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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

Phase 1
18 Years
Not Enrolling
Melanoma (Skin)

Thank you

Trial Information

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



- 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.


- 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

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.

Inclusion Criteria


- 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


- 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


- 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

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Douglas S. Tyler, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke Cancer Institute


United States: Institutional Review Board

Study ID:




Start Date:

October 2007

Completion Date:

Related Keywords:

  • Melanoma (Skin)
  • stage IIIB melanoma
  • stage IIIC melanoma
  • recurrent melanoma
  • Melanoma



Memorial Sloan-Kettering Cancer CenterNew York, New York  10021