# Presentation: 896746

## Initiating phase 1 clinical trials in pediatric oncology National Cancer Institute Perspective

- Barry Anderson, MD, PhD
- Pediatric Section
- Cancer Therapy Evaluation Program
- NCI
- FDA 17 Oct 02

## Barriers/Challenges to theStudy of New Agents inPediatric Oncology

**Infrastructure**
- Prioritization of new agents
- Access to new agents
- Appropriate timing of phase 1 study
- Pediatric specific challenges and innovative approaches to targeted therapy drug development

## NCI-Supported Infrastructurefor Phase 1 Trials in Children with Cancer

- COG Phase 1/Pilot Consortia:
*21 institutions*
*Currently 12 phase 1 trials ** *
- Pediatric Brain Tumor Consortium:
*To evaluate new treatment approaches (new drugs, neurosurgical approaches, and radiation therapy strategies)*
*10 institutions and an Operations Center*
*Currently 5 phase 1 trials*

## NCI-Supported Infrastructurefor Phase 1 Trials in Children with Cancer

- Clinical studies via NCI grant funds:
- St. Jude Children’s Research Hospital
- New Approaches to Neuroblastoma Treatment* (NANT)*
*To study new agents/therapies in high-risk neuroblastoma*
*12 institutions*
*Currently 4 phase 1 trials*
- NCI Pediatric Oncology Branch

## Barriers/Challenges to the Study of New Agents in Pediatric Oncology

- Infrastructure
**Prioritization of new agents**
- Access to new agents
- Appropriate timing of phase 1 study
- Pediatric specific challenges and innovative approaches to targeted therapy drug development

## Challenges for Pediatric Oncology Drug Development-Prioritization

*Limited numbers of patients*
*Many agents will never be studied*
*Future progress in identifying better treatments depends upon picking the “right” agents*

## Challenges for Pediatric Oncology Drug Development-Prioritization: anti-VEGF agents

- SU5416
- rhuMB-VEGF
- Neovastat
- IM862
- PTK787A
- Aplidine
- Angiozyme

- ZD6474
- SU6668
- SMART Anti-VEGF
- IMC-1C11
- CP-564,959
- CGP-41251

## NCI-COG Effort to Establish Pediatric Preclinical Testing Program

- Goal to help prioritize among available new agents
- Evidence from rhabdomyosarcoma that preclinical models can predict agent activity in clinical trial
- Efforts underway to establish coordinated structure, testing procedures, sponsor-investigator legal agreements and funding for a nationwide testing program

## Barriers/Challenges to the Study of New Agents in Pediatric Oncology

- Infrastructure
- Prioritization of new agents
**Access to new agents**
- Appropriate timing of phase 1 study
- Pediatric specific challenges and innovative approaches to targeted therapy drug development

## Challenges for Pediatric Oncology Drug Development-Access to Agents (Sponsor)

- Financial disincentives to sponsor
- Pediatrics outside drug development plan
- Limited drug supply restricted to “high priority” studies
- Perceived risk of excessive legal liability from toxicity in children
- Perceived need to demonstrate activity in adult patients prior to initiating pediatric studies
- Need for correlative study information in targeted or biologic agent development

## Challenges for Pediatric Oncology Drug Development-Access to Agents (Patient)

*How to achieve access to new treatment approaches on a broad scale?*
*Phase 1 trials enroll limited numbers of patients *
- waiting lists, lotteries, frequent study closures
*Access more appropriate through group-wide phase 2 trials and pilot studies*
*Special exception programs can provide access in specific situations*

## Barriers/Challenges to the Study of New Agents in Pediatric Oncology

- Infrastructure
- Prioritization of new agents
- Access to new agents
**Appropriate timing of phase 1 study**
- Pediatric specific challenges and innovative approaches to targeted therapy drug development

## Appropriate Timing of Initiation of Pediatric StudyEndpoint MTD

*Upon determination of the adult recommended phase II dose-  *
**Pragmatic reasons**:
- limited numbers of children eligible for pediatric phase I trials
- avoid agents failing early phase adult trials
**Ethical reasons**:
- optimizing potential benefit while minimizing the risk of significant toxicities

## Appropriate Timing of Initiation of Pediatric StudyTargeted Agent

*Upon ****detection of targeted biologic activity**** in adult phase I trials**-  *
**Pragmatic reasons**:
- limited numbers of children eligible for pediatric phase I trials
- avoid agents failing early phase adult trials
**avoid invasive correlative studies**** **
**Ethical reasons**:
- optimizing potential benefit while minimizing the risk of significant toxicities
**regulatory limits on invasive research procedures of greater than minimal risk  without benefit**

## Challenges for Pediatric Oncology Drug Development-Pediatric Realities

*Limited numbers of patients*
*Many agents will never be studied*
***Regulatory and ethical differences between adult and pediatric phase 1 study conduct****** ***

## Barriers/Challenges to the Study of New Agents in Pediatric Oncology

- Infrastructure
- Prioritization of new agents
- Access to new agents
- Appropriate timing of phase 1 study
**Pediatric specific challenges and innovative approaches to targeted therapy drug development**

## Challenges for Pediatric Oncology Drug Development-Pediatric Realities

- Children may receive an experimental treatment posing potentially greater than minimal risk _if_ there is the potential for direct benefit
- Children may only participate in research with no prospect of direct benefit to the child (invasive tissue collection) “provided the risk represents a minor increase over minimal risk”

## Challenges for Pediatric Oncology Drug Development-Pediatric Realities

- Potential benefit associated with the experimental agent does not connote benefit to the experimentally related tissue collection
- Risk/benefit analysis considered separately for the two research components

## Adapting Targeted Agent Development to Pediatric Realities

- Developing pediatric alternatives to invasive biopsy:
- Minimally invasive surrogate tissue sampling
- Buccal mucosa, peripheral blood cells, bone marrow cells
- Tumor cell isolation from accessible tissues
- Peripheral blood or bone marrow
- Non-invasive imaging modalities
- Correlation of PK in children to drug levels associated with anti-tumor activity and/or target modulation in preclinical models and adults

## Barriers/Challenges to theStudy of New Agents inPediatric Oncology

- Infrastructure
- Prioritization of new agents
- Access to new agents
- Appropriate timing of phase 1 study
**Pediatric specific challenges and innovative approaches to targeted therapy drug development**

## Barriers/Challenges to theStudy of New Agents in Pediatric Oncology

- Pharmaceutical sponsors lack incentive to develop pediatric-specific targeted agents:
- EWS-FLI
- PAX-FKHR
- Can NCI grant programs stimulate development of agents targeted at pediatric tumors?
- NCI RAID program

## Childhood Cancer Molecular Targets Solicitation

- Solicitation of the Public Health Service for Small Business Innovation Research (SBIR) contract proposals [PHS 2003-1] entitled, **“DEVELOPMENT OF NOVEL AGENTS DIRECTED AGAINST CHILDHOOD CANCER MOLECULAR TARGETS”**, is now available at _[http://grants1.](http://grants1.nih.gov/grants/funding/sbir.htm)__[nih](http://grants1.nih.gov/grants/funding/sbir.htm)__[.](http://grants1.nih.gov/grants/funding/sbir.htm)__[gov](http://grants1.nih.gov/grants/funding/sbir.htm)__[/grants/funding/](http://grants1.nih.gov/grants/funding/sbir.htm)__[sbir](http://grants1.nih.gov/grants/funding/sbir.htm)__[.](http://grants1.nih.gov/grants/funding/sbir.htm)__[htm](http://grants1.nih.gov/grants/funding/sbir.htm)_
- Closing date for receipt of proposals is November 8, 2002

## Childhood Cancer Molecular Targets Solicitation

- Alternative SBIR funding mechanism relevant to childhood cancer molecular targets is the _**Fl**_**exible System to **_**A**_**dvance **_**I**_**nnovative **_**R**_**esearch for Cancer Drug Discovery by Small Businesses (FLAIR)**
**FLAIR** allows both Small Business Innovation Research (SBIR) applications and Small Business Technology Transfer (STTR) applications.
- For STTR applications the PI may be at an academic institution, and a university or other non-profit research institution must establish a collaborative relationship with a small business concern.
- Deadline is is November 12, 2002

## Summary

*Progress depends upon*
*A well-functioning infrastructure for early phase studies in children*
*Wise prioritization among available agents*
*Access to new agents from pharmaceutical sponsors*
*Innovative adaptations of clinical research approaches to pediatric realities*
*Maintaining public confidence that pediatric cancer drug development is conducted with the best interest of children in mind*