1. FDA Case Studies Pediatric Oncology Subcommittee March 4, 2003

2. Case 1 Dosing and Proof of Concept Submitted Pediatric and Adult Disease are the Same

3. Case 1 Types of studies: Two Phase I dose- finding studies in children with hematologic malignancies –from supplemental (S) NDA and from original (O) NDA Size of data set: –for efficacy/safety: 39 [31(S) + 8(O) ] –for PK: 33 [27(S) + 6 (O) ]

4. Type of Information Submitted Safety PK PK-PD Proof of concept Case 1

5. Results Safety: similar to adults; MTD not reached PK: parameters similar to adult values PK-PD relationship: no correlation Proof of concept –remissions induced in the same malignancy in pediatrics as in adults, although in a limited number of pediatric patients –remissions occurred in approximately the same proportion as in adults Case 1

6. Comparison between Children & Adults Same side effects as adults but lower grade Lack of PK-PD relationship –exposure (area under the concentration-time curve) and Day 28 white blood cell count Lack of clear dose-proportionality –starting dose chosen to provide similar exposure to adult doses –lack of relationship between dose and exposure overlap between AUCs for different doses Case 1

8. Issues & Conclusions Efficacy and extrapolation –first time extrapolation has been used for approval Challenge in finding a pediatric dosage Case 1

9. Case 2 Dosing Submitted Pediatric and Adult Disease are the Same

10. Case 2 Type of study: Single Phase II pharmacokinetic study in malignant and non-malignant life-threatening conditions Size of data set: –24 patients –ages 5 months to 16 years

11. Type of Information Submitted Safety –Clinical Adverse Events and laboratory abnormalities PK/PD –Multiple sampling in each patient with initial dosing based on body weight and subsequent adjustment based on PK/PD information Case 2

12. Results Safety: generally similar to adults PK/PD: Suggested pediatric dosing based on population PK – Two-step dosing based on body weight – 12 kg Case 2

13. Comparison between Children & Adults Pediatric data indicate need for higher dosage in smaller children (by weight) Case 2

14. Issues & Conclusions Limited safety information and dosing recommendations added to Special Populations - Pediatric section Case 2

15. Case 3 Dosing and Proof of Concept Submitted Preliminary Activity in a Disease found only in Pediatric Patients with the Approved Indications for Diseases found only in Adults

16. Case 3 Types of studies: –Phase I dose-finding study in children with solid tumors and hematologic malignancies –Phase II open label single arm study for response rate in children with refractory or relapsed solid tumors Size of data set: –Phase I: 48 (30 solid tumor + 18 leukemia), ages 1-15 years –Phase II: 108, ages <1 to 15 years

17. Type of Information Submitted Safety PK PK-PD Proof of concept Case 3

18. Results Safety: similar to adults; MTD not reached for leukemia, MTD for solid tumors higher than approved adult dose PK: parameters similar to adult values PK-PD relationship: no relationship between exposure and nadir white blood cell count due to maximal suppression at lowest dose Proof of concept –Consistent tumor responses seen in one class of solid tumors Case 3

19. Comparison between Children & Adults Higher doses tolerated in children Responses seen in some pediatric malignancies that are not found in adults Case 3

20. Issues & Conclusions The disease where activity was demonstrated in children is a pediatric disease that is rarely found in adults The approved indications are diseases found almost exclusively in adults Extrapolation of efficacy cannot be used Product labeling did not include the submitted pediatric data Product currently not approved for use in children Case 3

21. Case 4 Dosing and Response Submitted Lack of Activity

22. Case 4 Types of studies: Phase I dose-finding trial in solid tumors and hematologic malignancies Size of data set: –Solid tumors: 25 evaluable patients –Hematologic malignancies: 4 evaluable patients –Additional 17 patients treated; inevaluable –Ages 2-17

23. Case 4 Types of studies: Phase II stratified open- label study in solid tumors –Primary endpoint: Response rate Size of data set: –Designed to enroll at least 14 patients per subset –CNS tumors 21 patients –Soft tissue sarcoma 21 patients –Neuroblastoma 4 patients –Age < 21 (2 older ineligible pts excluded)

24. Type of Information Submitted Safety –Collected only AEs attributed to drug by PI –Post-marketing pediatric safety reports PK/PD –Abbreviated study reports (no primary data) Efficacy –Abbreviated clinical trial study reports Case 4

25. Results Safety: similar to adults PK: MTD, recommended Phase II dose identified PK/PD: Recommended Phase II dose too toxic; dose lowered Efficacy –RR 0 in CNS, neuroblastoma strata –Neuroblastoma arm closed early –1 CR and 1 PR in soft tissue sarcoma Case 4

26. Comparison between Children & Adults Toxicity profile similar in adults and children Recommended dose (after testing in Phase II) similar to that approved in adults Case 4

27. Issues & Conclusions Brief description of study included in the label Negative efficacy data included in the label No PK or dosing data included Case 4

28. Case 5 Dosing and Efficacy Submitted Spectrum of Diseases Including Approved Adult Indication

29. Case 5 Types of studies: –two Phase I studies included pharmacokinetics and dose determination data on patients with relapsed or refractory CNS & solid tumors –one single-arm Phase II study to evaluate efficacy in relapsed or refractory CNS & solid tumors Size of data set: –Phase I studies: 82 patients, ages 3 to 17; 19 patients had pharmacokinetic data –Phase II study: 122 patients, ages 3 to 17

30. Type of Information Submitted Safety PK/PD –multiple sampling in each patient with initial dosing based on body surface area Efficacy Case 5

31. Results Safety: similar to adults PK/PD –the pharmacokinetics of the drug are similar independent of previous treatment –no relationship between age and clearance Efficacy: Of 122 patients, 1 CR and 5 PR Case 5

32. Comparison between Children & Adults Similar clearance and volume of distribution values Response to therapy is different (worse in children) Responses occurred in a different histological subtype from the adult tumor Case 5

33. Issues & Conclusions This drug was approved for an adult disease that also exists in children, BUT did not show efficacy in that disease Responses were seen in a disease that occurs primarily in children and for which there is available effective therapy What information, if any, should be included in the labeling? Case 5

34. Case Summaries