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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

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
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
brief summary of swog 9035
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.
background for approval of melacine
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.
slide5
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.
slide6
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.

slide7
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.
outline of presentation
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

overview of melanoma
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

outcome depends on stage 15 year disease specific survival
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

intermediate thickness stage ii melanoma
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

15 year disease specific survival stage ii melanoma new ajcc staging system
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

options for adjuvant therapy of intermediate thickness stage ii melanoma
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

outline of presentation14
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

slide15

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

clinical development of melacine advanced stage patients
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.

clinical development of melacine stage ii patients
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.
clinical development of melacine stage ii patients cont d
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)

clinical development of melacine stage ii patients cont d19
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+)

clinical development of melacine stage ii patients cont d20
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

clinical development of melacine stage ii patients cont d21
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)
clinical development of melacine stage ii patients cont d22
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)

clinical development of melacine stage ii patients cont d23
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.

outline of presentation24
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

slide25

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
swog 9035 study coordinators
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
swog 9035 objectives
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.)

slide28

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

swog 9035 inclusion criteria
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
swog 9035 t3n0m0
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)
swog 9035 study design
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
swog 9035 patient disposition
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.
swog 9035 timing of rfs analysis
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
swog 9035 rfs analyses by swog itt population feb 2000 database
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)  
swog 9035 rfs analyses by swog itt population feb 2000 database36
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)
swog 9035 rfs analyses by swog itt patients feb 2000 database
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)

swog 9035 rfs analyses itt patients may 2001 database
SWOG‑9035: RFS AnalysesITT Patients (May 2001 Database)

Vaccine: N=345

Observation: N=338

(p=0.141)

(RFS benefit favored vaccine, not statistically significant)

association of hla and melacine benefit
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.
swog 9035 frequency of patients with the predefined hla phenotypes
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%

slide41
SWOG-9035: RFS Benefit for Melacine in Patients Expressing  2 of the 5 Predefined HLA Phenotypes (SWOG Analyses)
slide42
SWOG-9035: RFS Benefit for Melacine in Patients Expressing Each of the 5 Predefined HLA (SWOG Multivariate Analysis)
swog 9035 vaccine benefit in a2c3 patients feb 2000 database
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)
swog 9035 rfs analysis a2c3 patients feb 2000 database
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)

swog 9035 rfs analysis a2c3 patients may 2001 database
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)

swog 9035 rfs analysis a2c3 patients may 2001 database46
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)

swog 9035 rfs analysis observation patients may 2001 database
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)

swog 9035 overall survival a2c3 patients may 2001 database
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)

swog 9035 overall survival a2c3 patients may 2001 database50
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)

swog 9035 overall survival observation patients may 2001 database
SWOG‑9035: Overall Survival Observation Patients (May 2001 Database)

Observation / A2C3–: N=114

Observation / A2C3+: N=145

(p=0.233)

(A2C3 expression without vaccine did not prolong OS)

swog 9035 summary of follow up analysis by corixa of may 2001 database
SWOG-9035: Summary of Follow-up Analysis by Corixa of May 2001 Database
  • Vaccine is effective in prolonging RFS in A2C3+ patients (p=0.005).
  • Vaccine is effective in prolonging OS in A2C3+ patients (p=0.003).
  • Subsequent analysis by SWOG confirmed this assessment. (ASCO, May 2002)
swog 9035 vaccine safety
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”.
swog 9035 ae summary
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
swog 9035 ae summary55
SWOG-9035: AE Summary
  • Grade 3 toxicities reported in three or more patients:
    • Injection site reactions (11 patients, 3%)
    • Malaise/fatigue/lethargy (3 patients, <1%)
    • Diarrhea (3 patients, <1%)
    • Transient vision abnormalities (3 patients, <1%)
    • Fever in absence of infection (3 patients, <1%)
  • Grade 4 toxicity reported - None
swog 9035 summary
SWOG-9035: Summary
  • Melacine significantly improved RFS (p=0.005) and OS (p=0.003) 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 patient’s genetic capability to respond.
human leukocyte antigens hla
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
correlation of hla a2 and or c3 with vaccine benefit
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.

slide59

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)

outline of presentation60
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

issues affecting further development of the vaccine
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.

impact of intron a on study design
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 >4 mm without or with lymph node involvement.
  • Corollary Assumption: INTRON A is not approved for lesions of <4 mm without lymph node involvement.
ajcc staging system edition 6 issues
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 1.5–4.0 mm.
  • New AJCC Staging System upstages patients with ulcerated primary lesions.
lymphatic mapping and sentinel node biopsy
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.
lymphatic mapping and sentinel node biopsy issues
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.
outline of presentation66
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

proposed trial patient population
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
major eligibility criteria
Major Eligibility Criteria
  • Histologically diagnosed, surgically removed, Stage IIA (T2b and T3a) or IIB (T3b) cutaneous melanoma.
  • A2C3+
  • Lymphatic mapping and sentinel node biopsy required, if technically feasible.
  • No evidence of residual melanoma.
  • No prior or planned INTRON A, chemotherapy, radiation or biologic response modifier therapy for melanoma.
proposed stages for second pivotal trial
Proposed Stages for Second Pivotal Trial

* Balch et al JCO 19:3635, 2001

stratification factors
Stratification Factors
  • Pathologic Stage
    • T2b (1.0–2.0 mm, ulcerated primary) vs.
    • T3a (>2.0–4.0 mm, nonulcerated primary) vs.
    • T3b (>2.0–4.0 mm, ulcerated primary).
  • Gender
  • Site of primary
    • Extremities vs. head & neck and trunk
sample size timing of primary analysis
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: 3–4 years
  • Data cutoff date for primary analyses 5 years after enrollment of last patient
  • >80% power using a two‑sided test(alpha = 0.05)
slide72

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

endpoints
Endpoints
  • Efficacy: ITT Population
    • Primary Endpoint: relapse-free survival
    • Secondary Endpoint: overall survival
  • Safety:
    • Adverse Events:
      • Melacine and
      • Observation arms
outline of presentation74
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

issues for odac and the fda
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?

issues for odac and the fda76
Issues for ODAC and the FDA
  • Can/should patients with Stage IIIA (N1a) tumors, especially if <4 mm, but with one positive microscopic lymph node detected by sentinel node biopsy, be included in the proposed trial?
proposed stages for second pivotal trial77
Proposed Stages for Second Pivotal Trial

* Balch et al JCO 19:3635, 2001

summary
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.
summary cont
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.
slide80

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

slide81

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

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