Timing of the Initiation of Pediatric Clinical Oncology Studies

1. Timing of the Initiation of Pediatric Clinical Oncology Studies

2. Historical Timing for Initiation of Pediatric Phase I Clinical Trials • Following assessment of initial safety data and reasonable evidence of potential benefit After the completion and publication of adult phase I and/or phase II studies

3. Historical Timing for Initiation of Pediatric Phase I Clinical Trials • Following the completion of adult phase III trials • Following a successful NDA • At the first signs of “biologic activity” in adults • Initially in the pediatric population - Monoclonal antibodies for neuroblastoma - Cytotoxics for intrathecal administration

4. 75 Time (months) 50 25 CI-980 Flavopiridol Bryostatin Arsenic STI571 ET-743 O6BG Docetaxel Topotecan Temozolomide Irinotecan Gemcitabine ZD1839 Initiation of Phase I Pediatric Trial after Publication of Adult Phase I Trial Results Mean - 25 mo Median - 15 mo

5. Publication Phase I Trial Results Japan Publication Phase I Trial Results US Drug Approved for Adults 8/91 9/93 6/96 Pediatric Phase I Trials Initiated Drug Development Time Line Example

6. 1996 1998 2003 2008 Pediatric Drug Development Irinotecan Combination Studies Phase I Studies Phase III Studies Phase II Studies Adult Clinical Studies 3 - 5 yr 5 yr 2 yr Drug approved for adults 12 yr 18+ yr

7. Topotecan:Phase I to Phase III Study PhaseDate Initiated Phase I Study Sept, 1992 Phase I Combination study Oct, 1993 Phase II Study May, 1994 Phase II Combination study Oct, 1996 Phase III Study July, 1999 Phase III study completes accrual July, 2004

8. What is the optimal timing for the initiation of pediatric phase I clinical trials of new anticancer agents?

9. Considerations in the Initiation of Pediatric Phase I Clinical Trials • Type of agent and mechanism of action - novel agent vs. analog - non-specific cytotoxic vs. specific target • Underlying disease being treated - brainstem glioma vs. Hodgkin’s • Safety profile of the agent • Availability of pediatric formulations

10. Considerations in the Initiation of Pediatric Phase I Clinical Trials • Type of agent and mechanism of action - novel agent vs. analog - non-specific cytotoxic vs. specific target • Underlying disease being treated - brainstem glioma vs. Hodgkin’s • Safety profile of the agent • Availability of pediatric formulations

11. Optimal Timing for Initiation of Novel Agents • Early initiation is critical - Improve outcome for children with incurable CNS or other high-risk pediatric tumors - Develop alternative treatment strategies that may eliminate (or postpone) the need for XRT in children with developing nervous systems

12. What is early initiation for novel agents? • Evidence of biologic activity in adult phase I trials • Determination of the MTD and/or optimal biologic dose in adult trials • Upon the completion of preclinical studies (in vitro and in vivo) if target is primarily pediatric

13. Considerations for InitiatingTrials for New Analogs • Equivalent or superior activity in preclinical studies? • Advantages to the toxicity profile? • Advantages with regard to potential for drug interactions? • Advantages with regard to the formulation?

14. Conclusions • Timing for initiation of clinical trials of new agents is highly variable and in many instances has not been optimal • Ongoing communication between the pediatric cooperative groups, industry, the FDA, and NCI is required to ensure the earliest possible access to promising new agents with novel mechanisms of action

15. Conclusions • Pediatric studies for novel agents should be initiated as soon as there is evidence of biologic activity and an acceptable safety profile in early (phase I) adult clinical trials • Early access requires ongoing scrutiny and constant re-evaluation to ensure optimal prioritization, safety and potential for benefit for children with recurrent or refractory cancer