1. NDA#21-240 Histamine Dihydrochloride FDA Review December 13, 2000

2. Division of Oncology Drug Products 2 CDER/DODP Review Team Medical Reviewers: Judy H. Chiao, M.D. Donna Griebel, M.D. (TL) Statisticians: Rajeshwari Sridhara, Ph.D. Gang Chen, Ph.D. (TL) Biopharm:Gene Williams, Ph.D. Atiqur Rahman, Ph.D. (TL) Pharm/Tox:John Leighton, Ph.D. Margaret Brower. (TL) Chemistry:N. Chidambaram, Ph.D. Eric Duffy, Ph.D. (TL) CSO:Sean Bradley, R.Ph Dotti Pease (TL)

3. Division of Oncology Drug Products 3 Indication Indicated for adjunct use with IL-2 in the treatment of adult patients with advanced metastatic melanoma that has metastasized to the liver

4. Division of Oncology Drug Products 4 Outline of FDA Review Biology of metastatic melanoma Regulatory History Review issues (MP-US-M01) –Is survival difference in the ITT population (N=305) a persuasive finding? –Is survival difference in the liver subgroup (N=129) a persuasive finding? –Is the Histamine/IL-2 combination a well tolerated regimen?

5. Division of Oncology Drug Products 5 Metastatic Melanoma Chemo-resistant IL-2-based therapy effective in a minority of patients Survival varies from 12 mons –influenced by prognostic factors –difference in survival could be due to imbalances in prognostic factors rather than the treatment

6. Division of Oncology Drug Products 6 Prognostic Factors Number of organs involved by metastasis Site of metastasis –skin/lymph node vs. lung vs. others  LDH Low Albumin Disease free interval Prior disease stage Performance status Sex

7. Division of Oncology Drug Products 7 Regulatory History Summary of DODP comments on the design of registration studies for H/IL-2 –Two well controlled studies sufficiently powered to show superiority of the histamine/IL-2 combination over IL-2 alone –Pre-stratification with prognostic factors to ensure that the arms were balanced in patient characteristics that might affect survival

8. Division of Oncology Drug Products 8 Regulatory History –The International phase 3 study could not serve as a second well-controlled study Different treatment regimen: Histamine/IL-2 plus INF-  vs DTIC alone –Single arm study MA-0103 could not serve as a second well-controlled study Could not demonstrate the added benefit of histamine to IL-2 without a IL-2 alone arm Could not reliably evaluate survival in the absence of a control arm

9. Division of Oncology Drug Products 9 MP-US-M01: Study Design Open-label, RCT NOT stratified by any prognostic factors NOT stratified by the presence of liver metastasis at study entry Primary endpoint: overall survival

10. Division of Oncology Drug Products 10 Statistical Analysis Plan Original Protocol (7/1/97): –The primary objective is to evaluate the efficacy and safety of H/IL-2 in patients with metastatic melanoma who have not been treated or have failed other first- line therapies –Patients will be stratified in subgroup analyses: liver vs. no liver mets; prior treatment with DTIC or no DTIC

11. Division of Oncology Drug Products 11 Statistical Analysis Plan Last patient randomized on 3/26/99 Revised statistical plan (6/24/99): –The primary objective is to evaluate the clinical efficacy of H/IL-2 as compared to IL-2 alone in patients with metastatic melanoma –ITT subset will be used as the primary subset –All efficacy endpoints will be summarized for non-exploratory subgroup of patients with liver metastases at study entry

12. Division of Oncology Drug Products 12 Statistical Analysis Plan Revised statistical plan (9/14/99): –Three subgroups will be analyzed Patients with liver metastases at study entry Patients from centers enrolling  7 patients Patients with liver metastases from centers enrolling  7 patients Final statistical plan (11/18/99) –Two Null Hypotheses: ITT and liver subgroup

13. Division of Oncology Drug Products 13 Review Issue #1 Is survival difference in the ITT population a persuasive finding?

14. Division of Oncology Drug Products 14 FDA Comments Cut-off dates (3/8/00, 9/8/00) were NOT prespecified in the protocol FDA review of last f/u date of each patient –40 patients alive on 9/8/00 –33 (83%) had last f/u  30 days past 9/8/00 –4 died after 9/8/00 3 deaths on H/IL-2: 9/12, 9/18, 10/10 1 death on IL-2: 10/12

15. Division of Oncology Drug Products 15 Median Survival (months): ITT

16. Division of Oncology Drug Products 16 Hazard Ratio and P-value: ITT

17. Division of Oncology Drug Products 17 Overall Survival: ITT (Cut-off date: 3/8/00)  : H/IL-2 (N=152) ---: IL-2 (N=153) Log Rank p=0.1255 ProportionProportion

18. Division of Oncology Drug Products 18 Overall Survival: ITT (Cut-off date: 9/8/00)  : H/IL-2 (N=152) ---: IL-2 (N=153) Log Rank p=0.0526 ProportionProportion

19. Division of Oncology Drug Products 19 Overall Survival: ITT (FDA using most recent f/u data)  : H/IL-2 (N=152) ---- : IL-2 (N=153) Log Rank p=0.0650 ProportionProportion

20. Division of Oncology Drug Products 20 FDA Comments P-values of survival analysis are not adjusted for multiple comparisons

21. Division of Oncology Drug Products 21 FDA Comments Lack of internal consistency across the subgroups

22. Division of Oncology Drug Products 22 Median Survival (months): Subgroups

23. Division of Oncology Drug Products 23 Survival in Liver Met Subgroup : N=129 (Cut-off date: 9/8/00)  : H/IL-2 (N=55) ----: IL-2 (N=74) Log Rank p=0.0033 ProportionProportion

24. Division of Oncology Drug Products 24 Survival in No Liver Met Subgroup: N=176 (Cut-off date: 9/8/00)  : H/IL-2 (N=97) ---- : IL-2 (N=79) Log Rank p=0.7806 ProportionProportion

25. Division of Oncology Drug Products 25 Survival in Patients with Skin/Node/Lung Only Disease: N=82 (Cut-off date: 9/8/00)  : H/IL-2 (N=45) ----: IL-2 (N=37) Log Rank p=0.8217 ProportionProportion

26. Division of Oncology Drug Products 26 FDA Comments No supporting evidence from tumor response rate, time to tumor progression

27. Division of Oncology Drug Products 27 Secondary endpoint: Response

28. Division of Oncology Drug Products 28 Difference between FDA’s TTP and the applicant’s FDA TTP censored on the day of last imaging studies Death not counted PD unless PD on imaging studies PD based on the day of imaging studies

29. Division of Oncology Drug Products 29 Time to Tumor Progression: FDA Analysis in ITT (N=243) TTP days  : H/IL-2 (N=124) ----: IL-2 (N=119) Log Rank p=0.4108 ProportionProportion

30. Division of Oncology Drug Products 30 FDA Comments on Efficacy: ITT –Survival difference in the ITT population did not reach statistical significance. –P-value dependent on cut-off dates, which were not prespecified in the protocol –Lack of internal consistency across subgroups –No supporting evidence from tumor response, time to tumor progression

31. Division of Oncology Drug Products 31 Review Issue #2 Is survival difference in the liver met subgroup a persuasive finding ?

32. Division of Oncology Drug Products 32 FDA Comments Imbalances in prognostic factors consistently favor the histamine/IL-2 arm

33. Division of Oncology Drug Products 33 Patient Characteristics in the Liver Subgroup

34. Division of Oncology Drug Products 34 FDA Comments Large shifts in hazard ratio and p- value in the FDA adjusted analysis indicate that these imbalances contributed to the observed survival difference in the liver subgroup

35. Division of Oncology Drug Products 35 Adjusted Survival Analysis of the Liver Subgroup (Cut-off 9/8/00)

36. Division of Oncology Drug Products 36 FDA Comments The treatment effect of the histamine/IL-2 combination is most apparent in the small group of patients (N=20) with liver only disease.

37. Division of Oncology Drug Products 37 Median Survival (months): Liver Subgroups

38. Division of Oncology Drug Products 38 FDA Comments No supporting evidence of tumor response, time to tumor progression

39. Division of Oncology Drug Products 39 Secondary endpoint: Response in the Liver Subgroup

40. Division of Oncology Drug Products 40 Time to Tumor Progression: LM Subgroup (N=96)  : H/IL-2: N=42 ---- : IL-2: N=54 Log Rank p=0.1315 SurvivingSurviving

41. Division of Oncology Drug Products 41 FDA Comments on Efficacy in the Liver Subgroup Imbalances in prognostic factors consistently favor the histamine/IL-2 arm. These imbalances contributed to the observed survival difference between the two arms (FDA adjusted analysis) Treatment effect of the histamine/IL-2 combination is most apparent in the small group of patients with liver only disease No supporting evidence from tumor response, time to tumor progression

42. Division of Oncology Drug Products 42 Review Issue #3 Is the histamine/IL-2 combination a well tolerated treatment regimen?

43. Division of Oncology Drug Products 43

44. Division of Oncology Drug Products 44 IL-2 Regimen

45. Division of Oncology Drug Products 45 Histamine/IL-2 Regimen

46. Division of Oncology Drug Products 46 Compliance with Treatment Vials or pre-filled syringes were not returned to study sites to check for compliance Inadequate assessment by patient diary: –Original protocol did not require the use of a diary –201 patients did not complete diaries (dosing information available on 76 patients from home care records)

47. Division of Oncology Drug Products 47 MP-US-M01: Safety

48. Division of Oncology Drug Products 48 Death within 30 Days of Last Dose 33 patients (11%) died within 30 days of last dose of study medication –20 died in the liver subgroup (16%) Cause of death: –3 deaths (H/IL-2) attributed to study medication by the applicant –2 deaths (IL-2) of unknown causes –12 deaths: cannot rule out study medication by FDA –16 deaths related to progression (11 had documentation)

49. Division of Oncology Drug Products 49 Grade 3 Toxicity

50. Division of Oncology Drug Products 50 Grade 4 Toxicity 6% patients suffered grade 4 toxicity. Specific types of grade 4 toxicities were rare (incidence  1%): MI, cardiac arrest, CHF, hypotension, syncope, seizure, ascites, dyspnea, liver failure

51. Division of Oncology Drug Products 51 Safety from Single Arm Study MA-0103 90 patients enrolled in the study –16 (18%) died within 30 days of the last dose 35 had liver metastases –8 (23%) died within 30 days of the last dose

52. Division of Oncology Drug Products 52 Safety from Single Arm Study MA-0103 49 patients (54%) suffered grade 3 toxicities asthenia (16%) chest pain (7%) nausea (8%)edema/effusion (6%) vomiting (7%) anorexia (3%) headache (8%) dyspnea (3%) altered MS (2%)

53. Division of Oncology Drug Products 53 Overall Summary Only ONE study Survival difference in the ITT population did not reach statistical significance

54. Division of Oncology Drug Products 54 Overall Summary Survival difference in the subgroup of patients with liver metastases should be interpreted with caution –Imbalances in prognostic factors favor H/IL-2 arm –Effect of these imbalances precludes a reliable assessment of the efficacy of the histamine/IL-2 combination –No supportive evidence from tumor response rate or time to tumor progression

55. Division of Oncology Drug Products 55 Overall Summary 58% suffered grade 3-4 toxicities and 11% died within 30 days of the last dose of study medications –Not possible to assess whether toxicities were due to underlying disease or treatment in the absence of a non-IL-2 arm –Grade 3-4 toxicities in recent DTIC trial is 36% and death within 30 days is 8 % Poor documentation of patient compliance precludes adequate assessment of treatment tolerability