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
- 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
- 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
- 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
- To determine the pharmacokinetics of systemic BSO and regional melphalan in these
- To determine if BSO alters the mRNA expression signature of melphalan resistance.
- To determine, preliminarily, the efficacy of systemic BSO and regional melphalan in
- To correlate baseline mRNA expression signature of melphalan resistance with treatment
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
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.
Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose of melphalan when administered as an isolated limb infusion in combination with a systemic infusion of buthionine sulfoximine (BSO)
Douglas S. Tyler, MD
Duke Cancer Institute
United States: Food and Drug Administration
|Duke Comprehensive Cancer Center||Durham, North Carolina 27710|
|M. D. Anderson Cancer Center at University of Texas||Houston, Texas 77030-4009|