Presentation at PhUSE 2007

1. PhUSE
Lisbon, Portugal – 8-10 October 2007
Web-Triage
An Application for patient
registration in phase I dose
Early Drug Development
escalation studies
In Oncology
Microsoft Tools Stream (MT02)
Angelo Tinazzi
Data Management and Programming Unit
SENDO Tech S.r.l. – Milan (ITALY)
co-authors
Alessandro Cattaneo
SENDO Tech S.r.l.
Paolo Ferroni, Lucio Ferraresi
Eventi Telematici – Milan (ITALY)

2. SENDO (Southern Europe New Drug Organisation)
Non profit Academic Research Organisation (ARO)
Early Drug Development in Oncology
Coordinating a Network of oncology-hospitals
5 phase I (2 in Italy, 3 in Switzerland)
~ 30 phase II (Italy, Switzerland, Spain)
Pre-clinical Laboratory (PK, PD)
Head Quarter based in Milan
Clinical Development
Clinical Operations
Data-Management
Biostatistics
Medical Writing
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

3. SENDO (Southern Europe New Drug Organisation) - Partners
HQ-Activities
Core activities
Clinical development
IOSI, Bellinzona,
Head quarters
Trial design
Clinical Operation
INT, Milano
Luca Gianni
Cristiana Sessa Selected Milano & MoA
Screening
Data Center 12
ViaClinicalModrone,
Visconti di trials
Regulatory
18 people
Pharmacokinetics
Monitoring
Pharmacodynamics
Logistic
IEO, Milan HGVdH Barcelona
Filippo deBraud Josè Baselga
and also ....
CHUV Lausanne, KSSG S Gallen,
Istituto Mario Negri Milano
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

4. Drug Development Process – Study Phases
Classic Clinical Development
Phase I Phase II Phase III Phase IV
Tolerability Activity Efficacy Surveillance
Approval
FDA/EMEA/…
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

5. Phase I Dose Escalation studies in Oncology
Conducted in humans
Conducted in cancer patients
Usually with advanced disease
Failing previous ‘standard’ therapies
Good Performance Status
Dose escalation
Pre-defined dose-levels (Fibonacci series)
The starting dose is usually 1/10 the median lethal
dose in mouse or other animals (LD10)
Maximum Tolerated Dose (MTD), the dose where 2/3
or 2/6 DLTs are experienced
Recommended Dose (RD), the dose before MTD
where no more than 1/6 DLTs are experienced
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

6. Examples of Dose Limiting Toxicities (DLT)
Drug Related Toxicities, such as
Absolute granulocyte count <0.5 x10^9/L lasting
>= 5 days
Platelets <50 x10^9/L
Failure to deliver therapy in day 8 due to drug
related toxicity
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

7. Example of a Dose Escalation Protocol
Dose level Dose Dose
(cohort) increment (mg/m2)
1 1 2 3
Starting dose 0.10
2 4 5 6 7 8 9
100% 0.20
3 10 11 12 17 18 19 RD
67% 0.33
4 13 14 15 16 17 …
50% 0.50 MTD
5
33% 0.67
6
33% 0.89
7
33% 1.18
8
33% 1.57
9
33% 2.08
x1 x2 x3 Patient Cohort (patient nr. x1, x2, x3, …)
Dose Limiting Toxicities
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

8. Ethical Issues in Phase I in Oncology
Maximising patients exposure to potentially
therapeutic doses
Minimising patients treated at ineffective
doses
Minimising patients treated at toxic doses
Historically low probability of response in
phase I trials
Unknown toxicity and benefit of new agent
Informed Consent
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

9. Accrual Issues in Phase I in Oncology
Better selection of patients
Appropriate education of referring physicians
Apply fewer restrictions in eligibility criteria
The window of opportunity of starting a phase
I trial may be limited because the clinical
course of these end-stage patients is
unpredictable
No more than 2-3 investigator sites per trial
Concurrent trials
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

10. Patient Triage
The french word ‘triage’ means ‘picking out’ (sorting)
and it was used in World War I, when a ‘system’ was
adopted for the sorting of wounded soldiers into
specific groups requiring differential medical
interventions according to the severity of their injuries
…a similar approach is used in emergency unit
unit to ration limited medical resources and in
Phase I studies in oncology…..
In phase I trials, patients have to be selected as soon
as possible so that investigators can be prepared to
treat a new patient
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

11. The Web-Triage Application: User Requirements
Defining Study Characteristics
Dose Levels
Data to be Collected, including pre-registration data
Library for Study items (i.e. chemotherapy regimens)
Opening or Close dose-levels according to dose-
escalation rules
Manage concurrent dose-escalation trials
The Investigators can review study status (dose-level
cohorts) and propose candidates
The Study Project Managers need to be alerted as
soon as a candidate is proposed
Review and approve|reject patient candidate
Manage dose-levels (close, open and re-open)
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

12. The Web-Triage Application: Take a tour (1)
Study Information: The Dose Levels
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

13. The Web-Triage Application: Take a tour (2)
Investigator Login: List of enabled open Trials
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

14. The Web-Triage Application: Take a tour (3)
The Investigator Propose a Candidate
The first dose-escalation (7.5+40), is going to be closed, no DLT criteria reached
The 15+40 Opened dose-level, has slots available
EPTD, it is the planned administration starting date for next patients
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

15. The Web-Triage Application: Take a tour (3)
Data-entry functionality
Prior Chemotherapy
Dictionary
Online Data
Validation
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

16. The Web-Triage Application: Take a tour (4)
Study Project Manager Reviews the Study Status
The candidate is eligible and accepted for registration
The candidate is not fully eligible and accepted for registration
The candidate is not eligible and not suitable for study registration
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

17. Automatic Communication
Via email
Once a candidate is proposed (from Inv HQ)
Once a candidate is accepted/rejected (from HQ Inv)
Once a candidate is confirmed for registration (from HQ
Inv)
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

18. The Web-Triage Application: System Design
ASP.NET
unified software development model that includes the
services necessary to build enterprise-class Web
applications
MS SQL Server 2005
IIS (version 6.0) Web Server
HTTPS SSL 128/256 bit for data-encryption
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

19. The Web-Triage Application: N-Tier Concept
N-Tier System
A Client-Server Architecture,
where each module is
developed separately
Presentation Layer
Workflow Layer
Business Rule Layer
Data Layer
Data Store
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

20. Triage Network Architecture
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

21. The Web-Triage Application: Technical References
HTTP://MSDN2.MICROSOFT.COM/EN-
US/LIBRARY/MS973279.ASPX
HTTP://WWW.MICROSOFT.COM/BELUX/MSDN/NL/
COMMUNITY/COLUMNS/HYATT/NTIER1.MSPX
HTTP://MSDN2.MICROSOFT.COM/IT-
IT/NETFRAMEWORK/DEFAULT.ASPX
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

22. Conclusions
Conducting phase I oncology studies has major
potential pitfalls
Fast accrual is required in phase I oncology
studies for both ethical and economical issues
The Accrual is a crucial step in succeeding and
a tool such as Web-Triage may improve
timeline and quality
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

23. Questions
Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triage: an applicaition for patient Registration in Phase I
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dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)