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

Duke University

Status and phase

Completed

Phase 1

Conditions

Melanoma (Skin)

Treatments

Drug: sorafenib tosylate

Drug: melphalan

Other: pharmacological study

Genetic: gene expression analysis

Genetic: protein expression analysis

Genetic: western blotting

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00565968

CDR0000575427

Pro00001344

Details and patient eligibility

About

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.

Full 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.

Enrollment

20 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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