1. 1 NDA 21-673 Clofarabine Cl-F-Ara-A Presented by Martin Cohen, M.D. at the December 01, 2004 meeting of the Oncologic Drugs Advisory Committee meeting

2. 2 NDA 21-673 Clofarabine Cl-F-Ara-A

3. 3 Proposed Indication Clofarabine is indicated for the treatment of pediatric patients 1 to 21 years old with refractory or relapsed acute leukemias.

4. 4 Clofarabine Dose and Schedule Recommended pediatric dose is 52 mg/m2 intravenously over 1 to 2 hours daily for 5 consecutive days. Treatment cycles are repeated every 2 to 6 weeks following recovery or return to baseline organ function.

5. 5 Clofarabine Pediatric Studies ProtocolSponsorPhaseDisease CLO-222Ilex2AML CLO-212Ilex2ALL ID-99-383MDACC1Hematologic malignancies

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

7. 7 Inclusion criteria Age < 21 > 25% marrow blasts First or subsequent relapse and/or refractory (AML), Second or subsequent relapse and/or refractory (ALL) Ambulatory performance status Adequate organ status

8. 8 Response Definitions CR: - no circulating blasts or extramedullary disease; - an M1 bone marrow (< 5% blasts); and - platelets >100 × 10 3 /mcL and ANC >1.0 × 10 3 /mcL). CRp: Patients who have met all criteria for CR except for recovery of platelet counts to > 100 × 10 3 /mcL. PR: : - no circulating blasts; - an M2 bone marrow (>5% and < 25% blasts); and appearance of normal progenitor cells - an M1 marrow that does not qualify for CR or CRp.

9. 9 Study participants 18 Sites – all in the United States 13 sites enrolled patients in CLO-222 14 sites enrolled patients in CLO-212 Independent response review panel Independent pathology review

10. 10 AML - Demographics and KPS VariableN=35 Age [median (range)12 (1 - 22) Sex Female Male 13 (37%) 22 (63%) Ethnicity Hispanic Caucasian Other 7 (20%) 19 (54%) 9 (26%) KPS 100 90-80 70-60 14 (40%) 17 (49%) 4 (11%)

11. 11 AML Prior Therapies Prior therapyN=35 Median number of prior induction regimens (range) 3 (1 -5) Prior transplants 1 2 13 (37%) 5 (14%)

12. 12 AML Best Response Response CategoryN=35% CR 0 0 CRp13 PR823 TF1954 NE*720 * 1 transplanted while hypoplastic; 2 early deaths; 2 d/c 1 st cycle; 2 ineligible

13. 13 AML - Patients Transplanted Clofarabine response No. of patients No of cycles CRp15 PR62-4 NE*31-4 TF21-2 * 2 study ineligible; 1 transplanted while still hypoplastic

14. 14 Clofarabine Efficacy Considerations Traditional endpoints: -Confirmed CR rate and duration, OS Current study confounding factors: -Some patients were transplanted early -Some patients had pre-CLO transplant Exploratory endpoint: TTP of CLO + transplant compared to TTP of prior therapy + transplant

15. 15 AML - Clofarabine + Transplant Patient14-0315-1706-3614-31 TTP for immediate prior treatment[s] (d) 2706030, 30 Prior Stem cell transplantYNY (2)N Transplant TTP (d)150-365, 485 - No. of clofarabine cycles5132 Clofarabine responseCRpPR Clofar + transplant TTP (d)519+465+130+93+ Post-clofarabine OS (w)93.6+67.9+16.4+24.9+

16. 16 ALL - Demographics and KPS VariableN=49 Age [median (range)12 (1 - 20) Sex Female Male 20 (41%) 29 (59%) Ethnicity Hispanic Caucasian Other 20 (41%) 9 (18%) KPS 100 90-80 70-50 15 (31%) 19 (39%) 14 (29%)

17. 17 ALL - Prior Therapies Prior therapyN=49 Median number of prior induction regimens (range) 3 (2 -6) Prior transplants 1 2 13 (27%) 2 (4%)

18. 18 ALL - Best Response Response CategoryN=49% CR 6 12.2 CRp48.2 PR510.2 TF2653.1 NE816.3

19. 19 ALL - Patients Transplanted Clofarabine response No. of patients No. of cycles of CLO CR12 CRp32,3,3 PR22,2 NE*12

20. 20 ALL - CR Patients: TTP from Clofarabine Alone Patient07-1806-47 TTP for immediate prior treatment[s] (d) 60, 3030, 30 Prior Stem cell transplantNN Transplant TTP (d)-- No. of clofarabine courses32 Clofarabine TTP (d)14376 Post-clofarabine OS (w)58.610.4+

21. 21 ALL - CRp Patients: TTP from Clofarabine + Transplant Patient09-2412-1414-40* TTP for immediate prior treatment (d) 12030 Prior Stem cell transplantYNN Transplant TTP (d)60-- No. of clofarabine courses322 Clofarabine TTP (d)259168+64 Post-clofarabine OS (w)63.1+42.09.1 * No post-clofarabine transplant

22. 22 MDACC Supporting Phase 1 study ResponseMDACCIRRP CR5/25 (20%)2 CR (ALL) 1 CRp (AML) 2 PR (ALL) PR3/25 (12%) --

23. 23 Clofarabine Exposure by Cycle CycleNMedian total mg/cycle 1113340 268283 324255 47185 54223 6-86~240

24. 24 Baseline Conditions; N=113 (%) TotalGrade 1Grade 2Grade 3/4 Tachycardia272034 Fatigue25196- Pyrexia221174 Nausea229121 Anorexia20767 Vomiting20137- Anxiety17512- Diarrhea13103-

25. 25 AE Summary; n=113 Patients with > 1 AE99% Patients with > 1 SAE83% Patients discontinued because of an AE 4% CTC Grade 3 AE53% CTC Grade 4 AE23% CTC Grade 5 AE20%

26. 26 Frequent AE’s; N=113 (%) TotalGrade 3Grade 4 Vomiting8391 Nausea73151 Febrile neutropenia59544 Diarrhea5210- Headache485- Pyrexia4015- Rigors373- Fatigue3731 Anorexia3046

27. 27 Other AE’s Infections (bacterial, fungal, viral) SIRS/capillary leak syndrome Renal insufficiency Hypotension Hepatobiliary toxicity (increased AST, ALT, bilirubin, alk phosphatase) Left ventricular systolic dysfunction Hand-foot syndrome

28. 28 Efficacy Conclusions Pediatric AML Standard Criteria 1 CRp (3%) and 8 PR’s (23%) among 35 treated patients Remission duration cannot be determined because of transplant

29. 29 Efficacy Conclusions Pediatric AML Exploratory 4 CLO + transplant patients had a longer TTP with that Rx than with the treatment immediately preceding CLO which may or may not have included transplant Of 2 patients with a prior transplant 1 had a longer TTP with clofarabine + transplant than with his preceding transplant. The other is too early to evaluate.

30. 30 Efficacy Conclusions Pediatric ALL Standard 6 CR’s (12%), 4 CRp’s (8%) and 5 PR’s among 49 treated patients. 2 CR’s who did not have a transplant had a longer time to progression than was achieved with their immediate prior therapies. 1 CRp who did not have a transplant had a longer time to progression than was achieved with his immediate prior therapy.

31. 31 Efficacy Conclusions Pediatric ALL Exploratory 2 CRp patients had a longer TTP with clofarabine + transplant than with the treatment immediately preceding clofarabine 1 of the above 2 patients had a pre-clofarabine transplant. This pt also had a longer TTP with clofarabine + transplant than with his preceding transplant regimen.

32. 32 Safety Conclusions Toxicity was as expected for a heavily pretreated acute leukemia population Principal toxicities were nausea, vomiting, diarrhea, hematologic toxicity, fever and febrile neutropenia, hepatobiliary toxicity, infections and renal toxicity. SIRS, tumor lysis syndrome, multi-organ failure, hypotension, renal insufficiency and left ventricular systolic dysfunction can also occur.

33. 33 Clofarabine Efficacy Considerations Traditional endpoints: -Confirmed CR rate and duration, OS Current study confounding factors: -Some patients were transplanted early -Some patients had pre-CLO transplant Exploratory endpoint: TTP of CLO + transplant compared to TTP of prior therapy + transplant