1. PHARMACY INITIATION SLIDES
NiCCC (G143)
(ENGOT-GYN1)
A Randomised Phase II study Of Nintedanib (BIBF1120) Compared To Chemotherapy in Patients With Recurrent Clear Cell Carcinoma Of The Ovary Or Endometrium
EudraCT Number:
Protocol Number: NiCCC2013
ISRCTN
PHARMACY INITIATION SLIDES
(Version 1.0 , 25th July 2014)

2. *******************************************************************
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)
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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

3. Trial Team Chief Investigator : Dr Ros Glasspool
International Chief Investigator: Dr Mansoor Mizra
Co-Investigator/
Translational Research Co-ordinator: Professor Ian McNeish
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

4. Pharmacy Initiation Protocol and treatment overview
IMP presentation and management
NiCCC IMP Stock Control Application
Site initiation process
Post site activation and monitoring arrangements

5. Protocol & treatment Overview

6. 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-TWiST (Quality-Adjusted Time Without Symptoms of Disease or Toxicity of Treatment)

7. Trial Eligibility 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 months of their last platinum dose
ECOG Performance status of ≤2
Life expectancy of >3 months
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 109L
-Haemoglobin ≥ 9.0 g/dL
-Proteinuria < grade 2 (CTCAE version 4)
-Glomerular Filtration Rate ≥40ml/min. (calculated using Cockroft & Gault equation or measured by EDTA clearance)
Female and > 18 years of age
Signed and dated written informed consent prior to admission to the trial in accordance with ICH-GCP guidelines and local legislation.
Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures.

8. Trial Eligibility 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)
Other malignancy diagnosed within 5 years of enrolment except for:
Non-melanomatous skin cancer (if adequately treated)
Cervical carcinoma in situ (if adequately treated)
Carcinoma in situ of the breast (if adequately treated)
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 1a (tumour invades less than one half of myometrium)
Grade 1 or 2
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 neurologic, psychiatric, infectious, hepatic, renal, or gastrointestinal diseases or laboratory abnormality
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
Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal) or antiviral therapy, including known hepatitis B and/or C infection and HIV-infection
Symptomatic CNS metastasis or leptomeningeal carcinomatosis

9. Trial Eligibility Exclusion Criteria continued:
Known, uncontrolled hypersensitivity to the investigational drugs or their excipients
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
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
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 G20210A mutation)
Known inherited predisposition to bleeding or thrombosis
History of a cerebral vascular accident, TIA or subarachnoid haemorrhage within the past 6 months
History of clinically significant haemorrhage in the 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 trial 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

10. 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 NiCCC 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-HT3 receptor antagonists tropisetron and/or dolasetron which are metabolized by cytochrome 2D6 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

11. Central Pathology Review Criteria and Eligibility Criteria met
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
Physicians choice of standard chemotherapy, from list below*.
Experimental Arm
Nintedanib 200mg BD continuously until progression or withdrawal from trial
Assessments
Clinical:
At screening, Day 1 and then every 4 weeks until week 24 and then every 8 weeks.
CA125:
At screening, day 1 and every 4weeks until week 24 then every 8 weeks until progression
CT Scans
Screening, and every 8 weeks until week 48 or until progression
Assessments
Clinical:
At screening, Day 1 of each course of chemotherapy
CA125:
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
Primary Endpoint: PFS
Secondary Endpoints: OS, QoL, QTWIST, ORR, & DCR at 12 weeks

12. Treatment and Duration
Experimental Arm
Nintedanib (BIBF1120) 200mg 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 (80mg/m2) IV Day 1, 8, 15 every 28 days, x6 cycles
Pegylated Liposomal Doxorubicin (PLD) (40mg/m2) IV every 28 days, x6 cycles
Topotecan (4mg/m2) IV Day 1, 8, 15 every 28 days, x6 cycles
Endometrial Cancer Patients:
Carboplatin (AUC 5) and Paclitaxel (175mg/m2) IV every 21 days, x6 cycles
Doxorubicin IV (60mg/m2) every 21 days x6 cycles

13. Nintedanib Dose Delays
Treatment with Nintedanib has to be interrupted if any of the criteria listed below are fulfilled:

14. 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

15. 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

16. 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

17. IMP Presentation and management

18. Investigational Medicinal Products - Summary
Provided by sponsor
Nintendanib
Store at 15-30oC
Provided free of charge
Shipped from Almac
Full accountability required using
NiCCC IMP Stock Control Application and
NiCCC Master Site Accountability Log
Hospital own stock
Paclitaxel
Pegylated liposomal doxorubicin
Topotecan
Carboplatin
Doxorubicin
Accountability for traceability purposes
Use NiCCC Control Arm Accountability log
Retain aseptic worksheets
Dose banding permitted

19. 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 NiCCC study. Include Protocol No: /EudraCT No
NiCCC 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.

20. Presentation of Nintedanib (BIBF1120) supplies
Open label
100mg x 30 capsules
150mg x 30 capsules
Multilanguage booklet label

21. 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 NiCCC 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.

22. Nintedanib receipt
If Elpro data logger has alarmed on arrival, quarantine the shipment at correct storage conditions and to and 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 NiCCC IMP Stock Control application.

23. 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

24. Nintedanib dispensing & accountability (2)

25. 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 an 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.

26. 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 NiCCC Control Arm IMP Accountability Log
Add following text in addition to standard dispensing label:
Protocol: NiCCC2013
EudraCT No:
Principal Investigator: XXXXXXXX
Subject no: XXXXXXXX
Sponsor: NHS Greater Glasgow and Clyde
For clinical trial use only

27. Defects and Temperature Deviations
Nintedanib
Quarantine stock under appropriate temperature conditions ie oC
Quarantine stock on NiCCC IMP stock control application
Complete the NiCCC IMP Temperature Deviation and Defect Report form providing as much detail as possible and 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

28. NICCC Stock Control Application

29. 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 or order replacement supplies.
Self-directed training using current User Guide and demo site. Information is provided in Appendix 1 of IMP Management & Accountability Manual.
Once training completed, ensure that documented on NiCCC Pharmacy Site Training Log and return a copy to CTC.

30. IMP Stock Control Application (2)
**LIVE** NiCCC IMP stock control application accessed via
Support: Please in the first instance to report any NiCCC IMP Stock control application problems.
Tel: +44 (0)

31. Pharmacy Site initiation Process

32. 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 NiCCC will complete Pharmacy Site Assessment Form and return to CR-UK CTU
A Staff Contact and Responsibilities Sheet must be completed for the lead pharmacist and any other pharmacy clinical trial staff who are delegated IMP management responsibilities. 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.

33. Site Set Up CTU GLASGOW  SITE INITIATION PROCESS SITE ACTIVATED
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 1st patient at site enters pre-pathology screen

34. Post site activation & Monitoring arrangements

35. NiCCC – 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/ /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 when the first patient at site has completed two cycles of treatment
A 2nd telephone monitoring visit will be conducted six months after the randomisation of the 1st patient at site
The 3rd 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.

36. Once site activated Site responsibilities
Ensure Pharmacy site file kept up to date
Maintain sufficient quantities of nintedanib 100mg and 150mg packs at site
Ensure NiCCC IMP Stock Control application and accountability logs are kept up to date
Inform CR-UK CTU Glasgow of any changes in contacts 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.

37. CONTACT DETAILS FOR CRUK CTU
Project Manager Clinical Trial Coordinator
Claire Lawless Laura Douglas
Tel: Tel:
Fax: Fax:
Pharmacovigilance Manager Pharmacovigilance CTC
Lindsey Connery Susannah Radford
Tel: Tel:
Fax: Fax:
Clinical Trial Monitor Postal Address
Calum Innes Cancer Research UK Clinical Trials Unit
Tel: Level 0,
Fax: Beatson West of Scotland Cancer Centre
Mobile : Great Western Road
Glasgow, G12 0YN