1. Investigator’s Meeting
Boehringer Ingelheim
Covance Central Laboratory Procedures
Toronto 23 February 2013
Investigator’s Meeting
This document contains confidential and proprietary information and is the exclusive property of Covance Central Laboratory Services Inc. The reproduction, distribution, modification, performance or other use of this document, or any of the information contained herein, in whole or in part, without the express written consent of Covance Central Laboratory Services Inc, is prohibited.

2. Covance Central Laboratory Services for 1230.14
Indianapolis, Indiana
Kawagoe City, Japan
Geneva, Switzerland
Singapore
Indianapolis
Singapore
Geneva
Tokyo

3. Central Laboratory Topics
Pharmakokinetic samples
Collection Summary Overview
Pharmacogenomic samples
Cytogenetic samples
Supplies

4. Summary Overview Kits are visit specific
1 Kit at C1 V1: Pharmacokinetic & Pharmacogenomic
1 Kit for Pharmacokinetic samples at
C1 V3
C2 V1
C4 V1,
C6 V1
Envelope and labels for Cytogenetic samples (blood and BM)
Bone marrow central review => From Quest to Quest

5. PharmacoKinetic samples
When?
Before start of infusion of Volasertib/ Placebo
Just before the end of infusion of Volasertib/ Placebo
Cycle 1 Day 1 & 15
Cycle 2 Day 1
Optional at Cycle 4 Day 1 & Cycle 6 Day 1
Remind:
after ECG
from the arm opposite to the infusion arm (or either forearm in case of central venous access)
record exact times (Objective is evaluate relation between PK‘s and ECG‘s Use the same watch for the ECG and the PK (use the ECG clock time to document PK sampling time or make sure the watch used to document PK sampling time shows the same clock time as the ECG machine) to allow correlation of ECG and PK

6. PharmacoKinetic samples (SM 1)
Plasma Preparation
Fill in all the required information on the appropriate labels of the two cryo tubes each for plasma. Please verify that the information given on the labels corresponds to the current visit, time point and patient n°.
Prepare plasma by centrifugation at approximately 3000 rpm (2100 g) for 15 minutes at 4 – 25°C / 40 – 77°F (preferably at 4°C / 40°F). Centrifugation should be done within 60 min after sampling!
Transfer immediately with a single use transfer pipette two plasma aliquots, one in each of the two labeled cryo tubes (at least 500 µL plasma in each tube). Make sure that the sample tubes are tightly closed.

7. PharmacoKinetic samples (SM 1)
Sample Storage
Store the aliquots in upright position in the appropriate cryo box (one box for aliquot 1 & one box for aliquot 2) immediately at -20°C / -4°F or below until shipment.
If possible store the cryo boxes for aliquot 1 and aliquot 2 samples in different freezers.
The temperature of the freezers should be monitored daily.
Thawing of the samples should be avoided. When samples unexpectedly thaw due to the freezer being unable to maintain the necessary temperature, the samples should be re-frozen as soon as possible and the trial team must be informed about this occurrence (Conditions e.g. temperature of freezer when discovering the incident and duration e.g. last checked and OK on DATE and TIME; problem detected on DATE and TIME; duration of the issue).

8. PharmacoKinetic samples (SM 1)
Shipment of the frozen PK samples
Wherever possible samples should be shipped on Monday, Tuesday or Wednesday to ensure prompt delivery during week days before Saturday. Make sure the samples will not arrive on weekends or public holidays.
Never send aliquot 1 and aliquot 2 of the same sample within the same shipment.
Shipment of the frozen PK samples to Covance should take place every 3 months together with PGx samples.
For packaging see the “Packaging Procedures” in the “Central Laboratory Service Manual” provided by Covance & Order dry ice on time (see Covance manual)

9. PharmacoKinetic samples (SM 1)
Completion of requisition forms
Provided in English
All information should be completed in English
Complete all required information and answer questions
Collection instructions and shipping condition
Ship white copies to Covance CLS with frozen PK aliquot 1 samples and PGx samples
Ship yellow copies to Covance CLS with frozen PK aliquot 2 samples
Retain pink copies for your records

10. Pharmacokinetic
Laminated card 10

11. Tubes are part of PK Kit (C1V1)
Pharmacogenomic sample
When?
Ideally at Cycle 1 Day 1 (could also be taken at any later visit)
Remind:
Patient must have signed a separate ICF
Optional participation
Tubes are part of PK Kit (C1V1)

12. Pharmacogenomics samples (SM 2 & SM 3)
Prepare the provided blood drawing tubes
2 mL EDTA whole blood tube (SM 2 PGxA)
8.5 mL PAXgene DNA tube (SM 3 – PGxB)
Fill in all the required information (patient number; date of blood collection) on the appropriate, pre-printed label on the blood drawing tubes. Please verify that the information given on the label corresponds to the current patient, visit and date.
Draw the blood samples into the provided blood drawing tubes.
Invert gently about 10 times, avoid vigorous shaking.
Carefully complete all required information on the “Laboratory Requisition Form for PGx” (provided by Covance).
Blood Sampling

13. Pharmacogenomics samples (SM 2 & SM 3)
Freeze the PGx blood samples immediately at -20°C / -4°F in upright position in the appropriate cryo box.
Store the cryo boxes at -20°C / -4°F or below until shipment.
The temperature of the freezers should be monitored daily.
Thawing of the samples should be avoided. When samples unexpectedly thaw due to the freezer being unable to maintain the necessary temperature, the samples should be re-frozen as soon as possible and the trial team must be informed about this occurrence (Conditions e.g. temperature of freezer when discovering the incident and duration e.g. last checked and OK on DATE and TIME; problem detected on DATE and TIME; duration of the issue).
Blood Sample Storage

14. Pharmacogenomics samples (SM 2 & SM 3)
Wherever possible samples should be shipped on Monday, Tuesday or Wednesday to ensure prompt delivery during week days before Saturday. Make sure the samples will not arrive on weekends or public holidays.
Shipment of the frozen PGx blood samples should take place always together with the frozen PK samples.(3-monthly).
For packaging see the “Packaging Procedures” in the “Central Laboratory Service Manual” provided by Covance.
When shipping the samples on dry ice to Covance, please include the completed and signed “Laboratory Requisition Form for PGx”.
Send the samples together with the appropriate documents (Requisition Form, List of contents) to Covance : See lab addresses reported in the shipping instruction provided with the investigator manual.
Shipment of the frozen PGx Blood samples
Similar procedure
as for PK

15. Pharmacogenetic sampling
Laminated card 15

16. Cytogenetic samples When? Diagnosis (screening)
At every BM assessment:
From Cycle 2 Visit 5, and every other cycle (C4V5, C6V5, C8V5, etc)
In case of suspicion of relapse or progression
EOT
Remind:
Must be shipped on the day of collection, directly to Ulm university

17. Instructions for sampling
Cytogenetic samples
Instructions for sampling
At SCREENING , before the study treatment starts, collect for Cytogenetic and Molecular genetic diagnostics:
40mL of peripheral blood,
5-10mL bone marrow (10 mL if ever possible),
and 10mL of blood (EDTA) for plasma preparation
For this procedure usual, sterile 10mL syringes (please use your clinic material) can be used.
Before filling the tubes it is necessary to have Heparin already in the syringes for anticoagulation.
for bone marrow: 1:10 [500 IE Heparin-Na/mL sample]
 fill 1 sterile 10mL syringe with bone marrow
for Heparin-Na-blood: 1:10 [500 IE-Na/mL sample]
 fill 4 sterile 10mL syringes with peripheral blood. Alternatively, standard syringes can be used. If no Na-Heparin syringes are available, also Li-Heparin syringes can be used
for plasma preparation
 fill a standard 10mL blood EDTA syringe (please use your clinic material)

18. Instructions for sampling
Cytogenetic samples
Instructions for sampling
After drawing of the samples:
Please close all syringes with a disposable sealing cap.
All syringes need always to be labelled with the special labels provided by Covance. Please complete the patient number and the date of sampling. Do not forget to mark the matrix of the sample.
Labelling of the samples:
Matrix: = Bone marrow, Blood, Plasma (mark it)
Last name: = BI (preprinted)
First name: = _ :_ _ _ _ (patient number)
Date of birth: = (dummy date of birth for all patients – preprinted)
Date of sampling |__||__|/|__||__|/|__||__|
day month year

19. Instructions for sampling
Cytogenetic samples
Complete the “Material delivery Form” available in the Covance Lab Manual:
Original copy shipped with samples
Store a copy at site, in ISF
Instructions for sampling

20. Instructions for sampling
Cytogenetic samples
Instructions for sampling
Before shipping to Ulm:
ensure your site is faxing the requisition form to Ulm (or )
So that shipment is expected and handled immediately on receipt

21. Shipped the day of collection
Cytogenetic samples
All syringes have to be packed according to the Lab manual from Covance,
and sent to the laboratory Prof. Dr. Döhner (University Hospital of Ulm- Germany)
If possible the samples have to be at the reference laboratory within 24 hours (up to 48 hours)
Shipped the day of collection
Instructions for sampling

22. Cytogenetic samples Results Results will be sent back to sites
Results are uploaded in eCRF by Ulm Laboratory
=> no need for site staff to enter Cytogenetics’ results in eCRF
Results

23. Cytogenetic samples Withdrawal of consent Important
If a patient actively withdraw the Informed Consent for biobanking of cytogenetic samples,
please fill in the separate document “Withdrawal of the Informed Consent
Fax it to Ulm
File in ISF the returned signed faxed from Ulm
Withdrawal of consent

24. Cytogenetic and Molecular Genetic Diagnosis
Laminated card 24

25. Initial Supplies Review packing list within initial shipment
Type of labkits provided at initial supply (3 of each) PK
Cycle 1 Day 1 (with PGX tubes),
Cycle 1 Day 15,
Cycle 2 Day 1,
Cycle 4 Day 1
Cycle 6 Day 1
Bulk supplies
1x Lab Manual and Quick Reference Guide
4x Miscellaneous labels for cardboard racks
2 x Cardboard racks (81 spaces) for PK samples
2 x Cardboard racks (25 spaces) for PGx samples
5x Envelopes and miscellaneous labels for Cytogenetic samples shipped to Ulm/Germany
Review packing list within initial shipment

26. Initial Supplies Shipping supplies Shipping boxes
Site specific shipping documents
Airway bills, Commercial Invoices, return address labels
Shipping supplies are provided by courier or Covance CLS, depending on courier arrangements
Refer to Covance CLS Investigator Manual and courier arrangements fax for country specific information

27. Covance CLS Resupply Requests
Request the following supplies from Covance CLS
Replacement of damaged, lost or expired kits
Shipping supplies (except when delivered by the courier)
Extra bulk supplies
18 working days in Russia
20-22 working days in Latin America
Secure website
Confirmatory  sent providing
the work order reference number
Allow a minimum of 7-9 working days for the delivery
of your resupply order, except:
Order supplies online:

28. Primary Reference Material
Please review the Covance CLS
Investigator Manual prior to first
patient visit
Covance CLS contact information
Toll Free and Direct telephone numbers
If Toll Free unavailable, call telephone operator for collect call to Covance CLS
Sample collection instructions
Packaging instructions

29. Key Points to Success / Lessons Learned (1/2)
Initial Supplies
Complete and submit requested information forms
Check packing list
Resupply Process
No automatic resupply
Check your inventory periodically
Please allow the minimum of 7-9 working days for delivery of resupply orders
Collection kits
Select appropriate kit, always check expiration date
Properly label all tubes/vials sent to Covance CLS
Requisitions
Submit Clear-Consistent-Complete & Query Free Requisitions

30. Key Points to Success / Lessons Learned (2/2)
Sample Processing
Follow instructions on requisitions and in manual
Packaging
Use Covance CLS/courier provided boxes
Order the dry ice early enough for your frozen shipments (some sites require 2 working days advance notice)
Shipping
Contact courier for pickup in advance
Contact Covance CLS for:
Laboratory questions
Courier issues

31. Questions
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