S0008: Chemotherapy Plus Biological Therapy in Treating Patients With Melanoma

• 5-year Overall Survival [ Time Frame: Every three months for a year, every six months for years 2-5, annual for years 5-10 ] [ Designated as safety issue: No ]
  Overall survival was measured from the date of registration to study until death from any cause with observations censored at the date of last contact for patients last known to be alive.
• 5-year Relapse-Free Survival [ Time Frame: Every three months for the first year, every 6 months for years 2-5, annually for years 6-10 ] [ Designated as safety issue: No ]
  Measured from date of registration to date of first observation of progressive disease or death due to any cause.

RATIONALE: Interferon alfa may interfere with the growth of cancer cells. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Interleukin-2 may stimulate a person's white blood cells to kill melanoma cells. It is not yet known whether interferon alfa is more effective with or without combination chemotherapy and interleukin-2 for melanoma.

PURPOSE: Randomized phase III trial to compare the effectiveness of interferon alfa with or without combination chemotherapy consisting of cisplatin, vinblastine, and dacarbazine, plus interleukin-2, in treating patients who have melanoma.

OBJECTIVES:

• Compare the overall survival and disease-free survival of patients with high-risk melanoma treated with interferon alfa vs cisplatin, vinblastine, and dacarbazine plus interferon alfa and interleukin-2.
• Compare the toxic effects of these treatment regimens in these patients.
• Determine the relationship between minimal residual disease (MRD) status at 12 weeks and 52 weeks and overall survival of patients treated with these regimens.
• Compare the effects of these treatment regimens on the MRD status of these patients.
• Determine the relationship between clinical characteristics (number of involved lymph nodes, ulcerated primary, and extracapsular extension) and MRD in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to nodal status (N1 or N2 vs N3), degree of lymph node involvement (micrometastases only vs any macrometastases, including satellite/in-transit metastases), and ulceration of the primary tumor (yes vs no vs unknown primary). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive interferon alfa IV on days 1-5 of weeks 1-4 followed by interferon alfa subcutaneously (SC) on days 1, 3, and 5 of weeks 5-52 in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive cisplatin IV over 30 minutes followed by vinblastine IV on days 1-4. Patients also receive dacarbazine IV over 1 hour on day 1, interleukin-2 IV over 96 hours on days 1-4, and interferon alfa SC on days 1-5, 8, 10, and 12. In addition, patients receive filgrastim (G-CSF) SC on days 6-15. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

PROJECTED ACCRUAL: A total of 410 patients (205 per treatment arm) will be accrued for this study within 3 years.

• Biological: interleukin-2
  Given IV
  Other Name: aldesleukin
• Biological: filgrastim
  Given subcutaneously
• Biological: interferon alfa
  Given IV and subcutaneously
• Drug: cisplatin
  Given IV
• Drug: dacarbazine
  Given IV
• Drug: vinblastine
  Given IV

• Active Comparator: Arm I
  Patients receive interferon alfa IV on days 1-5 of weeks 1-4 followed by interferon alfa subcutaneously (SC) on days 1, 3, and 5 of weeks 5-52 in the absence of disease progression or unacceptable toxicity.
  Intervention: Biological: interferon alfa
• Experimental: Arm II
  Patients receive cisplatin IV over 30 minutes followed by vinblastine IV on days 1-4. Patients also receive dacarbazine IV over 1 hour on day 1, interleukin-2 IV over 96 hours on days 1-4, and interferon alfa SC on days 1-5, 8, 10, and 12. In addition, patients receive filgrastim (G-CSF) SC on days 6-15. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Biological: interleukin-2
  • Biological: filgrastim
  • Biological: interferon alfa
  • Drug: cisplatin
  • Drug: dacarbazine
  • Drug: vinblastine

DISEASE CHARACTERISTICS:

• Histologically proven melanoma of cutaneous origin or from unknown primary at initial presentation of primary or first clinically detected nodal or satellite/in-transit recurrence

  • No distant metastases
  • No melanoma of ocular, mucosal, or other non-cutaneous origin

• One of the following criteria must apply for patients with newly diagnosed melanoma OR a previously diagnosed primary with current subsequent, clinical, regional nodal disease and/or satellite/in-transit disease:

  • Ulcerated primary melanoma with 1 or more involved lymph nodes (micro/occult or macro/clinically overt)

  • Non-ulcerated or unknown primary melanoma with one macro/clinically overt lymph node metastasis, including a single matted nodal mass

    • No non-ulcerated or unknown primary tumor and a single micrometastatic lymph node
  • Non-ulcerated melanoma with two or more lymph node metastases (micro/occult or macro/clinically overt) and/or matted nodes
  • Any satellite/in transit metastasis with or without lymph node involvement
• Patients with recurrent disease must have recurrent disease in the regional nodal basin of a prior complete lymphadenectomy
• Multiple regional nodal basin involvement allowed if they are appropriate anatomic drainage basins for primary site

• Patients must be disease free at time of enrollment based on the following surgical criteria:

  • Patients at initial presentation of melanoma must undergo adequate wide excision of primary lesion
  • Patients with previously diagnosed melanoma must have all disease resected with pathologically negative margins and no disease at primary site or second resection of primary
  • Full lymphadenectomy required of all patients including those with positive sentinel nodes or positive satellite/in-transit metastasis
• No more than 56 days since prior lymphadenectomy OR surgery to remove recurrent disease after prior complete lymphadenectomy
• Must be willing to participate in minimal residual disease studies if registered on the study on 3/1/2003 or later

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Zubrod 0-1

Life expectancy:

• Not specified

Hematopoietic:

• Absolute granulocyte count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• SGOT or SGPT no greater than 2 times ULN
• LDH and alkaline phosphatase no greater than 2 times ULN (above normal value requires a contrast-enhanced CT scan or MRI of liver)
• No known recent hepatitis positivity by PCR

Renal:

• Creatinine no greater than 1.5 mg/dL OR
• Creatinine clearance at least 75 mL/min

Cardiovascular:

• No congestive heart failure
• No coronary artery disease
• No serious cardiac arrhythmia
• No prior myocardial infarction

• Normal cardiac stress test required if any of the following are present:

  • Over age 50
  • Abnormal EKG
  • History of cardiac disease

Pulmonary:

• No symptomatic pulmonary disease

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No autoimmune disorders or conditions of immunosuppression

• No other prior malignancy within the past 5 years except the following:

  • Adequately treated basal cell or squamous cell skin cancer
  • Carcinoma in situ of the cervix
  • Adequately treated stage I or II cancer in remission
• HIV negative
• No known AIDS or HIV-1 associated complex

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior immunotherapy, including interferon, interleukin, levamisole, or other biologic response modifiers
• No other concurrent biologic therapy

Chemotherapy:

• No prior chemotherapy (including infusion or perfusion therapy)
• No other concurrent chemotherapy

Endocrine therapy:

• No concurrent systemic corticosteroids or topical steroid creams
• Concurrent steroid antihistamines allowed if no alternative
• No concurrent hormonal therapy

Radiotherapy:

• No prior radiotherapy

  • Prior postlumpectomy radiotherapy for breast cancer allowed
• No concurrent radiotherapy

Surgery:

• See Disease Characteristics
• No concurrent surgery

Other:

• No concurrent anti-hypertensive medications (arm II only)
• No concurrent immunosuppressive agents
• No other concurrent anticancer therapy
• Antihistamines allowed if no alternative medication suitable

• National Cancer Institute (NCI)
• Eastern Cooperative Oncology Group
• Cancer and Leukemia Group B
• Children's Oncology Group