NCT00661336

A Phase I Trial of Normothermic Isolated Limb Infusion (ILI) With Melphalan Plus Buthionine Sulfoximine (BSO) in Patients With Locally Advanced Malignant Melanoma

An Open-Label, Multicenter, Phase 1 Dose Escalation Study to Evaluate Safety, Tolerability and Anti-tumor Activity of Systemic Buthionine Sulfoximine (BSO) in Combination With Normothermic Isolated Limb Infusion of Melphalan in Subjects With Locally Advanced In-Transit Malignant Melanoma

• Status: Withdrawn
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 0 (actual)
• Sponsor: Duke University · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

RATIONALE: Buthionine sulfoximine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. Sometimes when chemotherapy is given, it does not stop the growth of tumor cells. The tumor is said to be resistant to chemotherapy. Giving buthionine sulfoximine together with chemotherapy may reduce drug resistance and allow the tumor cells to be killed. PURPOSE: This phase I trial is studying the side effects and best dose of melphalan when given as an isolated limb infusion together with buthionine sulfoximine in treating patients with persistent or recurrent stage III malignant melanoma.

Detailed description

OBJECTIVES: Primary * To determine the maximum tolerated dose of melphalan when administered as an isolated limb infusion in combination with a systemic infusion of buthionine sulfoximine (BSO) in patients with persistent or recurrent stage IIIB or IIIC in-transit malignant melanoma. Secondary * To define the dose-limiting toxicity of regional melphalan when administered with systemic BSO in these patients. * To determine whether the combination of systemic BSO and regional melphalan can yield clinical responses in patients who have not responded well to prior melphalan-based regional treatment. * To determine the effectiveness of systemic BSO in decreasing tumor glutathione (GSH) levels and its effect on GST activity and GST expression. * To examine the correlation between tumor GSH levels and GSH levels in peripheral blood mononuclear cells to determine if the latter can serve as a surrogate marker for tumor GSH depletion. * To determine the pharmacokinetics of systemic BSO and regional melphalan in these patients. * To determine if BSO alters the mRNA expression signature of melphalan resistance. * To determine, preliminarily, the efficacy of systemic BSO and regional melphalan in these patients. * To correlate baseline mRNA expression signature of melphalan resistance with treatment efficacy. OUTLINE: This is a multicenter, dose-escalation study of melphalan. Patients receive buthionine sulfoximine (BSO) IV continuously on days 1-3 and melphalan as an isolated limb infusion (ILI) over 30 minutes on day 2 in the absence of progressive disease or unacceptable toxicity. Patients undergo biopsies and blood sample collection at baseline, immediately before and during ILI, and then at 12 weeks after ILI or at the time of disease progression. Samples are analyzed for GST genotype, tumor glutathione (GSH) levels (by enzymatic assay or HPLC/fluorescence detection \[FLD\]), drug pharmacokinetics, and mRNA expression signature of melphalan resistance. After completion of study treatment, patients are followed at 2, 6, and 12 weeks, every 3 months for 1 year, and then every 6 months for up to 2 years.

Conditions

• Melanoma (Skin)

Interventions

Type	Name	Description
DRUG	buthionine sulfoximine
DRUG	melphalan
GENETIC	microarray analysis
OTHER	high performance liquid chromatography
OTHER	laboratory biomarker analysis
OTHER	pharmacological study
PROCEDURE	biopsy

Timeline

• Start date: 2008-04-01
• Primary completion: 2009-12-01
• First posted: 2008-04-18
• Last updated: 2015-03-13

Locations

2 sites across 1 country: United States