# Presentation: 856140

## How Are Potential New Therapies for Childhood Cancer Identified? Role of Pediatric Preclinical Testing18 July, 2002

- Malcolm A. Smith, MD, PhD
- Head, Pediatric Section, CTEP, NCI

## The Need for New Agents for the Treatment of Children with Cancer

- There are many children for whom current therapy is not adequate
- Inadequate because of insufficient efficacy
- Inadequate because of excessive toxicity

## The Need to Prioritize New Agents for Children with Cancer

- There are dozens of new agents and hundreds of combinations of agents potentially applicable to the treatment of childhood cancers.

## NCI CTEP Development Pipeline

- *as of January 2000

## The Need to Prioritize New Agents for Children with Cancer

- There are dozens of new agents and hundreds of combinations of agents potentially applicable to the treatment of childhood cancers
- Only a small subset of these agents can be evaluated in phase 1 studies in children and even fewer in phase 2 and 3 studies

## Pediatric Preclinical Testing Program--Hypotheses

**The rate of discovery of more effective therapies for children with cancer will be increased by selecting “active” agents for phase 1 and phase 2 evaluation**
**A systematic approach to pediatric preclinical testing will increase the percentage of “active” agents studied in clinical trials in children with cancer**

## Pediatric Preclinical Testing-The Potential for Prediction

- Strong correlation between the activity of agents against rhabdomyosarcoma xenografts and clinical activity of the same agents
- Melphalan first identified as an active agent against rhabdomyosarcoma in xenograft models
- Topoisomerase 1 inhibitors identified as active agents against rhabdomyosarcoma & neuroblastoma xenograft models
- Neuroblastoma cell lines established at different points of therapy acquire a sustained drug-resistant phenotype that mirrors the clinical resistance pattern of patients

## What about Adult Studies Showing Lack of Predictive Value for Preclinical Models

- Johnson, J. I., et al. Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br.J Cancer, *84*: 1424-1431, 2001
- Demonstrated general lack of tumor-specific predictive power for preclinical models
- Predictive utility of adult preclinical models is limited in part by their inability to consider  differences in  pharmacokinetics between humans and mice

## Of Mice and Men—The Importance of Preclinical Pharmacology

- Mice may tolerate much higher systemic exposures of some drugs compared to humans
- DMP0840, 15-20X higher
- carzelesin, 80X higher
- sulofenur, 8X higher
- Mice may tolerate lower systemic exposures of other drugs
- Etoposide
- Pediatric preclinical testing program must evaluate preclinical pharmacology of tested agents in order to account for differences in human & mice PK.

## Slide 10

## Slide 11

## Issues for Pre-clinical Program—Access to Agents through Pharmaceutical Sponsors

- Issues to address with pharmaceutical sponsors:
- Intellectual property
- Data sharing
- Other factors affecting timing of access
- CTEP sponsored meeting May 29 with pharmaceutical and academic lawyers and with NIH technology transfer staff
- Made significant progress towards development of model MTA that would facilitate access of pediatric preclinical program to new agents

## Issues for Pre-clinical Program—Identifying Molecular Targets & Pathways

- Substantial proportion of new agents under development have defined molecular targets
- Essential to determine expression of these targets in pediatric tumors.
- NCI is collaborating with COG Phase 1/Pilot Consortium to develop *tissue arrays* and *protein arrays* and to develop *gene expression profiles* for pediatric cell lines and xenografts.

## From Targets to Pediatric Therapies

**Identified **
**Target**

**NCI**

**COG Phase I **
**Consortia**

**Biology**
**Studies of **
**Signaling**
**Pathways**

**Pre-Clinical **
**Drug Testing **
**Consortium**

**Pharmaceutical**
**Companies**

**COG Phase III**

**NCI RAID**

**NANT**

**PBTC**

## Identifying Potential New Therapies—Closing Comments

- Predictive preclinical models of childhood cancers may increase the rate of discovery of more effective therapies for children with cancer
- A systematic application of these preclinical models is needed to validate their utility
- An assessment of the feasibility of establishing a pediatric preclinical testing program is ongoing at NCI