# Presentation: 066990

## 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 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

**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

**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. **

## 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. **

## 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. **

## 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 

**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 pivotal****trial **
**6.****	****Issues for ODAC and the FDA **

## 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**

- From: **Balch et al JCO 19:3635,  2001**

**Stage I (n=9176)**

**Stage II (n=5739)**

**Stage III (n=1525)**

**Stage IV (n=1158)**

## 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**** **

- From: **Balch et al JCO 19:3635,  2001**

**Stage IIA (1–2 mm, ulceration)****                 (2–4 mm, no ulceration)**

**Stage IIB (2–4 mm, ulceration)****                 (>4 mm, no ulceration)**

## 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 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 pivotal****trial **
**6.****	****Issues for ODAC and the FDA **

## Melacine Vaccine

**Melacine Vaccine**

**Detox****TM**
**250 ********g CWS + 25 ********g MPL**

***Melanoma Antigens***
**gp100****Gangliosides GD****2****, GD****3****Melan A/MART 1****MAGE-1, -2, -3****Tyrosinase, TRP-1****HMW-MAA**

***Immunological Adjuvants***
**CWS ****     Cell wall skeleton****     *****Mycobacterium phlei***
**MPL ****     Monophosphoryl lipid A****     *****Salmonella minnesota***

**Melanoma Lysate**
**20 x 10****6**** tumor cell equivalents**
**of Mel S and Mel D cell lines**

## 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

_**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)

_**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’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’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’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’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’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 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 pivotal****trial **
**6.****	****Issues for ODAC and the FDA **

## 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

**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 

**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.)  **

## SWOG-9035: Trial Design

**SWOG-9035: Trial Design**

**Surgery to Remove Tumor**

**Stratification and Randomization**

**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**

**Observation**

**Vaccine IM given for a total of 40 doses over the first two years**

## 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

**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 in****AJCC Staging System (edition 4)**

## 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 

**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

**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: Baseline Comparability: ITT Population (N=689) 

| Variable | Vaccine(n=346) | Observation(n=343) | p-value |
| --- | --- | --- | --- |
| Tumor Thickness     (1.50–3.00) | 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 |

## 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 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 SWOG****ITT Patients**** (Feb 2000 Database)**

**Observation:  N=343**

**Vaccine:  N=346**

**(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)

**Observation:  N=338**

**Vaccine:  N=345**

**(p=0.141)**

**(RFS benefit favored vaccine, not statistically significant)**

## 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 

**553 of 689 patients HLA phenotyped   **
**HLA-A2   = 46%**
**HLA-C3   = 29%**
**HLA-B44 = 25%**
**HLA-A28 =   9%**
**HLA-B45 =   1% **
**	****    ****A2C3+ = 58%**

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

| Subgroup | Comparison | p-value |
| --- | --- | --- |
| 0–1 match* (n=402)
 | Vaccine (n=213) vs. Observation (n=189) | 0.93 |
| 2 matches*  (n=151) | Vaccine (n=81) vs. Observation (n=70) | 0.0002 |
| *Number of matches with:  HLA‐A2 ‐A28, ‐B44, ‐B45, and ‐C3.  |  |  |

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

|  | % Patients | Vaccine Benefit |
| --- | --- | --- |
| HLA-A2 | 	46% | p=0.009 |
| HLA-C3 | 	29% | p=0.02 |
| HLA-B44 | 	25% | p=0.27 |
| HLA-A28 | 	9% | Insufficient # |
| HLA-B45 | 	1% | Insufficient # |

## 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) 

**Observation / A2C3+: N=145**

**Vaccine / A2C3+: N=178 **

**(p=0.002)**

**(Vaccine significantly prolonged RFS in A2C3****+**** patients)**

## SWOG‐9035: RFS Analysis A2C3+ Patients (May 2001 Database)

**Observation / A2C3+: N=145**

**(p=0.005)**

**Vaccine / A2C3+: N=178**

**(Vaccine significantly prolonged RFS in A2C3****+**** patients)**

## SWOG‐9035: RFS Analysis A2C3–  Patients (May 2001 Database)

**Observation / A2C3–: N=114**

**Vaccine / A2C3–: N=116**

**(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)**

## 5-Year RFS Estimate

| Subgroup | Treatment | N | 5-Year RFS | p-value |
| --- | --- | --- | --- | --- |
| A2C3+ | VaccineObservation | 178145 | 75%63% | 0.007 |
| A2C3– | Vaccine Observation | 116114 | 62%62% | 0.993 |
| [Log-rank test] |  |  |  |  |

## 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 Database)

**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

**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

**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 

**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 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 

**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)

**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

**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.  **

## Genes Linked to Class I HLA with Immune Response Functions

**	****(High level of linkage disequilibrium defines distinct haplotypes)**

**Genes Linked to Class I HLA with Immune Response Functions**

## 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 pivotal****trial **
**6.****	****Issues for ODAC and the FDA **

## Issues Affecting Further Development of the Vaccine 

**Changes in standard care that affect****attempts 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

**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

**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

**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

**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 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 pivotal**__**trial**_** **
**6.****	****Issues for ODAC and the FDA **

## 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

**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

| SWOG-9035: Old AJCC Staging |  |  | Proposed Trial:New AJCC Staging |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Stage | T | Thickness(mm) | Path. Stage | TNM | Thickness(mm) | Ulcer. | 5-Year* Surv. |
|  IB | T2 | 0.76–1.5 |  IB | T2a | 1.01–2.0 | No | 89% |
|  IIA | T3 | 1.5–4.0 |  IIA | T2b | 1.01–2.0 | Yes | 77% |
|  |  |  |  | T3a | 2.01–4.0 | No | 79% |
|  |  |  |  IIB | T3b | 2.01–4.0 | Yes | 63% |
|  IIB | T4 | >4.0 |  | T4a | > 4.0 | No | 67% |
|  |  |  |  IIC | T4b | > 4.0 | Yes | 45% |
|  |  |  |  IIIA | N1a | Any | No | 69% |

**Proposed Stages for Second Pivotal Trial**

*** Balch et al JCO 19:3635,  2001**

## 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  

**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) **

## Proposed Trial Design:  Same as SWOG-9035

**Proposed Trial Design:  Same as SWOG-9035**

**Surgery to Remove Tumor**

**Stratification and Randomization**

**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**

**Observation**

**Vaccine IM given for a total of 40 doses over the first two years**

## Endpoints 

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

## 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 pivotal****trial **
**6.****	**_**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 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 Trial

| SWOG-9035: Old AJCC Staging |  |  | Proposed Trial:New AJCC Staging |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Stage | T | Thickness(mm) | Path. Stage | TNM | Thickness(mm) | Ulcer | 5-Year* Surv. |
|  IB | T2 | 0.76–1.5 |  IB | T2a | 1.01–2.0 | No | 89% |
|  IIA | T3 | 1.5–4.0 |  IIA | T2b | 1.01–2.0 | Yes | 77% |
|  |  |  |  | T3a | 2.01–4.0 | No | 79% |
|  |  |  |  IIB | T3b | 2.01–4.0 | Yes | 63% |
|  IIB | T4 | >4.0 |  | T4a | > 4.0 | No | 67% |
|  |  |  |  IIC | T4b | > 4.0 | Yes | 45% |
|  |  |  |  IIIA | N1a | Any | No | 69% |

**Proposed Stages for Second Pivotal Trial**

*** Balch et al JCO 19:3635,  2001**

## 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.)

**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. **

## John Thompson, M.D.Professor of MedicineUniversity of Washington
Jeffrey Sosman, M.D.Professor of MedicineVanderbilt University
Walter Urba, Ph.D., M.D.Director, Cancer ResearchEarle A. Chiles Research Institute

**Jeffrey Sosman, M.D.****Professor of Medicine****Vanderbilt University**
**Walter Urba, Ph.D., M.D.****Director, Cancer Research****Earle A. Chiles Research Institute**

**SWOG 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

** ****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**

**Corixa Representatives**

## Slide 82