Web-Triage An Application for patient registration in phase I dose escalation studies

PhUSELisbon, Portugal – 8-10 October 2007

Web-TriageAn Application for patient registration in phase I dose escalation studies

Microsoft Tools Stream (MT02)

Angelo TinazziData Management and Programming Unit

SENDO Tech S.r.l. – Milan (ITALY)co-authors

Alessandro CattaneoSENDO Tech S.r.l.Paolo Ferroni, Lucio FerraresiEventi Telematici – Milan (ITALY)

Early Drug Development Early Drug Development In OncologyIn Oncology

2Tinazzi A Cattaneo A Ferraresi L Ferroni P WEB-Triag e: an applicaition for patient Registration in Phase I dose-escalation studies PhUSE 2007, MT02 (Lisbon, Portugal – 8-10 October 2007)

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


INT, Milano Luca Gianni

HGVdH BarcelonaJosè Baselga

IOSI, Bellinzona,Cristiana Sessa

IEO, MilanFilippo deBraud

and also .... CHUV Lausanne, KSSG S Gallen, Istituto Mario Negri Milano

Head quartersMilano

Via Visconti di Modrone, 12

18 people

Core activitiesTrial design

Selected Screening & MoAClinical trials

PharmacokineticsPharmacodynamics

HQ-ActivitiesClinical development

Clinical OperationData Center RegulatoryMonitoring

Logistic

SENDO (Southern Europe New Drug Organisation) - Partner s


Drug Development Process – Study Phases

Classic Clinical DevelopmentClassic Clinical Development

Phase I

Tolerability

Phase II

Activity

Phase III

Efficacy

Phase IV

Surveillance

Approval

FDA/EMEA/…


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 lethaldose 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


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


Example of a Dose Escalation Protocol

2.0833%9

1.5733%8

1.1833%7

0.8933%6

0.6733%5

0.5050%4

0.3367%3

0.20100%2

0.10Starting dose1

Dose (mg/m 2)

Doseincrement

Dose level (cohort)

Dose Limiting Toxicities

321

654 987

121110

151413 …1716

191817

x3x2x1 Patient Cohort (patient nr. x1, x2, x3, …)

RD

MTD


Ethical Issues in Phase I in Oncology

� Maximising patients exposure to potentiallytherapeutic doses

� Minimising patients treated at ineffectivedoses

� Minimising patients treated at toxic doses� Historically low probability of response in

phase I trials� Unknown toxicity and benefit of new agent� Informed Consent


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 clinicalcourse of these end-stage patients isunpredictable

� No more than 2-3 investigator sites per trial� Concurrent trials


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

In phase I trials, patients have to be selected as soon as possible so that investigators can be prepared to treat a new patient

…a similar approach is used in emergency unitunit to ration limited medical resources and in Phase I studies in oncology…..


� 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)

The Web-Triage Application : User Requirements


The Web-Triage Application : Take a tour (1)

� Study Information: The Dose Levels



� Investigator Login: List of enabled open Trials



� 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



� Data-entry functionality

Prior ChemotherapyDictionary

Online DataValidation



� 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


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)


The Web-Triage Application : System Design

� ASP.NETunified software development model that includes theservices 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


The Web-Triage Application : N-Tier Concept

� N-Tier SystemA Client-Server Architecture, where each module is developed separately� Presentation Layer

� Workflow Layer� Business Rule Layer� Data Layer

� Data Store


Triage Network Architecture


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


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


Questions

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Web-Triage An Application for patient registration in phase I dose escalation studies