. Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 18

Presentation of Nintedanib (BIBF 1120) supplies • Open label – 100 mg x 30 capsules • Multilanguage booklet label – 150 mg x 30 capsules Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 19

Nintedanib orders and distribution • Initial supply is sent automatically to site only when the first patient at site is registered to enter the pre-pathology screen. • Pharmacy sites are responsible thereafter for ensuring that sufficient supplies of nintedanib held at site • Replacement supplies must be manually ordered using the Ni. CCC Resupply Drug Order Form • Shipped in validated shippers with elpro temperature data logger from Almac • Follow the instructions on the Elpro monitor instruction sheet. PDF files for all shipments must be sent to the BI Elpro Libero Manager Database. • Automated response from the BI Elpro Libero Manager Database. Please print and retain in pharmacy site file. Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 20

Nintedanib receipt • If Elpro data logger has alarmed on arrival, quarantine the shipment at correct storage conditions and e-mail to IIS@almacgroup. com and R&DIMP@ggc. scot. nhs. uk as per instructions in IMP manual. Await written response. • If Elpro data logger arrives without an alarm, nintedanib supplies can be used and should be receipted on to the NICCC Master Site Accountability Log and receipted on to the Ni. CCC IMP Stock Control application. Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 21

Nintedanib dispensing & accountability (1) • Individual packs are not allocated, therefore any Med No of correct strength can be used for any patient. However: – use lowest available Med No of correct strength first to aid stock rotation – Add investigator and patient ID – Additional dispensing labels may be added as per local practice provided that pre-printed text is not obscured. • Accountability is via NICCC IMP stock control application and NICC Master Site Accountability Log • Handling information in IMP manual and MSDS available Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 22

Nintedanib dispensing & accountability (2) Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 23

Nintedanib patient returns & destruction • Sites should have local processes in place to ensure that any potential patient medication compliance issues can be addressed by the local PI or delegate in a timely manner. • Sites are permitted to destroy any patient returned study medication once returns documented on the IMP stock control application provided that any discrepancies are resolved. • Unused or expired medication can only be destroyed after written permission has been obtained from CR-UK CTU. Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 24

Control IMPs dispensing & accountability • Can use dose banded products – see IMP Management and Accountability Manual for requirements • Retain aseptic worksheets • Accountability for traceability purposes recorded on Ni. CCC Control Arm IMP Accountability Log • Add following text in addition to standard dispensing label: Protocol: Ni. CCC 2013 Eudra. CT No: 2013 -002109 -73 Principal Investigator: XXXX Patient ID: XXXX Sponsor: NHS Greater Glasgow and Clyde For clinical trial use only Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 25

Defects and Temperature Deviations • Nintedanib – Quarantine stock under appropriate temperature conditions ie. 1530 o. C – Quarantine stock on Ni. CCC IMP stock control application – Complete the Ni. CCC IMP Temperature Deviation and Defect Report form providing as much detail as possible and e-mail to CTC – Include temperature log (temperature excursion) or picture (defect). – Telephone if urgent. • Control IMPs – Temperature deviations, product complaints or recall should be managed as per local site operating procedures Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 26

NICCC STOCK CONTROL APPLICATION Ni. CCC – Pharmacy Site Initiation Slides v 2. 0, 24 Feb 2015 27

IMP Stock Control Application (1) • Simple, intuitive system to record receipt, dispensing, and destruction. • System does not automatically trigger replacement shipments and cannot be used toor order replacement supplies. • Self-directed training using current User Guide and Training Guide for Ni. CCC. • Once training completed, ensure that documented on Ni. CCC Pharmacy Site Training Log and return a copy to CTC. Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 28

IMP Stock Control Application (2) • **LIVE** Ni. CCC IMP stock control application accessed via http: //www. crukctuglasgow. org • Support: Please e-mail in the first instance to report any Ni. CCC IMP Stock control application problems. E-mail: mvls-it-ctu@glasgow. ac. uk Tel: +44 (0) 141 301 7204 Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 29

PHARMACY SITE INITIATION PROCESS Ni. CCC – Pharmacy Site Initiation Slides v 2. 0, 24 Feb 2015 30

Pharmacy Initiation Process • Site initiation process - Each member of study team is required to participate in site initiation to ensure compliance with the protocol and training on study procedures. Initiation will be done by site staff accessing on line initiation slides via CR-UK CTU website • Lead pharmacist for the Ni. CCC will complete Pharmacy Site Assessment Form and return to CR-UK CTU • At a minimum the lead pharmacist must be added on to the site Delegation and Study Specific Training Log. Other pharmacy clinical trial staff may be delegated IMP management responsibilities as per site requirements. These staff will be required to provided evidence of GCP training and current CV’s • Acknowledgement sheet must be completed for each member of the study who has viewed the initiation slide presentation to confirm completion. • Initiation Accreditation call - Prior to activation of the site a short initiation call will be completed with the main contact for the site. Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 31

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 SITE ACTIVATED Automatic NINTEDANIB shipment triggered by sponsor when 1 st patient at site enters pre-pathology screen Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 32

POST SITE ACTIVATION & MONITORING ARRANGEMENTS Ni. CCC – Pharmacy Site Initiation Slides v 2. 0, 24 Feb 2015 33

Ni. CCC – MONITORING UK SITES 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 3 rd visit will take the form of an on site monitoring visit 12 months after randomisation of the first patient at a site. 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 – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 34

Once site activated Site responsibilities • Ensure Pharmacy site file kept up to date • Maintain sufficient quantities of nintedanib 100 mg and 150 mg packs at site • Ensure Ni. CCC IMP Stock Control application and accountability logs are kept up to date • Inform CR-UK CTU Glasgow of any changes in personnel or arrangements for pharmacy • Action amendments where required. Sponsor responsibilities • • Forward amendments in a timely manner Review and amend IMP management process as required Help solve problems & provide support as required. Action Points will be followed up by the monitor until resolved. Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 35

CONTACT DETAILS FOR CRUK CTU Sponsor Clinical Trial Technician Eliza Valentine Tel: 0141 211 8554 E-mail: R&DIMP@ggc. scot. nhs. uk Project Manager Claire Lawless Tel: 0141 301 7947 Fax: 0141 301 7946 E-mail: claire. lawless@glasgow. ac. uk Sponsor Clinical Trial Pharmacist Paula Morrison Tel: 0141 211 8554 E-mail: R&DIMP@ggc. scot. nhs. uk Clinical Trial Coordinator Laura Douglas Tel: 0141 301 7215 Fax: 0141 301 7219 E-mail: laura. douglas@glasgow. ac. uk Pharmacovigilance Manager Lindsey Connery Tel: 0141 301 7209 Fax: 0141 301 7213 E-mail: lindsey. connery@glasgow. ac. uk Pharmacovigilance CTC Susannah Radford Tel: 0141 301 7211 Fax: 0141 301 7213 E-mail: susannah. radford@glasgow. ac. uk Clinical Trial Monitor Calum Innes Tel: 0141 301 7948 Fax: 0141 301 7187 Mobile : 07825 030 429 E-mail: calum. innes@glasgow. 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 Ni. CCC – Pharmacy Site Initiation Slides v 2. 0 24 Feb 2015 36