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MELACINE ® Vaccine

MELACINE ® Vaccine. Purpose: Discuss Proposed Second Pivotal Trial of Melacine Vaccine as Adjuvant Therapy for Intermediate Thickness Stage II Melanoma in Patients who Express HLA-A2 and/or HLA-C3. Background for I ntermediate Thickness Stage II Melanoma . ~ 1/4 of melanoma patients

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MELACINE ® Vaccine

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  1. MELACINE® Vaccine Purpose: Discuss Proposed Second Pivotal Trial of Melacine Vaccine as Adjuvant Therapy for Intermediate Thickness Stage II Melanoma in Patients who Express HLA-A2 and/or HLA-C3

  2. Background for Intermediate Thickness Stage II Melanoma • ~1/4 of melanoma patients • 5-year survival rate of ~63–79% • No approved adjuvant therapy to prevent relapse • No adjuvant therapy routinely recommended • Unmet medical need

  3. Brief Summary of SWOG-9035 • Compared Melacine vs. observation in patients with intermediate thickness Stage II melanoma. • Non-significant trend in RFS for Melacine in ITT population. • Highly significant RFS benefit for Melacine in patients with 2 of 5 predefined HLA. • The dominant effect was in patients who expressed HLA-A2 and/or HLA-C3 (A2C3+). • In A2C3+ patients, Melacine was associated with a highly significant increase in both RFS and OS.

  4. Background for Approval of Melacine • Accelerated Approval for A2C3+ patients was discussed with the FDA, and was considered not to be an option, as these patients were a subgroup of the ITT population. • A second pivotal trial that confirms the efficacy of Melacine in A2C3+ patients will be required for approval.

  5. GOAL • To replicate SWOG-9035 as closely as possible, but with only A2C3+ patients, in order to confirm the benefit of Melacine in this patient population.

  6. Issues for Further Development of Melacine as Adjuvant Therapy for Intermediate Thickness Stage II Melanoma 1. The first pivotal trial took 10 years and the second will take another 8–10 years. 2. Key issues need to be addressed now to design a second pivotal trial sufficient to confirm the first pivotal trial results for regulatory approval.

  7. Issues for Further Development of Melacine as Adjuvant Therapy for Intermediate Thickness Stage II Melanoma (cont’d) 3. Changes in current standard practice affect attempts to replicate the first pivotal trial. 4. At the suggestion of FDA, guidance from ODAC is being sought on trial design. • The primary question is whether the patient populations chosen are appropriate for an observation only control arm.

  8. Outline of Presentation 1. Overview of Stage II Melanoma 2. Overview of clinical development of Melacine vaccine 3. Detailed results of SWOG-9035 4. Issues affecting further development of the vaccine 5. Proposed second randomized pivotaltrial 6. Issues for ODAC and the FDA

  9. Overview of Melanoma • Incidence of Melanoma (U.S. 2001): • Estimated new cases = 51,400 • Estimated deaths = 7,800 • Probability of Developing Melanoma: • 1 in 75 (birth to death) ACS:SEER Database

  10. Outcome Depends on Stage:15-Year Disease Specific Survival Stage I (n=9176) Stage II (n=5739) Stage III (n=1525) Stage IV (n=1158) From: Balch et al JCO 19:3635, 2001

  11. Intermediate Thickness Stage II Melanoma Primary tumor: Old AJCC: 1.5–4.0 mm New AJCC: 1.0–4.0 mm Node negative Metastasis negative 5-year survival ~63–79%* depending on thickness and ulceration 24% of melanoma patients (AJCC Database)* * Balch et al. JCO 19:3635, 2001

  12. 15-Year Disease Specific Survival: Stage II Melanoma - New AJCC Staging System Stage IIA (1–2 mm, ulceration) (2–4 mm, no ulceration) Stage IIB (2–4 mm, ulceration) (>4 mm, no ulceration) From: Balch et al JCO 19:3635, 2001

  13. Options for Adjuvant Therapy of Intermediate Thickness Stage II Melanoma Adjuvant therapy – To prevent relapse • No approved drugs • None routinely recommended • One ongoing US pivotal trial (ECOG-1697) (INTRON® A 4 weeks vs. observation) • No other ongoing US Phase 3 trials NCI:PDQ

  14. Outline of Presentation 1. Overview of Stage II Melanoma 2. Overview of clinical development ofMelacine vaccine 3. Detailed results of SWOG-9035 4. Issues affecting further development of the vaccine 5. Proposed second randomized pivotaltrial 6. Issues for ODAC and the FDA

  15. Melacine Vaccine Melanoma Lysate 20 x 106 tumor cell equivalents of Mel S and Mel D cell lines Detox™ 250 mg CWS + 25 mg MPL Immunological Adjuvants CWS Cell wall skeletonMycobacterium phlei MPL Monophosphoryl lipid ASalmonella minnesota Melanoma Antigens gp100Gangliosides GD2, GD3Melan A/MART 1MAGE-1, -2, -3Tyrosinase, TRP-1HMW-MAA

  16. Clinical Development of Melacine:Advanced Stage Patients 1985: Trials initiated by Malcolm Mitchell, MD 1988: Phase 2 & 3 trials initiated by RIBI Imm ~300 Stage IV patients treated Independent Review of 198 patients 11 (6%) Objective responses (5 CR, 6 PR) (4 CR maintained 7+ to 10+ years) Well tolerated safety profile 2000: Approved in Canada for disseminated malignant melanoma.

  17. Clinical Development of Melacine:Stage II Patients 1990: Decision to test in Stage II patients as adjuvant therapy — based on: • Modest efficacy with low toxicity in advanced patients • Presumed greater efficacy as adjuvant therapy: – Smaller tumor burden – Less tumor-induced immunosuppression – Longer time for immune response to work against tumor.

  18. Clinical Development of Melacine: Stage II Patients (cont’d) 1990: SWOG-9035 – initiated design planning Apr 1992: SWOG-9035 – enrollment initiated 1992: Mitchell published “Association of HLA Phenotype with Response to Active Specific Immunotherapy of Melanoma” (JCO, 10:1558, 1992)

  19. Clinical Development of Melacine: Stage II Patients (cont’d) 1992: Mitchell Results – Advanced patients •70 patients with disseminated melanoma treated with Melacine vaccine. •5 HLA were associated with Melacine benefit (A2, A28, B44, B45 and C3) •Benefit for Melacine in patients with 2 of the associated HLA. •Benefit for Melacine strongest in patients expressing HLA-A2 and/or -C3 (A2C3+)

  20. Clinical Development of Melacine: Stage II Patients (cont’d) 1994: SWOG-9035 amended to include HLA typing Nov 1996: Enrollment completed 689 total patients 553 (80%) patients HLA typed - 383 prospectively - 170 retrospectively

  21. Clinical Development of Melacine: Stage II Patients (cont’d) Feb 2000: Primary SWOG data analysis RFS benefit for vaccine All patients: ITT (p=0.040) Sep 2000: SWOG analyzed HLA data • RFS benefit for vaccine in patients that expressed 2 of 5 predefined HLA (p=0.0002) • RFS benefit for vaccine in A2C3+ patients (p=0.004)

  22. Clinical Development of Melacine: Stage II Patients (cont’d) Sep 2000: End-of-Phase 3 meeting with FDA Discussed additional data sweep Nov 2000–Apr 2001: SWOG conducted data sweep May 2001: Corixa analyzed follow up data RFS, all patients: ITT (p=0.141) RFS, A2C3+ patients: (p=0.005) OS, A2C3+ patients (p=0.003) (Analysis confirmed by SWOG)

  23. Clinical Development of Melacine: Stage II Patients (cont’d) Jun 2001: Results submitted to FDA Oct 2001: Accelerated Approval as adjuvant therapy in Stage II A2C3+ patients discussed with FDA FDA requires a second Phase 3 trial Feb 2002: ODAC consulted for advice concerning appropriate patient population to confirm the first pivotal trial results.

  24. Outline of Presentation 1. Overview of Stage II Melanoma 2. Overview of clinical development ofMelacine vaccine 3. Detailed results of SWOG-9035 4. Issues affecting further development of the vaccine 5. Proposed second randomized pivotaltrial 6. Issues for ODAC and the FDA

  25. SWOG‑9035:“RANDOMIZED TRIAL OF ADJUVANT IMMUNOTHERAPY WITH AN ALLOGENEIC MELANOMA VACCINE FOR PATIENTS WITH INTERMEDIATE THICKNESS, NODE NEGATIVE MALIGNANT MELANOMA (T3N0M0)” • Multi-center • Open-label • Conducted by SWOG • IND held by Corixa

  26. SWOG‑9035: Study Coordinators • Vernon K. Sondak, M.D.Surgery • Jeffrey A. Sosman, M.D. HLA Phenotyping • Raymond A. Kempf, M.D.Medical Oncology • Ralph J. Tuthill, M.D.Pathology • P.Y. Liu, Ph.D. Biostatistics

  27. SWOG‑9035: Objectives • To compare Melacine vs. Observation for RFS and OS. 2. To evaluate the toxicity of Melacine as adjuvant therapy. 3. To explore the interaction between patient HLA types and vaccine effectiveness for RFS and OS. (Objective 3: Added by protocol amendment in Sept 1994 based on Mitchell publication.)

  28. SWOG-9035: Trial Design Surgery to Remove Tumor Stratification and Randomization Observation Vaccine IM given for a total of 40 doses over the first two years Disease relapse evaluated every three months for the first two years Disease relapse evaluated every four months for the next three years, then annually until death

  29. SWOG‑9035: Inclusion Criteria • Primary cutaneous melanoma • Completely resected • Clinical or pathologic nodal staging • T3N0M0 • Clinically negative regional nodes • Regional lymph node dissection not required • No evidence of metastatic disease

  30. SWOG-9035: T3N0M0 • T3 defined as: 1.5–4 mm in thickness or • Clark’s level IV invasion — when Breslow’s thickness was unknown for technical reasons such as: • Shave biopsies • Tangential excisions • Corresponded to Stage IIA inAJCC Staging System (edition 4)

  31. SWOG‑9035: Study Design • Patient stratification: • Gender • Lymph node dissection/staging • Primary tumor thickness • 1.5–3.0 mm vs. • 3.01–4.00 mm vs. • Clark’s level IV – if Breslow’s thickness was unknown

  32. SWOG‑9035: Patient Disposition • 689 patients randomized • 346 vaccine • 343 observation • All treatment assignments were based on entry pathology. Centralized pathology and surgical reviews were conducted after randomization.

  33. SWOG‑9035: Timing of RFS Analysis • Data cutoff for SWOG RFS analysis:Feb 2000 • Predefined number of events had occurred per SWOG Statistical Center. • 228 (33%) relapses or deaths • Median follow-up for all patients was 4.1 years • Minimum time since registration of last patient was 3 years

  34. SWOG‑9035: Baseline Comparability: ITT Population (N=689)

  35. SWOG‑9035: RFS Analyses by SWOG:ITT Population (Feb 2000 Database) • All 3 stratification factors had a significant effect on RFS • Tumor Thickness: ( 3 vs. > 3 mm) (p=0.001) • Gender: (Female vs. Male) (p=0.0001) • Lymph Node Staging: (Yes vs. No)(p=0.019)  

  36. SWOG‑9035: RFS Analyses by SWOG: ITT Population(Feb 2000 Database) • RFS was the primary endpoint • Vaccine had a significant effect on RFS • Significantly longer for vaccine vs. observation (Cox model; ITT population) • p=0.040, adjusted for stratification factors • Hazard ratio = 0.76(95% C.I. = 0.59–0.99)

  37. SWOG‑9035: RFS Analyses by SWOGITT Patients (Feb 2000 Database) Vaccine: N=346 Observation: N=343 (p=0.040, adjusted for stratification factors, Cox model) (Vaccine significantly prolonged RFS in all patients)

  38. SWOG‑9035: RFS AnalysesITT Patients (May 2001 Database) Vaccine: N=345 Observation: N=338 (p=0.141) (RFS benefit favored vaccine, not statistically significant)

  39. Association of HLA and Melacine Benefit • 5 HLA (A2, A28, B44, B45 and C3) were shown to be associated with Melacine benefit in disseminated melanoma(Mitchell et al., 1992) • Benefit for Melacine in patients with2 of the associated HLA. • Benefit for Melacine was strongest in patients expressing HLA-A2 and/or -C3 (A2C3+). • SWOG-9035 was amended in 1994 to examine if similar benefit occurred in Stage II patients.

  40. SWOG-9035: Frequency of Patients with the Predefined HLA Phenotypes • 553 of 689 patients HLA phenotyped • HLA-A2 = 46% • HLA-C3 = 29% • HLA-B44 = 25% • HLA-A28 = 9% • HLA-B45 = 1% A2C3+ = 58%

  41. SWOG-9035: RFS Benefit for Melacine in Patients Expressing  2 of the 5 Predefined HLA Phenotypes (SWOG Analyses)

  42. SWOG-9035: RFS Benefit for Melacine in Patients Expressing Each of the 5 Predefined HLA (SWOG Multivariate Analysis)

  43. SWOG-9035: Vaccine Benefit in A2C3+ Patients (Feb 2000 Database) Vaccine had a significant effect on RFS • Significantly longer for vaccine vs. observation (Cox model; A2C3+ population) • p=0.002, adjusted for stratification factors • Hazard ratio = 0.56(95% C.I. = 0.38–0.84)

  44. SWOG‑9035: RFS Analysis A2C3+ Patients (Feb 2000 Database) Vaccine / A2C3+: N=178 Observation / A2C3+: N=145 (p=0.002) (Vaccine significantly prolonged RFS in A2C3+ patients)

  45. SWOG‑9035: RFS Analysis A2C3+ Patients (May 2001 Database) Vaccine / A2C3+: N=178 Observation / A2C3+: N=145 (p=0.005) (Vaccine significantly prolonged RFS in A2C3+ patients)

  46. SWOG‑9035: RFS Analysis A2C3– Patients (May 2001 Database) Vaccine / A2C3–: N=116 Observation / A2C3–: N=114 (p=0.773) (Vaccine did not prolong RFS in A2C3– patients)

  47. SWOG‑9035: RFS Analysis Observation Patients (May 2001 Database) Observation / A2C3–: N=114 Observation / A2C3+: N=145 (p=0.963) (A2C3 expression without vaccine did not prolong RFS)

  48. 5-Year RFS Estimate

  49. SWOG‑9035: Overall Survival A2C3+ Patients (May 2001 Database) Vaccine / A2C3+: N=178 Observation / A2C3+: N=145 (p=0.003) (Vaccine significantly prolonged OS in A2C3+ patients)

  50. SWOG‑9035: Overall Survival A2C3– Patients (May 2001 Database) Observation / A2C3–: N=114 Vaccine / A2C3–: N=116 (p=0.294) (Vaccine did not prolong OS in A2C3– patients)

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