Childhood Cancer Survival Trends

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Childhood Cancer Survival Trends
5 Yr Survival
1974-76
1977-79
1980-82
1960-63
1970-73
1983-85
1986-88
1989-91
1991-97
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High-Risk Neuroblastoma 1978 - 1995
1
0.8
0.6
Probability of Overall Survival

0.4
0.2
1978-1985 N507
1
2
3
4
5
6
7
8
9
10
Years from Diagnosis

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Rhabdomyosarcoma Treatment
4
Doxorubicin Cardiotoxicity
Risk of CHF
Risk of CHF
Cumulative anthracycline dose mg/m2
Time from start of anthracyline therapy yr
Kremer et al JCO 2001
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Pediatric Phase 1 Trial of Gleevec

• Phase 1 trial
• Recommended dose
• PK
• Response

• Potential targets
• bcr-abl
• PDGF-R
• c-kit

• Ph Leukemias
• Osteosarcoma
• Synovial sarcoma
• Ewings sarcoma
• Desmoplastic sarcoma
• AML
• GIST

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Criteria for Pediatric Phase 1 Study

• Availability of new agent for pediatric studies
• Relevance of drug target in pediatric
  malignancies
• Activity in pre-clinical model systems
• Experience in adult clinical trials

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Initiating Pediatric Phase 1 Trials
Time
Adult Trials
Phase 1
Phase 2
Phase 3
Phase 4
Phase 1
Pediatric Trials
Phase 1
Phase 1
Phase 1
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Limitations of Current Approach

• Historically, patient numbers were rate limiting
  step for phase 1 trials.
• Currently, insufficient number of new agents are
  in pediatric phase 1trials
• Phase 1 trials initiated following drug approval
  for adults results in use in children without any
  pharmacologic, safety or efficacy data

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COG Phase 1 Consortium
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Current 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 lt 15 minutes Necessitated
development of waiting lists
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Recommendations

• Improve early access to new agents for
  pre-clinical studies
• Initiate phase 1 trials of select agents when
• Initial cohort(s) of adult patients in phase 1
  are evaluable
• Evidence of biologic activity observed

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