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Melphalan

Buthionine Sulfoximine

Antineoplastic Agents, Alkylating

Alkylating Agents

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Immunologic Factors

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Radiation-Protective Agents

buthionine sulfoximine

melphalan

microarray analysis

high performance liquid chromatography

laboratory biomarker analysis

pharmacological study

biopsy

Douglas S. Tyler, MD

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.

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.

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

National Cancer Institute (NCI)

Duke University

Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neoplasms, Neuroepithelial

Neoplasms, Glandular and Epithelial

C. Patrick Reynolds, MD, PhD

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Some tumors become resistant to chemotherapy drugs. Combining buthionine sulfoximine with chemotherapy may reduce resistance to the drug and allow more tumor cells to be killed.

PURPOSE: Phase I trial to study the effectiveness of melphalan, buthionine sulfoximine, and G-CSF in treating children with progressive neuroblastoma that has not responded to previous therapy.

OBJECTIVES: I. Describe the toxic effects of combined chemotherapy with buthionine sulfoximine (BSO) and melphalan (L-PAM) in pediatric patients with progressive neuroblastoma. II. Determine the pharmacokinetics of BSO/L-PAM in pediatric patients. III. Assess the ability of BSO to deplete glutathione by at least 90% in tumor metastatic to bone marrow, in normal marrow, and in peripheral blood lymphocytes. IV. Estimate the response rate in these patients treated with BSO/L-PAM within the confines of a pilot study.

OUTLINE: The following acronyms are used: BSO Buthionine sulfoximine, NSC-326231 L-PAM Melphalan, NSC-8806 G-CSF Granulocyte Colony-Stimulating Factor, NSC-614629 Single-Agent Chemotherapy with Drug Resistance Inhibition. L-PAM/BSO.

PROJECTED ACCRUAL: At least 18 patients will be entered to provide an adequate number of patients with marrow involvement; if the BSO dose is increased to achieve adequate GSH depletion in the marrow, an additional 12 patients will be entered. If less than 50% of patients have tumor metastatic to marrow at entry, there will be a proportional increase in the total number of patients required.

Chemotherapy in Treating Children With Neuroblastoma

PILOT STUDY OF BUTHIONINE SULFOXIMINE (BSO) IN COMBINATION WITH MELPHALAN FOR HIGH RISK NEUROBLASTOMA PATIENTS

Children's Hospital Los Angeles

Lenograstim

Dose fixed at a bolus of 3 gm/M2 given over 30 minutes followed by a continuous infusion of 1 gm/M2/hour for 72 hours (total 72.5 hours).Total daily infusion dose (minus the initial bolus)will be 24 gm/m2/day.

The dose level of melphalan will be assigned at study entry onto protocol. There will be 6 dose levels ranging from 20mg/m2/day x 2 days (dose level 1a) to 62.5 mg/m2/day x 2 days (dose level 6a). The starting dose level will be 1a, with a decrease to level 0a (15mg/m2/day x2 days) if there is unacceptable toxicity.

Stem cells will be infused intravenously on day 0 , 24 hours after BSO continuous infusion is completed.Infused within 1.5 hours of thawing via a central venous catheter over 15-30 minutes.

Peripheral blood stem cell infusion

5 microgram/kg/day , subcutaneous or intravenous, given daily beginning day 0. First dose to begin 4 hours after completion of stem cell infusion and then to continue till ANC \>/= 1500 mm3 for three consecutive days.

Filgrastim

Samuel Volchenboum, MD

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with bone marrow or peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells.

PURPOSE: Phase I trial to study the effectiveness of melphalan and buthionine sulfoximine followed by bone marrow or peripheral stem cell transplantation in treating children who have resistant or recurrent neuroblastoma.

OBJECTIVES:

* Determine the maximum tolerated dose of melphalan when combined with buthionine sulfoximine and followed by autologous bone marrow or peripheral blood stem cell support in children with resistant or recurrent high-risk neuroblastoma.
* Assess the toxic effects of this regimen in these patients.
* Determine the pharmacokinetics of this regimen in these patients.
* Determine the response rate of patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of melphalan.

Patients receive buthionine sulfoximine IV as a bolus over 30 minutes followed by a 72-hour continuous infusion beginning on day -4; melphalan IV over 15 minutes on days -3 and -2; autologous peripheral blood stem cells or bone marrow IV over 15-30 minutes on day 0; and filgrastim (G-CSF) subcutaneously or IV once daily beginning on day 0 and continuing until blood counts recover.

Cohorts of 3-6 patients receive escalating doses of melphalan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients are followed at 84 days and then 2 months later if there is a complete and/or partial response. Patients who continue therapy on other protocols are followed before starting the new therapy. All patients are followed for life for any delayed toxic effects to protocol therapy and secondary malignancies.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study within 2-3 years.

N99-02: Melphalan and Buthionine Sulfoximine

Modulation of Intensive Melphalan (L-PAM) by Buthionine Sulfoximine (BSO) Autologous Stem Cell Support for Resistant or Recurrent High-Risk Neuroblastoma (IND 69-112)

Collection of blood samples for PK studies is optional and not required for study entry.

Collection of blood samples for biologic studies is optional and not required for study entry.

New Approaches to Neuroblastoma Therapy Consortium

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase I Trial of Normothermic Isolated Limb Infusion (ILI) With Melphalan Plus Buthionine Sulfoximine (BSO) in Patients With Locally Advanced Malignant Melanoma	NCT00661336	Melanoma (Skin)	buthionine sulf... melphalan microarray anal... high performanc... laboratory biom... pharmacological... biopsy	18 Years -	Duke University
Chemotherapy in Treating Children With Neuroblastoma	NCT00002730	Neuroblastoma	buthionine sulf... melphalan	- 21 Years	Children's Hospital Los Angeles
N99-02: Melphalan and Buthionine Sulfoximine	NCT00005835	Neuroblastoma	buthionine sulf... melphalan Peripheral bloo... Filgrastim	- 30 Years	New Approaches to Neuroblastoma Therapy Consortium
A Phase I Trial of Normothermic Isolated Limb Infusion (ILI) With Melphalan Plus Buthionine Sulfoximine (BSO) in Patients With Locally Advanced Malignant Melanoma	NCT00661336	Melanoma (Skin)	buthionine sulf... melphalan microarray anal... high performanc... laboratory biom... pharmacological... biopsy	18 Years -	Duke University
N99-02: Melphalan and Buthionine Sulfoximine	NCT00005835	Neuroblastoma	buthionine sulf... melphalan Peripheral bloo... Filgrastim	- 30 Years	New Approaches to Neuroblastoma Therapy Consortium

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