1. 1 NDA 21-877 Nelarabine

2. 2 Proposed Indication Nelarabine is indicated for the treatment of patients with T-cell acute lymphoblastic leukemia (ALL) and T-cell lymphoblastic lymphoma (LBL) whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens.

3. 3 Submitted Phase 2 Studies StudyTotal Pts Pts receiving proposed dose COG14970 CALGB39

4. 4 Nelarabine Dose and Schedule Pediatric: Nelarabine 650 mg/m2/day administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days. Adult: Nelarabine 1,500 mg/m2 administered intravenously over 2 hours on days 1, 3 and 5 repeated every 21 days.

5. 5 Response Definitions CR: - no circulating blasts or extramedullary disease; - an M1 bone marrow ( 1.5 × 10 3 /mcL - platelets >100 × 10 3 /mcL and Hgb >10 or 11 g/dL. CR*: - Patients who have met all criteria for CR except for recovery of peripheral blood counts or marrow cellularity. Independent review of marrow aspirates and/or biopsies for responders whose slides were available

6. 6 Study Objectives Primary Objective - CR plus CR* rate Secondary Objectives - Remission duration - Overall survival ( OS) - Safety

7. 7 Pediatric Study

8. 8 Inclusion criteria Age < 21 Refractory or recurrent T-ALL or T-LBL First or subsequent relapse Performance status >50 Adequate organ status Patients with >grade 2 neurotoxicity were excluded.

9. 9 Study participants 78 Sites: United States and Canada 109 Investigators Independent pathology review

10. 10 COG Study Groups Group Description N 2 T-ALL or T-LBL in second or later relapse (>25% marrow blasts, with or without concomitant extramedullary relapse – other than CNS) 39 1 T-ALL or T-LBL in first relapse (>25% marrow blasts, with or without concomitant extramedullary relapse – other than CNS) 31

11. 11 AML - Demographics and KPS VariableGroup 2Group 1 Age [mean (range)]11.5 2 mo-21 yrs 11.6 2-21 yrs Sex F/M36%/64%13%/87% Ethnicity White Black Hispanic Other 64% 8% 18% 10% 61% 19% 16% 3% KPS 100 90-80 70-60 50-40 21% 39% 21% 13% 29% 58% 6%

12. 12 COG - Disease Characteristics VariableGroup 2Group 1 Diagnosis ALL LBL 79% 21% 90% 10% Disease Sites Marrow CNS Extramedullary 92% 3% 44% 100% 3% 32%

13. 13 Group 2 Prior Therapies Prior inductions 2 3 4 5 Unknown N=39 69% 18% 5% 3%

14. 14 COG Best Response ResponseGroup 2 N=39 Group 1 N=31 CR 5 (13%) 13 (42%) CR+CR*9 (23%)15 (48%)

15. 15 Response by Disease Type Group 2Group 1 ALL N=31 LBL N=8 ALL N=28 LBL N=3 CR (%)3 (10)2 (25)13 (46)0 CR+CR* (%) 7 (23)2 (25)15 (54)0

16. 16 T-ALL/LBL - Patients Transplanted GroupNo. of patients % 24 of 944 110 of 1567

17. 17 Non-Transplant Remission duration (weeks) Group 2Group 1 42.1 (IT+Sys @ week 14) 9.3 6.1 3.6 3.3 33.1 (Sys @ week 8) 9.1 (IT) 6.3 2.3 1.4+

18. 18 Adult Study

19. 19 CALGB - Demographics and KPS VariableGroup 2 N=28 Group 1 N=11 Age [median (range)] 31.5 16-65 yrs 30.0 23-66 yrs Sex F/M18%/82% Ethnicity White Black Hispanic Other 61% 32% 4% 3% 91% 0% 9% PS 0-1 2 3 72% 14% 72% 19% 9%

20. 20 CALGB - Disease Characteristics Variablegroup 2 N=28 group 1 N=11 Diagnosis ALL LBL 61% 39% 82% 18% Extramedullary Disease 71%55% Prior Transplant14%9%

21. 21 CALGB Best Response ResponseGroup 2 N=28 Group 1 N=11 CR 5 (18%) 2 (18%) CR+CR*6 (21%)3 (27%)

22. 22 Response by Disease Type Group 2Group 1 ALL N=17 LBL N=11 ALL N=9 LBL N=2 CR (%)3 (18)2 (22)1 (11)1 (50) CR+CR*4 (24)2 (22) 1 (50)

23. 23 CALGB - Patients Transplanted GroupNo. of patients % 21 of 617 11 of 333

24. 24 CALGB Non-Transplant Remission duration (weeks) Group 2Group 1 195+ 30 19 15 4 217 5

25. 25 Supportive Phase 1 Trials GroupNo. of Studies No. of Patients CR Pediatric32536% Adult32516%

26. 26 Grade 3/4 Non-Neurologic AE’s; Pediatric N=84 Hematologic (~90%) Infections (3%) Increased Transaminases (4%) Increased Bilirubin (9%) Decreased Albumin (6%) Decreased Potassium (6%) Asthenia (1%)

27. 27 Pediatric Neurologic AE’s N=84 (%) TermGrade 3/4All Grades Headache617 Somnolence27 Hypoesthesia46 Neuropathy712 Seizures66 Paresthesias14 Tremor04 Ataxia12

28. 28 Grade 3/4 Non-Neurologic AE’s; Adult N=103 Hematologic (~70%) Infections (9%) Gastrointestinal (3%) Fatigue (12%) Asthenia (1%) Respiratory Disorders (10%) Transaminase increase (2%)

29. 29 Adult Neurologic AE’s N=103 (%) TermGrade 3/4All Grades Headache115 Somnolence023 Hypoesthesia217 Neuropathy218 Dizziness021 Paresthesias015 Tremor05 Ataxia29

30. 30 Efficacy Conclusions >2 Prior Induction Regimens ResponsePediatric N=39 Adult N=28 CR (%) 5 (13) 5 (18) CR+CR*9 (23)6 (21)

31. 31 Efficacy Conclusions 1 Prior Induction Regimen ResponsePediatric N=31 Adult N=11 CR (%) 13 (42) 2 (18) CR+CR*15 (48)3 (27)

32. 32 Efficacy Conclusions >2 Prior Induction Regimens ResponseALL N=52 LBL N=24 CR (%) 7 (13) 5 (21) CR+CR*12 (23)6 (25)

33. 33 Safety Conclusions Principal toxicities in pediatric patients were laboratory abnormalities Principal toxicities in adult patients were hematologic, gastrointestinal, fever, fatigue and respiratory. Neurologic toxicity was dose limiting. Most neurologic toxicity resolved over time.

34. 34 Nelarabine Efficacy Considerations Traditional endpoints: - CR rate and duration, OS Study confounding factor: - Transplantation