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

Primary Purpose

Recurrent Melanoma, Stage III Melanoma

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
isolated limb perfusion
melphalan
recombinant tumor necrosis factor family protein
pharmacological study
laboratory biomarker analysis
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Recurrent Melanoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • American College of Surgeons Oncology Group

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm I

Arm II

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.
Incidence of adverse events, graded according to NCI CTC version 2.0
The quantification and between-arm comparison of toxicity will be studied.

Secondary Outcome Measures

Local progression-free survival
Time to event outcome models will be based on proportional hazard regression.
Overall survival
Time to event models will be based on proportional hazard regression.

Full Information

First Posted
November 1, 1999
Last Updated
July 15, 2013
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00003789
Brief Title
Melphalan With or Without Tumor Necrosis Factor in Treating Patients With Locally Advanced Melanoma of the Arm or Leg
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2013
Overall Recruitment Status
Completed
Study Start Date
March 1999 (undefined)
Primary Completion Date
January 2004 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Recurrent Melanoma, Stage III Melanoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
216 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I
Arm Type
Experimental
Arm Description
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 Title
Arm II
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
isolated limb perfusion
Other Intervention Name(s)
isolated limb infusion
Intervention Description
Undergo isolated limb perfusion
Intervention Type
Drug
Intervention Name(s)
melphalan
Other Intervention Name(s)
Alkeran, CB-3025, L-PAM, L-phenylalanine mustard, L-Sarcolysin
Intervention Description
Given via limb perfusion
Intervention Type
Biological
Intervention Name(s)
recombinant tumor necrosis factor family protein
Other Intervention Name(s)
tumor necrosis factor, Tumor Necrosis Factor Family Protein
Intervention Description
Given via slow injection into the arterial line
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
CR proportion
Description
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.
Time Frame
Up to 3 months after completion of study treatment
Title
Incidence of adverse events, graded according to NCI CTC version 2.0
Description
The quantification and between-arm comparison of toxicity will be studied.
Time Frame
Up to 1 month after completion of study treatment
Secondary Outcome Measure Information:
Title
Local progression-free survival
Description
Time to event outcome models will be based on proportional hazard regression.
Time Frame
Up to 12 years
Title
Overall survival
Description
Time to event models will be based on proportional hazard regression.
Time Frame
Up to 12 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Douglas Fraker
Organizational Affiliation
American College of Surgeons
Official's Role
Principal Investigator
Facility Information:
Facility Name
American College of Surgeons Oncology Group
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States

12. IPD Sharing Statement

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

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