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

Basic Trial Information

Objectives

I.  Establish the efficacy of 1 year of adjuvant treatment with interferon 
alpha (IFN-A) at maximum tolerated doses in improving the disease-free and 
overall survival of melanoma patients at high risk for recurrence after 
definitive surgery for deep primary lesions or for regional lymph node 
recurrence.

II.  Evaluate the efficacy and tolerance of long-term adjuvant low-dose (3 
MU/day, 3 x weekly) IFN-A in comparison to 1 year of treatment at maximum 
tolerated doses in the same patient population.

Entry Criteria

Disease Characteristics:

Completely resected, histopathologically documented cutaneous
melanoma of 1 of the following TNM stages at high risk for
recurrence:

  T4 N0 M0 (deep primary, i.e., greater than 4 mm Breslow
  depth, with or without lymphadenectomy)

  T1-4 N1 M0 (primary melanoma with regional lymph node
  metastases found at lymphadenectomy but clinically
  undetectable, i.e., occult)

  T1-4 N1-2 M0 (primary melanoma with clinically apparent,
  i.e., overt, regional lymph node metastases confirmed by
  lymphadenectomy)

  T1-4 N1-2 M0 (recurrence of melanoma at the site of
  proximal regional lymph node resection)

Definitive surgery and randomization within 56 days of
initial biopsy required, as follows:

  Wide excision of primary with 2 cm margins

  Full lymphadenectomy
     Lymphadenectomy not required in T4 N0 M0 patients

  Pathologic confirmation of adequate surgical margins (e.g.,
  2 cm minimum for lesions of greater than 1 mm Breslow
  depth) required

  Distal interphalangeal amputation required for subungual
  melanoma

Randomization within 42 days of lymphadenectomy required in
patients entering with recurrent regional lymph node disease

No melanoma of unknown or noncutaneous primary site

No local recurrence or satellite lesions

No more than 1 involved lymph node group allowed

No extra nodal extension or soft tissue invasion

Registration on protocol E-2690 (An Evaluation of the In Vivo
Mechanism of Interferon Alfa-2b) prior to registration on this
protocol required unless ineligible solely because of HIV or
hepatitis B infection

Prior/Concurrent Therapy:

Biologic therapy:
  No prior adjuvant immunotherapy

Chemotherapy:
  No prior adjuvant chemotherapy

Endocrine therapy:
  Not specified

Radiotherapy:
  No prior adjuvant radiotherapy

Surgery:
  Complete surgical resection required

Other:
  No preoperative infusion or perfusion therapy
  No concurrent requirement for the following:
     Steroids
     Nonsteroidal anti-inflammatory agents
     Other prostaglandin synthetase inhibitors
     Antihistamines
     Other immunomodulators

Patient Characteristics:

Age:
  Physiologic 18 to 70

Performance status:
  ECOG 0 or 1

Hematopoietic:
  WBC at least 4,000
  Platelets at least 125,000
  Hematocrit at least 33%

Hepatic:
  Bilirubin no more than 2 x normal
  SGOT no more than 2 x normal

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

Cardiovascular:
  No CHF (NYHA classification greater than 2)
  No history of treatment with anthracyclines
  No ventricular or supraventricular arrhythmia requiring
  treatment

Other:
  No medical or psychiatric disorders precluding therapy,
  e.g.:
     No organic brain syndrome
     No significant impairment of basal cognitive function
     No depression
  No second malignancy except:
     In situ cervical cancer
     Basal and squamous cell skin cancer
     (exceptions may be discussed with study chairman)

Expected Enrollment

A total of 625 patients will be entered over an estimated 4.5 years.

Outline

Randomized study.

Arm I:  Biological Response Modifier Therapy.  Interferon alpha (Schering), 
IFN-A, NSC-377523.  High dose for 1 year.

Arm II:  Biological Response Modifier Therapy.  IFN-A.  Chronic low dose.

Arm III:  No Further Treatment.

Chen M, Harrington DP, Ibrahim JG: Bayesian cure rate models for malignant melanoma: a case-study of Eastern Cooperative Oncology Group trial E1690 . [Abstract] J R Stat Soc Ser C Appl Stat 51 (2): 135-50, 2002.

Kirkwood JM, Richards T, Zarour HM, et al.: Immunomodulatory effects of high-dose and low-dose interferon alpha2b in patients with high-risk resected melanoma: the E2690 laboratory corollary of intergroup adjuvant trial E1690. Cancer 95 (5): 1101-12, 2002.[PUBMED Abstract]

Rao UN, Ibrahim J, Flaherty LE, et al.: Implications of microscopic satellites of the primary and extracapsular lymph node spread in patients with high-risk melanoma: pathologic corollary of Eastern Cooperative Oncology Group Trial E1690. J Clin Oncol 20 (8): 2053-7, 2002.[PUBMED Abstract]

Kirkwood JM, Ibrahim JG, Sondak VK, et al.: High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18 (12): 2444-58, 2000.[PUBMED Abstract]

Kirkwood JM, Ibrahim J, Sondak V, et al.: Preliminary analysis of the E1690/S9111/C9190 Intergroup postoperative adjuvant trial of high-and-low-dose IFNa2b (HDI and LDI) in high-risk primary or lymph node metastatic melanoma. [Abstract] Proceedings of the American Society of Clinical Oncology 18: A2072, 537a, 1999.

Kirkwood JM, Sosman J, Ernstoff M, et al.: A study of the mechanism of IFN alfa-2b in high-risk melanoma in the ECOG/Intergroup trial E1690. [Abstract] Proc Am Assoc Cancer Res 36(3815): 641, 1995.

Ibrahim JG, Chen MH, Chu H: Bayesian methods in clinical trials: a Bayesian analysis of ECOG trials E1684 and E1690. BMC Med Res Methodol 12: 183, 2012.[PUBMED Abstract]

Rao UN, Lee SJ, Luo W, et al.: Presence of tumor-infiltrating lymphocytes and a dominant nodule within primary melanoma are prognostic factors for relapse-free survival of patients with thick (t4) primary melanoma: pathologic analysis of the e1690 and e1694 intergroup trials. Am J Clin Pathol 133 (4): 646-53, 2010.[PUBMED Abstract]

Bonetti M, Gigliarano C, Muliere P: The Gini concentration test for survival data. Lifetime Data Anal 15 (4): 493-518, 2009.[PUBMED Abstract]

Kilbridge KL, Cole BF, Kirkwood JM, et al.: Quality-of-life-adjusted survival analysis of high-dose adjuvant interferon alpha-2b for high-risk melanoma patients using intergroup clinical trial data. J Clin Oncol 20 (5): 1311-8, 2002.[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

Lawrence Flaherty, MD, Protocol chair		Ph: 313-576-8715; 800-527-6266 Email: flaherty@karmanos.org

Cancer and Leukemia Group B

Jon Richards, MD, PhD, Protocol chair		Ph: 847-268-8200 Email: jrichards@oncmed.net

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