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

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

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Melanoma; Stage III Melanoma
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: pharmacological study; Drug: isolated limb perfusion; Drug: melphalan; Biological: recombinant tumor necrosis factor family protein

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 216
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • American College of Surgeons Oncology Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: isolated limb perfusion; Undergo isolated limb perfusion; Other Names: isolated limb infusion; Drug: melphalan; Given via limb perfusion; Other Names: Alkeran; CB-3025; L-PAM; L-phenylalanine mustard; L-Sarcolysin
Experimental: 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.	Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: isolated limb perfusion; Undergo isolated limb perfusion; Other Names: isolated limb infusion; Biological: recombinant tumor necrosis factor family protein; Given via slow injection into the arterial line; Other Names: tumor necrosis factor; Tumor Necrosis Factor Family Protein

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Douglas Fraker, American College of Surgeons

Study record dates

Study Major Dates

• Study Start: March 1, 1999
• Primary Completion (Actual): January 1, 2004

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): July 16, 2013
• Last Update Submitted That Met QC Criteria: July 15, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Necrosis; Melanoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Melphalan
• Other Study ID Numbers: NCI-2012-01843; U10CA076001 (U.S. NIH Grant/Contract); Z0020; ACOSOG-Z0020; CDR0000066929; NCI-03-C-0137