Sorafenib and Isolated Limb Infusion of Melphalan in Treating Patients With Stage III Melanoma of the Arm or Leg

Sponsor

Duke University (Other)

Overall Status

Completed

CT.gov ID

NCT00565968

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

RATIONALE: Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as melphalan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sorafenib may also make tumor cells more sensitive to melphalan. Giving sorafenib together with an isolated limb infusion of melphalan may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of sorafenib when given together with an isolated limb infusion of melphalan in treating patients with stage III melanoma of the arm or leg.

Condition or Disease	Intervention/Treatment	Phase
Melanoma (Skin)	Drug: melphalan Drug: sorafenib tosylate Genetic: gene expression analysis Genetic: protein expression analysis Genetic: western blotting Other: pharmacological study	Phase 1

Detailed Description

OBJECTIVES:

Primary

To determine the dose-limiting toxicities and maximum tolerate dose of systemic sorafenib tosylate in combination with regionally administered melphalan by isolated limb infusion in patients with stage IIIB or IIIC intransit extremity melanoma.

Secondary

To characterize the safety and tolerability of this regimen in these patients.
To assess the antitumor activity of this regimen, as evidenced by best overall response and duration of response, in these patients.
To characterize the duration of progression-free survival of these patients.
To characterize the pharmacokinetics of melphalan.
To assess alterations in selected gene and protein expression profiles following treatment.

OUTLINE: This is a multicenter, dose-escalation study of sorafenib tosylate.

Patients receive oral sorafenib tosylate twice daily on days 1-14 and melphalan via isolated limb infusion into the upper or lower extremities on day 8.

Patients undergo tumor biopsies at baseline and in weeks 2 and 12 for gene expression analysis and western blot analysis. Patients also undergo blood sample collection periodically for pharmacokinetic analysis of melphalan.

After completion of study treatment, patients are followed every 3 months for 1 year and then every 6 months for 2 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Dose Escalation Trial to Evaluate Safety and Efficacy of Oral Sorafenib (Nexavar) With Regional Melphalan Via Normothermic Isolated Limb Infusion (ILI) in Patients With Intransit Extremity Melanoma

Study Start Date :

Oct 1, 2007

Actual Primary Completion Date :

Aug 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sorafenib dose escalation	Drug: melphalan Drug: sorafenib tosylate Genetic: gene expression analysis Genetic: protein expression analysis Genetic: western blotting Other: pharmacological study

Arm

Intervention/Treatment

Experimental: Sorafenib dose escalation

Drug: melphalan

Drug: sorafenib tosylate

Genetic: gene expression analysis

Genetic: protein expression analysis

Genetic: western blotting

Other: pharmacological study

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose [1 year]

Secondary Outcome Measures

Safety and tolerability [2 years]
Antitumor activity, as evidenced by best overall response and duration of response [3 years]
Duration of progression-free survival [3 years]
Pharmacokinetics of melphalan [3 years]
Tumor gene and protein expression profiles following treatment [3 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed primary or recurrent extremity melanoma
Stage IIIB or IIIC disease
Patients with stage IIIC disease must have had regional lymph nodes previously removed
Disease to be treated by regional therapy must be distal to the planned site of tourniquet placement
Bidimensionally measurable disease by caliper or radiological method
Must have identifiable target lesions for disease assessment
Patients with a single lesion must have archived tumor tissue available for research analysis
No stage IV disease
No known brain metastasis
Patients with neurological symptoms must have undergone a CT scan or MRI of the brain within the past 4 weeks to exclude brain metastasis

PATIENT CHARACTERISTICS:

ECOG or Zubrod performance status 0-1
Life expectancy > 6 months
Hemoglobin ≥ 9.0 g/dL
WBC ≥ 3,000/mm^3
ANC ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
ALT and AST ≤ 2.5 x ULN
INR < 1.5 or PT/PTT normal
Creatinine ≤ 1.5 x ULN
Not pregnant or nursing
Negative serum pregnancy test
Fertile patients must use effective contraception
Must have a palpable femoral or axillary pulse in the extremity to be treated
No cardiac disease, including any of the following:
NYHA class III or IV congestive heart failure
Unstable angina (i.e., angina symptoms at rest) or new onset angina within the past 3 months
Myocardial infarction within the past 6 months
No cardiac ventricular arrhythmias requiring antiarrhythmic therapy
No uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg or diastolic BP > 90 mm Hg, despite optimal medical management
No known HIV infection
No chronic hepatitis B or C
No active clinically serious infection > CTCAE grade 2
No thrombotic or embolic events (e.g., cerebrovascular accident or transient ischemic attacks) within the past 6 months
No signs or symptoms of vascular insufficiency (i.e., any history of blood clots or other ischemic peripheral vascular disease)
No evidence or history of bleeding diathesis or coagulopathy
No pulmonary hemorrhage or bleeding event ≥ CTCAE grade 2 within the past 4 weeks
No other hemorrhage or bleeding event ≥ CTCAE grade 3 within the past 4 weeks
No serious nonhealing wound, ulcer, or bone fracture
No significant traumatic injury within the past 4 weeks
No condition that impairs the patient's ability to swallow whole pills
No malabsorption problem
No known history of allergic reactions and/or hypersensitivity to melphalan, sorafenib tosylate, or any other agent used in the study
No psychiatric condition or diminished capacity that would compromise giving informed consent, or interfere with study compliance
No history of other malignancies, except for any of the following:
Adequately treated basal cell or squamous cell carcinoma of the skin
Curatively treated in situ carcinoma of the uterine cervix, prostate cancer, or superficial bladder cancer
Other curatively treated solid tumor with no evidence of disease for ≥ 5 years

PRIOR CONCURRENT THERAPY:

Recovered from prior therapy
No prior sorafenib tosylate
Prior melphalan via isolated limb infusion allowed
No antineoplastic therapy, radiotherapy, or any other investigational drug within the past 4 weeks
No major surgery or open biopsy within the past 4 weeks
No concurrent Hypericum perforatum (St. John wort) or rifampin
Concurrent anti-coagulation treatment with warfarin or heparin allowed