S0008: Chemotherapy Plus Biological Therapy in Treating Patients With Melanoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase III Trial of High Dose Interferon Alfa 2-b Versus Cisplatin, Vinblastine, DTIC Plus IL-2 and Interferon in Patients With High Risk Melanoma

Conditions
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Melanoma (Skin)

Intervention / Treatment
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* Biological: interleukin-2
* Biological: filgrastim
* Biological: interferon alfa
* Drug: cisplatin
* Drug: dacarbazine
* Drug: vinblastine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I<br>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. | Biological: interferon alfa<br>* Given IV and subcutaneously<br>|
| Experimental: Arm II<br>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. | Biological: interleukin-2<br>* Given IV<br>* Other names: aldesleukin;Biological: filgrastim<br>* Given subcutaneously<br>Biological: interferon alfa<br>* Given IV and subcutaneously<br>Drug: cisplatin<br>* Given IV<br>Drug: dacarbazine<br>* Given IV<br>Drug: vinblastine<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year Overall Survival | 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. | Every three months for a year, every six months for years 2-5, annual for years 5-10 | 
| 5-year Relapse-Free Survival | Measured from date of registration to date of first observation of progressive disease or death due to any cause. | Every three months for the first year, every 6 months for years 2-5, annually for years 6-10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity | Number of patients with Grade 3-5 adverse events that are related to study drug by given type of adverse event | While on treatment, patients on the HDIFN arm were assessed weekly for the 1st month, then every 2 weeks for the 2nd month, then every 3 months therafter; patients on the biochemo arm were assessed daily for the 1st 5 days, then weekly thereafter. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III melanoma, recurrent melanoma