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

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

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

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  1. Initiating phase 1 clinical trials in pediatric oncologyNational Cancer Institute Perspective Barry Anderson, MD, PhD Pediatric Section Cancer Therapy Evaluation Program NCI FDA 17 Oct 02

  2. Barriers/Challenges to theStudy of New Agents inPediatric 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

  3. NCI-Supported Infrastructurefor 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

  4. NCI-Supported Infrastructurefor 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

  5. 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

  6. 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

  7. SU5416 rhuMB-VEGF Neovastat IM862 PTK787A Aplidine Angiozyme ZD6474 SU6668 SMART Anti-VEGF IMC-1C11 CP-564,959 CGP-41251 Challenges for Pediatric Oncology Drug Development-Prioritization: anti-VEGF agents

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. Appropriate Timing of Initiation of Pediatric StudyEndpoint 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

  14. Appropriate Timing of Initiation of Pediatric StudyTargeted 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

  15. 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

  16. 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

  17. 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”

  18. 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

  19. 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

  20. Barriers/Challenges to theStudy of New Agents inPediatric 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

  21. Barriers/Challenges to theStudy 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

  22. 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.nih.gov/grants/funding/sbir.htm • Closing date for receipt of proposals is November 8, 2002

  23. 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

  24. 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

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