# Presentation: 258120

## Childhood Cancer Survival Trends

**Childhood Cancer Survival Trends**

**5 Yr Survival [%]**

**1960-63**

**1970-73**

**1974-76**

**1977-79**

**1980-82**

**1983-85**

**1986-88**

**1989-91**

**1991-97**

## High-Risk Neuroblastoma 1978 - 1995

**0.2**

**0.4**

**0.6**

**0.8**

**1**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

**Years from Diagnosis                                 **

**Probability of Overall Survival                           **

**1978-1985  N=507 **

**High-Risk Neuroblastoma 1978 - 1995**

## Rhabdomyosarcoma Treatment

**Rhabdomyosarcoma Treatment**

**Notes:**
This graph shows the number of patients from a recent front line treatment protocol for rhabdomyosarcoma that experienced one of these toxicity grades as their worst toxicity on the trial.  A total of 1062 patients were treated on one of seven regimens.
Over 80% of patients had at least one toxicity that was severe, life-threatening or fatal.
22 of the 32 deaths were from sepsis during neutropenia. Other drug-related causes of death include ADRS (1), cardiac toxicity (2), radiation toxicity (3), metabolic complications (2), CNS toxicity (1), and hemorrhage during thrombocytopenia (1).
This is standard therapy for childhood cancer cancer.

## Doxorubicin Cardiotoxicity

**Cumulative anthracycline dose [mg/m****2****]**

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

**Risk of CHF [%]**

**Risk of CHF [%]**

**Kremer *****et al***** JCO 2001**

## 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**
** ****Ewing’s sarcoma**
** ****Desmoplastic sarcoma**
** ****AML**
** ****GIST**

**Notes:**
An improved understanding of pediatric tumor biology will eventually form the cornerstone of how we prioritize agents for pediatric development. Our experience with STI-571 serves as a paradigm for the direction we will move towards over the upcoming grant cycle. We have completed a phase 1 trial of STI in children with Ph+ leukemia. 20 patients over 4 dose levels were studied, and pharmacokinetic data was available from all patients entered. Responses were observed in a number of patients.
We know, however, that STI-571 targets not only the bcr-abl kinase, but also the PDGF-R and c-kit pathways. Based on a knowledge of pediatric tumors known to overexpress these targets, we are pursuing a phase 2 trial of this agent in osteosarcoma...

Morphologic and cytogenetic response

## “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**

## Initiating Pediatric Phase 1 Trials

- Phase 1

- Phase 2

- Phase 3

- Phase 4

- Time

- Adult
- Trials:

- Pediatric
- Trials:

- Phase 1

- Phase 1

- Phase 1

- Phase 1

## 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**

## COG Phase 1 Consortium

## 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 < 15 minutes
- Necessitated development of waiting lists

## 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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