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 ] entitled, “DEVELOPMENT OF NOVEL AGENTS DIRECTED AGAINST CHILDHOOD CANCER MOLECULAR TARGETS”, is now available at r.htm r.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 Flexible System to Advance Innovative Research 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