0

20

40

60

80

100

Childhood Cancer Survival TrendsChildhood Cancer Survival Trends

5 Yr 5 Yr Survival Survival

[%][%]

WilmsWilmsALLALL

NBNB

AMLAML

1960

-63

1960

-63

1970

-73

1970

-73

1974

-76

1974

-76

1977

-79

1977

-79

1980

-82

1980

-82

1983

-85

1983

-85

1986

-88

1986

-88

1989

-91

1989

-91

1991

-97

1991

-97

0.20.2

0.40.4

0.60.6

0.80.8

11

11 22 33 44 55 66 77 88 99 1010Years from Diagnosis Years from Diagnosis

Prob

abili

ty o

f Ove

rall

Surv

ival

Pr

obab

ility

of O

vera

ll Su

rviv

al

1978-1985 N=507 1978-1985 N=507

1986-1995 N=675 1986-1995 N=675

High-Risk Neuroblastoma 1978 - 1995High-Risk Neuroblastoma 1978 - 1995

0

100

200

300

400

500

600

700

Mild Moderate Severe LifeThreatening

Fatal

Rhabdomyosarcoma TreatmentRhabdomyosarcoma TreatmentWorst Degree of Any Toxicity (n=1062)Worst Degree of Any Toxicity (n=1062)

No. of No. of PatientsPatients

Adapted from Crist Adapted from Crist et alet al, J Clin Oncol June 2001, J Clin Oncol June 2001

Doxorubicin CardiotoxicityDoxorubicin Cardiotoxicity

0

2

4

6

8

10

0 5 10 15 200

10

20

30

40

50

0 100 200 300 400 500 600 700 800

Cumulative anthracycline Cumulative anthracycline dose [mg/mdose [mg/m22]]

Time from start of Time from start of anthracyline therapy [yr]anthracyline therapy [yr]

Risk of Risk of CHF [%]CHF [%]

Risk of Risk of CHF [%]CHF [%]

Kremer et al JCO 2001

Pediatric Phase 1 Trial of Gleevec Pediatric Phase 1 Trial of Gleevec

• Phase 1 trialPhase 1 trial– Recommended doseRecommended dose– PKPK– ResponseResponse

• Potential targetsPotential targets– bcr-ablbcr-abl– PDGF-RPDGF-R– c-kitc-kit

– Ph+ LeukemiasPh+ Leukemias– OsteosarcomaOsteosarcoma– Synovial sarcomaSynovial sarcoma– Ewing’s sarcomaEwing’s sarcoma– Desmoplastic sarcomaDesmoplastic sarcoma– AMLAML– GISTGIST

““Criteria” for Pediatric Phase 1 StudyCriteria” for Pediatric Phase 1 Study

• Availability of new agent for pediatric Availability of new agent for pediatric studiesstudies

• Relevance of drug target in pediatric Relevance of drug target in pediatric malignanciesmalignancies

• Activity in pre-clinical model systemsActivity in pre-clinical model systems• Experience in adult clinical trialsExperience in adult clinical trials

Initiating Pediatric Phase 1 TrialsInitiating Pediatric Phase 1 Trials

Phase 1Phase 1 Phase 2Phase 2 Phase 3Phase 3 Phase 4Phase 4

TimeTime

Adult Adult Trials:Trials:

Pediatric Pediatric

Trials:Trials:

Phase 1Phase 1

Phase 1Phase 1Phase 1Phase 1

Phase 1Phase 1Phase 1Phase 1Phase 1Phase 1

PK, PD, PGPK, PD, PG

Limitations of Current ApproachLimitations of Current Approach• Historically, patient numbers were Historically, patient numbers were

rate limiting step for phase 1 trials. rate limiting step for phase 1 trials. • Currently, insufficient number of new Currently, insufficient number of new

agents are in pediatric phase 1trialsagents are in pediatric phase 1trials• Phase 1 trials initiated following drug Phase 1 trials initiated following drug

approval for adults results in use in approval for adults results in use in children without any pharmacologic, children without any pharmacologic, safety or efficacy datasafety or efficacy data

COG Phase 1 ConsortiumCOG Phase 1 Consortium

Current COG Phase 1 TrialsCurrent COG Phase 1 Trials• Solid Tumors

– PS-341– ZD1839– Flavopiridol

• Neuroblastoma– Hu14.18-IL2

• Select CNS Tumors– Gadolinium-Texaphyrin– Temozolomide/CCNU – Cereport/Carboplatin

• Hematologic– Arsenic Trioxide– R115777– IDEC-Y2B8

Dose levels fill in < 15 minutesDose levels fill in < 15 minutes

Necessitated development of Necessitated development of waiting listswaiting lists

RecommendationsRecommendations

• Improve early access to new agents Improve early access to new agents for pre-clinical studiesfor pre-clinical studies

• Initiate phase 1 trials of select agents Initiate phase 1 trials of select agents whenwhen– Initial cohort(s) of adult patients in Initial cohort(s) of adult patients in

phase 1 are evaluablephase 1 are evaluable– Evidence of biologic activity observed Evidence of biologic activity observed

Drug X Target Defined?

Testing @MTD

Tumor A Tumor B Tumor C Tumor D Tumor E

Yes

No

Active in Model(s)?Full Dose

Response/PK

Other Tumor Models Available?

Orthotopic Models

Additional Transgenic

Models

Results to Steering Committee

No

Yes

Yes

Yes

No

Transgenic Model?

Transgenic Model

Yes

No

Testing @MTD

Drug X Target Defined?

Testing @MTD

Tumor A Tumor B Tumor C Tumor D Tumor E

Yes

No

Active in Model(s)?Full Dose

Response/PK

Other Tumor Models Available?

Orthotopic Models

Additional Transgenic

Models

Results to Steering Committee

No

Yes

Yes

Yes

No

Transgenic Model?

Transgenic Model

Yes

No

Testing @MTD