MELACINE

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 6379
• 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 810 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 (contd)

• 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)
• ACSSEER Database

10
Outcome Depends on Stage15-Year Disease
Specific Survival
Stage I (n9176)
Stage II (n5739)
Stage III (n1525)
Stage IV (n1158)
From Balch et al JCO 193635, 2001
11
Intermediate Thickness Stage II Melanoma

• Primary tumor Old AJCC 1.54.0 mm
  New AJCC 1.04.0 mm
• Node negative
• Metastasis negative
• 5-year survival 6379 depending on
  thickness and ulceration
• 24 of melanoma patients (AJCC
  Database)

Balch et al. JCO 193635, 2001
12
15-Year Disease Specific Survival Stage II
Melanoma - New AJCC Staging System
Stage IIA (12 mm, ulceration)
(24 mm, no ulceration)
Stage IIB (24 mm, ulceration)
(gt4 mm, no ulceration)
From Balch et al JCO 193635, 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
• NCIPDQ

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
skeleton Mycobacterium phlei MPL
Monophosphoryl lipid A Salmonella minnesota
Melanoma Antigens gp100Gangliosides GD2,
GD3Melan A/MART 1MAGE-1, -2, -3Tyrosinase,
TRP-1HMW-MAA
16
Clinical Development of MelacineAdvanced 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 MelacineStage 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 (contd)

• 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, 101558, 1992)

19
Clinical Development of Melacine Stage II
Patients (contd)

• 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 (contd)

• 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 (contd)

• Feb 2000 Primary SWOG data analysis RFS
  benefit for vaccine All patients ITT
  (p0.040)
• Sep 2000 SWOG analyzed HLA data
• RFS benefit for vaccine in patients that
  expressed ?2 of 5 predefined HLA (p0.0002)
• RFS benefit for vaccine in A2C3 patients
  (p0.004)

22
Clinical Development of Melacine Stage II
Patients (contd)

• Sep 2000 End-of-Phase 3 meeting with FDA
  Discussed additional data sweep
• Nov 2000Apr 2001 SWOG conducted data
  sweep
• May 2001 Corixa analyzed follow up data
  RFS, all patients ITT (p0.141) RFS, A2C3
  patients (p0.005) OS, A2C3
  patients (p0.003) (Analysis
  confirmed by SWOG)

23
Clinical Development of Melacine Stage II
Patients (contd)

• 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-9035RANDOMIZED 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 1.54 mm in thickness or
• Clarks level IV invasion when Breslows
  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
• 1.53.0 mm vs.
• 3.014.00 mm vs.
• Clarks level IV if Breslows 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 analysisFeb 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 (N689)
Variable Vaccine(n346) Observation(n343) p-value
Tumor Thickness (1.503.00) 76 77 0.821
LN Staging (Yes) 25 23 0.636
Gender (Female) 40 43 0.384
Ulceration (Yes) 23 25 0.306
Primary Disease Site (Extremity) 51 43 0.063
35
SWOG-9035 RFS Analyses by SWOGITT Population
(Feb 2000 Database)

• All 3 stratification factors had a significant
  effect on RFS
• Tumor Thickness (? 3 vs. gt 3 mm) (p0.001)
• Gender (Female vs. Male) (p0.0001)
• Lymph Node Staging (Yes vs. No)(p0.019)  

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)
• p0.040, adjusted for stratification factors
• Hazard ratio 0.76(95 C.I. 0.590.99)

37
SWOG-9035 RFS Analyses by SWOGITT Patients
(Feb 2000 Database)
Vaccine N346
Observation N343
(p0.040, adjusted for stratification factors,
Cox model)
(Vaccine significantly prolonged RFS in all
patients)
38
SWOG-9035 RFS AnalysesITT Patients (May 2001
Database)
Vaccine N345
Observation N338
(p0.141)
(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)
Subgroup Comparison p-value
01 match (n402) Vaccine (n213) vs. Observation (n189) 0.93
?2 matches (n151) Vaccine (n81) vs. Observation (n70) 0.0002
Number of matches with HLA-A2 -A28, -B44, -B45, and -C3. Number of matches with HLA-A2 -A28, -B44, -B45, and -C3. Number of matches with HLA-A2 -A28, -B44, -B45, and -C3.
42
SWOG-9035 RFS Benefit for Melacine in Patients
Expressing Each of the 5 Predefined HLA (SWOG
Multivariate Analysis)
Patients Vaccine Benefit
HLA-A2 46 p0.009
HLA-C3 29 p0.02
HLA-B44 25 p0.27
HLA-A28 9 Insufficient
HLA-B45 1 Insufficient
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)
• p0.002, adjusted for stratification factors
• Hazard ratio 0.56(95 C.I. 0.380.84)

44
SWOG-9035 RFS Analysis A2C3 Patients (Feb 2000
Database)
Vaccine / A2C3 N178
Observation / A2C3 N145
(p0.002)
(Vaccine significantly prolonged RFS in A2C3
patients)
45
SWOG-9035 RFS Analysis A2C3 Patients (May 2001
Database)
Vaccine / A2C3 N178
Observation / A2C3 N145
(p0.005)
(Vaccine significantly prolonged RFS in A2C3
patients)
46
SWOG-9035 RFS Analysis A2C3 Patients
(May 2001 Database)
Vaccine / A2C3 N116
Observation / A2C3 N114
(p0.773)
(Vaccine did not prolong RFS in A2C3 patients)
47
SWOG-9035 RFS Analysis Observation Patients
(May 2001 Database)
Observation / A2C3 N114
Observation / A2C3 N145
(p0.963)
(A2C3 expression without vaccine did not prolong
RFS)
48
5-Year RFS Estimate
Subgroup Treatment N 5-Year RFS p-value
A2C3 VaccineObservation 178145 7563 0.007
A2C3 Vaccine Observation 116114 6262 0.993
Log-rank test Log-rank test Log-rank test Log-rank test Log-rank test
49
SWOG-9035 Overall Survival A2C3 Patients
(May 2001 Database)
Vaccine / A2C3 N178
Observation / A2C3 N145
(p0.003)
(Vaccine significantly prolonged OS in A2C3
patients)
50
SWOG-9035 Overall Survival A2C3 Patients
(May 2001 Database)
Observation / A2C3 N114
Vaccine / A2C3 N116
(p0.294)
(Vaccine did not prolong OS in A2C3 patients)
51
SWOG-9035 Overall Survival Observation Patients
(May 2001 Database)
Observation / A2C3 N114
Observation / A2C3 N145
(p0.233)
(A2C3 expression without vaccine did not prolong
OS)
52
SWOG-9035 Summary of Follow-up Analysis by
Corixa of May 2001 Database

• Vaccine is effective in prolonging RFS in A2C3
  patients (p0.005).
• Vaccine is effective in prolonging OS in A2C3
  patients (p0.003).
• Subsequent analysis by SWOG confirmed this
  assessment. (ASCO, May 2002)

53
SWOG-9035 Vaccine Safety

• Adverse events Treated Population
• Assessed by SWOG Toxicity Criteria.
• Recorded only for the Melacine patients.
• Not recorded for symptoms that were certainly or
  most likely due to disease or other non-treatment
  cause.

54
SWOG-9035 AE Summary

• 96 reported at least one AE
• Majority AE were mild to moderate
• 23 Maximum Grade 1 Toxicity
• 65 Maximum Grade 2 Toxicity
• 9 Maximum Grade 3 Toxicity
• 0 Grade 4 Toxicity
• AE comparable for A2C3 and A2C3 patients

55
SWOG-9035 AE Summary

• Grade 3 toxicities reported in three or more
  patients
• Injection site reactions (11 patients, 3)
• Malaise/fatigue/lethargy (3 patients, lt1)
• Diarrhea (3 patients, lt1)
• Transient vision abnormalities (3 patients, lt1)
• Fever in absence of infection (3 patients, lt1)
  
• Grade 4 toxicity reported - None

56
SWOG-9035 Summary

• Melacine significantly improved RFS (p0.005) and
  OS (p0.003) in patients who expressed HLA-A2
  and/or HLA-C3.
• Minimal toxicity
• Results are highly encouraging for patients with
  melanoma and for cancer vaccines in general.
• Results are consistent with predictions that in
  the post-genomic era, therapies will be tailored
  to patients genetic capability to respond.

57
Human Leukocyte Antigens (HLA)

• HLA plays a central role in immune response,
  immune surveillance and immune regulation.
• Bind peptide fragments of antigens - Present
  antigen to T cells - Trigger T cell responses
  
• Highly polymorphic Each HLA binds a different
  set of antigenic peptides
• Peptide binding governs T cell responsiveness vs.
  non-responsiveness

58
Correlation of HLA-A2 and/or -C3with Vaccine
Benefit

• Mechanism is unknown
• Several plausible explanations
• 1. Class I HLA presents antigens to and
  activates CTL. HLA-A2 and C3 may preferentially
  present one or more of the Melacine antigens to
  CTL.
• 2. HLA-A2 and C3 may be linked to other
  polymorphic immune response (IR) genes
  responsible for benefit of the vaccine.

59
Genes Linked to Class I HLA with Immune Response
Functions
MICA, MICB TNFb, TNFa HSP70 C2, C4
(complement components) Class II HLA-DR, DQ,
DPTAP, LMPOther uncharacterized genes with as
yet unknown functions (High level of linkage
disequilibrium defines distinct haplotypes)
60
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

61
Issues Affecting Further Development of the
Vaccine

• Changes in standard care that affectattempts to
  replicate and to confirm results
  of SWOG-9035 in A2C3 patients.

1. Interferon alfa-2b (INTRON A) has been
approved as an adjuvant therapy in patients at
high risk for recurrence. 2. New AJCC
Staging System is in use with different cutoffs
and parameters. 3. Lymphatic mapping and
sentinel node biopsy is commonly employed.
62
Impact of INTRON A on Study Design

• INTRON A was not approved at initiation of
  SWOG-9035.
• INTRON A is now approved for patients at high
  risk for systemic recurrence.
• Package insert does not define high risk of
  recurrence.
• General Assumption INTRON A is approved for
  lesions gt4 mm without or with lymph node
  involvement.
• Corollary Assumption INTRON A is not approved
  for lesions of lt4 mm without lymph node
  involvement.

63
AJCC Staging System (Edition 6) Issues

• New AJCC Staging System has thickness break
  points at 1, 2 and 4 mm rather than 0.76, 1.5 and
  4 mm.
• SWOG-9035 Entered patients with lesions of
  1.54.0 mm.
• New AJCC Staging System upstages patients with
  ulcerated primary lesions.

64
Lymphatic Mapping and Sentinel Node Biopsy

• Divides patients who were previously clinically
  staged as LN negative into pathologically staged
• Lymph node negative
• Lymph node positive
• Patients with pathologically staged positive
  lymph nodes are now commonly offered INTRON A.

65
Lymphatic Mapping and Sentinel Node Biopsy
Issues

• SWOG-9035 25 pathologically staged
• Proposed Trial Pathologically staged whenever
  feasible.
• As a consequence
• Proposed patient population will exclude patients
  with lymph nodes containing microscopic tumor
  detectable only by biopsy.
• Risk of recurrence of study population may be
  lower.

66
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

67
Proposed Trial Patient Population

• Includes Stage IIA (T2b, T3a)
• Stage IIB (T3b)
• Deemed intermediate risk for relapse.
• Higher Stages excluded
• Not represented in SWOG-9035
• May be INTRON A candidates
• Lower Stages excluded
• Not well represented in SWOG-9035
• Risk of relapse too low

68
Major Eligibility Criteria

1. Histologically diagnosed, surgically removed,
   Stage IIA (T2b and T3a) or IIB (T3b) cutaneous
   melanoma.
2. A2C3
3. Lymphatic mapping and sentinel node biopsy
   required, if technically feasible.
4. No evidence of residual melanoma.
5. No prior or planned INTRON A, chemotherapy,
   radiation or biologic response modifier therapy
   for melanoma.

69
Proposed Stages for Second Pivotal Trial
SWOG-9035 Old AJCC Staging SWOG-9035 Old AJCC Staging SWOG-9035 Old AJCC Staging Proposed TrialNew AJCC Staging Proposed TrialNew AJCC Staging Proposed TrialNew AJCC Staging Proposed TrialNew AJCC Staging Proposed TrialNew AJCC Staging
Stage T Thickness(mm) Path. Stage TNM Thickness(mm) Ulcer. 5-Year Surv.
IB T2 0.761.5 IB T2a 1.012.0 No 89
IIA T3 1.54.0 IIA T2b 1.012.0 Yes 77
T3a 2.014.0 No 79
IIB T3b 2.014.0 Yes 63
IIB T4 gt4.0 T4a gt 4.0 No 67
IIC T4b gt 4.0 Yes 45
IIIA N1a Any No 69
Balch et al JCO 193635, 2001
70
Stratification Factors

• Pathologic Stage
• T2b (1.02.0 mm, ulcerated primary) vs.
• T3a (gt2.04.0 mm, nonulcerated primary) vs.
• T3b (gt2.04.0 mm, ulcerated primary).
• Gender
• Site of primary
• Extremities vs. head neck and trunk

71
Sample Size Timing of Primary Analysis

• Total 700 A2C3 patients
• 350 patients per arm (vaccine vs. obs)
• Estimated 5-year RFS (based on SWOG-9035 and
  AJCC database)
• 70 in observation arm
• 80 in the vaccine arm
• Enrollment 34 years
• Data cutoff date for primary analyses 5 years
  after enrollment of last patient
• gt80 power using a two-sided test (alpha  0.05)

72
Proposed Trial Design Same as SWOG-9035
Surgery to Remove Tumor
Stratification and Randomization
Vaccine IM given for a total of 40 doses over the
first two years
Observation
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
73
Endpoints

• Efficacy ITT Population
• Primary Endpoint relapse-free survival
• Secondary Endpoint overall survival
• Safety
• Adverse Events
• Melacine and
• Observation arms

74
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 developmentof the
  vaccine
• 5. Proposed second randomized pivotaltrial
• 6. Issues for ODAC and the FDA

75
Issues for ODAC and the FDA

• 1. Is it agreed that treatment with INTRON A is
  not necessary for the proposed intermediate
  risk patient population that includes patients
  with Stage IIA (T2b and T3a) and IIB (T3b)
  tumors?

76
Issues for ODAC and the FDA

• Can/should patients with Stage IIIA (N1a) tumors,
  especially if lt4 mm, but with one positive
  microscopic lymph node detected by sentinel node
  biopsy, be included in the proposed trial?

77
Proposed Stages for Second Pivotal Trial
SWOG-9035 Old AJCC Staging SWOG-9035 Old AJCC Staging SWOG-9035 Old AJCC Staging Proposed TrialNew AJCC Staging Proposed TrialNew AJCC Staging Proposed TrialNew AJCC Staging Proposed TrialNew AJCC Staging Proposed TrialNew AJCC Staging
Stage T Thickness(mm) Path. Stage TNM Thickness(mm) Ulcer 5-Year Surv.
IB T2 0.761.5 IB T2a 1.012.0 No 89
IIA T3 1.54.0 IIA T2b 1.012.0 Yes 77
T3a 2.014.0 No 79
IIB T3b 2.014.0 Yes 63
IIB T4 gt4.0 T4a gt 4.0 No 67
IIC T4b gt 4.0 Yes 45
IIIA N1a Any No 69
Balch et al JCO 193635, 2001
78
Summary

• Adjuvant therapy for intermediate thickness Stage
  II melanoma is an unmet medical need.
• In SWOG-9035 Melacine prolonged RFS and OS in
  Stage II patients who expressed ?2 of 5
  predefined HLA types or expressed HLA-A2 and/or
  C3.

79
Summary (cont.)

• The mechanism by which Melacine provides a
  benefit is unknown, but is associated with immune
  response genes.
• Corixa needs consensus on the second Phase 3
  trial design to replicate SWOG-9035 in order to
  confirm the benefit of Melacine in this patient
  population and for approval.

80
SWOG Representatives

• John Thompson, M.D.Professor of
  MedicineUniversity of Washington
• Jeffrey Sosman, M.D.Professor of
  MedicineVanderbilt University
• Walter Urba, Ph.D., M.D.Director, Cancer
  ResearchEarle A. Chiles Research Institute

81
Corixa Representatives

• Martin A. Cheever, M.D.VP, Medical Affairs
• Cindy Jacobs, Ph.D., M.D.Senior VP, Clinical
  Development
• Monica Krieger, Ph.D.VP, Regulatory Affairs
• Charles Richardson, Ph.D.Senior VP,
  Manufacturing Site Manager
• Kenneth Von Eschen, Ph.D.Medical Director
• Heather Tully, M.S.Manager, Biostatistics

82
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