initiating phase 1 clinical trials in pediatric oncology national
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Initiating phase 1 clinical trials in pediatric oncology
National Cancer Institute Perspective
Barry Anderson, MD, PhDPediatric Section
Cancer Therapy Evaluation ProgramNCI
FDA 17 Oct 02
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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”
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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
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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
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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
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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
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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
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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
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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