Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Alternate Title

Vaccine Therapy Compared With High-Dose Interferon-alfa in Treating Patients With High-Risk Melanoma

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Closed 18 and over NCI E-1694 CAN-NCIC-ME9, MDA-DM-E1694, MSKCC-96008, SWOG-9512, CAN-NCIC-E1694, MSKCC-E1694, SWOG-E1694, E1694, ME9

Objectives

I. Compare relapse free and overall survival in patients with high risk 
melanoma treated with vaccination with ganglioside GM2 covalently conjugated 
to keyhole limpet hemocyanin plus immunologic adjuvant QS21 (GM2-KLH/QS21) vs 
high dose interferon alfa-2b (IFN-A).

II. Determine the correlation between preexisting or vaccine induced IgM 
antibody response against GM2 and relapse free and overall survival in 
patients immunized with GM2-KLH/QS21.

III. Compare the quality of life in these patients before and after these 
treatments.

Entry Criteria

Disease Characteristics:

Malignant melanoma of a cutaneous origin with newly diagnosed primary disease
or first clinically detected nodal recurrence in 1 of the following
categories:
 T4 N0 M0
  Deep primary melanoma (greater than 4.0 mm Breslow depth) with or without
  prior lymphadenectomy
 T1-4 N1 M0
  Primary melanoma with regional lymph node metastases found at
  lymphadenectomy but clinically undetectable
 T1-4 N1-2 M0
  Primary melanoma with clinically apparent regional lymph node metastases
   confirmed by lymphadenectomy OR
  Clinically detected recurrence of melanoma at the proximal regional lymph
   node basin confirmed by lymphadenectomy OR
  Clinically or histologically detected primary melanoma involving multiple
   regional nodal groups confirmed by lymphadenectomy
 Tx N1-2 M0
  Clinically detected single site of nodal metastatic melanoma arising from
  an unknown primary and confirmed by lymphadenectomy

Primary lesion completely resected by wide excision with minimum 1.0 cm margin

Randomization required within 56 days of definitive surgery and within 70 days
of initial biopsy

No ocular melanoma, melanoma of mucosal origin, or any other noncutaneous
melanoma

No soft tissue involvement by gross extranodal extension of tumor or any gross
extracapsular invasion or grossly apparent satellite lesions

No regional recurrence in transit, i.e., metastases involving skin or
subcutaneous tissue or lymph nodes more than 2 cm from primary tumor but not
beyond the regional lymph node

Must also register for E1695

Prior/Concurrent Therapy:

No prior treatment on this protocol

Biologic therapy:
 No prior immunotherapy, including tumor vaccines, interferons, interleukins,
  levamisole, or other biologic response modifiers, for any cancer

Chemotherapy:
 No prior chemotherapy for any cancer

Endocrine therapy:
 For patients randomized to receive GM2-KLH/QS21:
  No concurrent corticosteroids or any systemic steroids, except
   antihistamines if there is no alternative medication

Radiotherapy:
 No prior radiotherapy for any cancer

Surgery:
 See Disease Characteristics

Other:
 For patients randomized to receive GM2-KLH/QS21:
  No concurrent immunosuppressive medication

Patient Characteristics:

Age:
 18 and over

Performance status:
 ECOG 0 or 1

Hematopoietic:
 WBC at least 3,000/mm3
 Platelet count at least 125,000/mm3
 Hematocrit at least 33%

Hepatic:
 Bilirubin no greater than 2 times normal
 AST no greater than 2 times normal
 Alkaline phosphatase no greater than 2 times normal *
 LDH no greater than 2 times normal *
  * Negative contrast enhanced liver CT or MRI required if elevated

Renal:
 Creatinine no greater than 1.8 mg/dL
 BUN no greater than 33 mg/dL

Cardiovascular:
 No NYHA class III/IV status
 No active ischemic or cerebrovascular disease

Other:
 HIV negative
 Hepatitis surface antigen negative
 No severe allergy to shellfish
 No autoimmune disorder, immunosuppressive condition, or treatment with
  systemic corticosteroids
 No organic brain syndrome or significant impairment of basal cognitive
  function
 No CNS-demyelinating, inflammatory disease or hereditary or acquired
  peripheral neuropathy
 No psychiatric or medical condition contraindicating protocol participation
 No second malignancy within past 5 years except:
  Nonmelanomatous skin cancer
  Lobular carcinoma in situ of the breast
  Carcinoma in situ of the cervix
  Atypical melanocytic hyperplasia or Clark I melanoma in situ
 Not pregnant or nursing  
 Negative pregnancy test
 Fertile patients must use effective contraception

Expected Enrollment

A total of 851 patients will be accrued for this study over approximately 3.3 
years.

Outline

This is a randomized, multicenter study.  Patients are stratified by number of 
positive nodes at lymphadenectomy (0 vs. 1 vs. 2 or 3 vs. 4 or more), gender, 
and serological assessment.   Patients are randomized to 1 of 2 treatment 
arms.  

Arm I:
Patients receive ganglioside GM2 covalently conjugated to keyhole limpet 
hemocyanin plus immunologic adjuvant QS21 (GM2-KLH/QS21) by subcutaneous 
injection every week for 4 weeks and then at weeks 12, 24, 36, 48, 72, 84, and 
96.   

Arm II:
Patients receive interferon alfa-2b (IFN-A) IV over 20 minutes 5 days each 
week for 4 weeks and then by subcutaneous injection 3 times each week for 48 
weeks. 

Patients are followed every 6 months until year 5 and then annually 
thereafter. 

Whalen J, Lee S, Sondak VK, et al.: Post-adjuvant (salvage) therapy of high-risk melanoma patients following the intergroup E1694 trial. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-2896, 2003.

Kirkwood JM, Ibrahim JG, Sosman JA, et al.: High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 19 (9): 2370-80, 2001.[PUBMED Abstract]

Kilbridge KL, Cole B, Weeks JC, et al.: Quality-of-life (QOL) adjusted analysis of high-dose adjuvant interferon alfa-2B (HDI) for melanoma based on E1694/S9512/C509801, E1690/S9111/C9190 and E1684. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1398, 2002.

Kirkwood JM, Manola J, Ibraham J, et al.: Pooled-analysis of four ECOG/Intergroup trials of high-dose interferon Alfa-2b (HDI) in 1916 patients with high-risk resected cutaneous melanoma. [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-1395, 2001.

Kirkwood JM, Sosman JA, Ernstoff MS, et al.: Overview of the role of high-dose IFN(2b(HDI) in the therapy of high-risk resectable melanoma. J Immunother 23(5): 595, 2000.

Sondak VK, Wolfe JA: Adjuvant therapy for melanoma. Curr Opin Oncol 9 (2): 189-204, 1997.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

John Kirkwood, MD, Protocol chair		Ph: 412-692-4724

Southwest Oncology Group

Jeffrey Sosman, MD, Protocol chair		Ph: 615-322-4967; 800-811-8480 Email: jeff.sosman@vanderbilt.edu

M. D. Anderson Cancer Center at University of Texas

Merrick Ross, MD, Protocol chair		Ph: 713-745-5030; 800-392-1611

Memorial Sloan-Kettering Cancer Center

Paul Chapman, MD, Protocol chair		Ph: 646-888-2378; 800-525-2225

NCIC-Clinical Trials Group

Neill Iscoe, MD, FRCPC, Protocol chair		Ph: 416-480-5847