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

1
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

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 Childrens 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
Challenges for Pediatric Oncology Drug
Development-Prioritization anti-VEGF agents

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

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

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-investigato
  r 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