childhood cancer survival trends
DESCRIPTION
Wilms. ALL. NB. AML. Childhood Cancer Survival Trends. 5 Yr Survival [%]. 1980-82. 1974-76. 1977-79. 1960-63. 1970-73. 1983-85. 1986-88. 1989-91. 1991-97. 1986-1995 N=675 . High-Risk Neuroblastoma 1978 - 1995. 1. 0.8. 0.6. - PowerPoint PPT PresentationTRANSCRIPT
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