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

Condition(s) targeted: Melanoma (Skin)

Intervention: melphalan (Drug); sorafenib tosylate (Drug); gene expression analysis (Genetic); protein expression analysis (Genetic); western blotting (Genetic); pharmacological study (Other)

Phase: Phase 1

Status: Recruiting

Sponsored by: Duke University

Official(s) and/or principal investigator(s):
Douglas S. Tyler, MD, Principal Investigator, Affiliation: Duke University

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.

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 design: Treatment, Open Label

Primary outcome:

Dose-limiting toxicity

Maximum tolerated dose

Secondary outcome:

Safety and tolerability

Antitumor activity, as evidenced by best overall response and duration of response

Duration of progression-free survival

Pharmacokinetics of melphalan

Tumor gene and protein expression profiles following treatment

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

Memorial Sloan-Kettering Cancer Center, New York, New York 10065, United States; Recruiting
Jill Kleczko, Phone: 646-227-2221

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: October 2007
Last updated: August 4, 2009