Melphalan With or Without Tumor Necrosis Factor in Treating Patients With Locally Advanced Melanoma of the Arm or Leg

Study Overview
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Brief Summary
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Randomized phase III trial to compare the effectiveness of hyperthermic isolated limb perfusion of melphalan with or without tumor necrosis factor in treating patients who have locally advanced melanoma of the arm or leg. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Heating melphalan to several degrees above body temperature and infusing it only to the area around the tumor may kill more tumor cells. It is not yet known whether combining melphalan with tumor necrosis factor is more effective than melphalan alone in treating melanoma.

Detailed Description
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OBJECTIVES: I. Compare hyperthermic isolated limb perfusion with melphalan with or without tumor necrosis factor, in terms of response proportion for lesions in the perfusion field, in patients with locally advanced extremity melanoma. II. Compare the local recurrence-free survival, improvement in regional symptoms related to tumor, and overall survival in patients treated with these regimens. III. Compare the toxicity of these regimens in these patients. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to tumor burden (high vs low), prior reperfusion (melphalan vs other), regional nodal site (yes vs no), and participating center. Patients are randomized to one of two treatment arms. ARM I: Patients undergo hyperthermic isolated perfusions of the lower limb by either the external iliac vessels or the common femoral vessels. Patients undergo perfusions of the upper extremity by the axillary artery and vein using an infraclavicular/axillary incision. Melphalan is introduced into the perfusion by slow injection over 5 minutes and allowed to remain for a total of 60 minutes. ARM II: Patients undergo hyperthermic isolated perfusions as in arm I. Tumor necrosis factor is administered by slow injection into the arterial line and allowed to remain for a total of 90 minutes. Melphalan is introduced into the perfusion as in arm I and allowed to remain for a total of 60 minutes. Patients are followed within 6 weeks, at 3, 6, and 12 months, every 6 months for 4 years, and then annually thereafter.

Official Title
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A Randomized Phase III Trial of Hyperthermic Isolated Limb Perfusion and Melphalan With and Without Tumor Necrosis Factor in Patients With Localized Advanced Extremity Melanoma

Conditions
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Recurrent Melanoma, Stage III Melanoma

Intervention / Treatment
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* Drug: isolated limb perfusion
* Drug: melphalan
* Biological: recombinant tumor necrosis factor family protein
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven locally advanced melanoma of an extremity One or more evaluable in-transit metastases All disease within the perfusion field of the extremity (with no local resection options short of amputation) Disease outside of perfusion field (with no local resection options short of amputation) if all the following are true: High tumor burden (more than 10 lesions or any single lesion greater than 3 cm) Presence of pain, edema, skin breakdown, or decreased mobility Greater than 80% of known tumor is within extremity perfusion field Life expectancy more than 6 months No brain metastases At least 1 bidimensionally measurable lesion Patients who received prior prophylactic isolated limb perfusion (ILP) must have 1 of the following: Disease-free interval for at least 6 months after prior ILP with melphalan Disease-free interval for at least 3 months after prior ILP with an agent other than melphalan Patients who received prior therapeutic ILP must have 1 of the following: Partial response of at least 3 months duration after prior ILP with melphalan Stable response or disease progression after ILP without melphalan (performed at least 3 months prior to study) Performance status - ECOG 0-2 Performance status - Zubrod 0-2 See Disease Characteristics Platelet count at least 100,000/mm^3 WBC greater than 2,500/mm^3 Hemoglobin greater than 9 g/dL Bilirubin less than 1.25 times ULN AST and ALT less than 2 times ULN Alkaline phosphatase less than 2 times ULN Coagulation studies normal or within 1 second of upper limit of normal (ULN) Creatinine less than 1.5 mg/dL Creatinine clearance greater than 50 mL/min Calcium less than 12 mg/dL No severe peripheral vascular disease (claudication or other ischemic peripheral vascular disease [e.g., venous thrombosis or occlusive peripheral arterial disease]) No New York Heart Association class II-IV heart disease (congestive heart failure) No uncontrolled or life-threatening cardiac arrhythmia No myocardial infarction within the past year No unstable angina No symptomatic cerebral or carotid artery disease No pulmonary embolism within the past year Other prior malignancy allowed if completed curative therapy, disease-free for at least 5 years, and at low risk for recurrence No active peptic ulcer disease within the past year Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No known melphalan hypersensitivity No known hypersensitivity to any component of tumor necrosis factor alpha formulation No contraindications to ionotropic agents (e.g., dopamine or neosynephrine) No concurrent infections uncontrolled with antibiotics HIV negative At least 1 month since prior biologic therapy See Disease Characteristics At least 1 month since prior chemotherapy At least 4 months since prior isolated limb perfusion At least 1 month since prior radiotherapy See Disease Characteristics At least 12 months since prior coronary artery surgery or angioplasty

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 |
| --- | --- |
| Experimental: Arm I<br>Patients undergo hyperthermic isolated perfusions of the lower limb by either the external iliac vessels or the common femoral vessels. Patients undergo perfusions of the upper extremity by the axillary artery and vein using an infraclavicular/axillary incision. Melphalan is introduced into the perfusion by slow injection over 5 minutes and allowed to remain for a total of 60 minutes. | Drug: isolated limb perfusion<br>* Undergo isolated limb perfusion<br>* Other names: isolated limb infusion;Drug: melphalan<br>* Given via limb perfusion<br>* Other names: L-Sarcolysin;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm II<br>Patients undergo hyperthermic isolated perfusions as in arm I. Tumor necrosis factor is administered by slow injection into the arterial line and allowed to remain for a total of 90 minutes. Melphalan is introduced into the perfusion as in arm I and allowed to remain for a total of 60 minutes. | Drug: isolated limb perfusion<br>* Undergo isolated limb perfusion<br>* Other names: isolated limb infusion;Biological: recombinant tumor necrosis factor family protein<br>* Given via slow injection into the arterial line<br>* Other names: Tumor Necrosis Factor Family Protein;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CR proportion | Response will be calculated based on the 3-month follow-up assessment of presence of absence of complete response. This will be done using the logistic regression model. | Up to 3 months after completion of study treatment | 
| Incidence of adverse events, graded according to NCI CTC version 2.0 | The quantification and between-arm comparison of toxicity will be studied. | Up to 1 month after completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local progression-free survival | Time to event outcome models will be based on proportional hazard regression. | Up to 12 years | 
| Overall survival | Time to event models will be based on proportional hazard regression. | Up to 12 years |