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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


Phase 1
18 Years
N/A
Not Enrolling
Both
Melanoma (Skin)

Thank you

Trial Information

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


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.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically proven primary or recurrent in-transit melanoma of the extremity

- Stage IIIB or IIIC disease, as determined by whole body imaging with a CT scan
of the chest, abdomen, and pelvis AND PET scan within the past 4 weeks

- Patients with stage IIIC disease must have undergone removal of regional
lymph nodes

- Patients with indeterminate staging must be reviewed by the study chairs
prior to study registration

- Previously treated with melphalan-based regional therapy and had persistent disease
at 3 months OR achieved a complete response but disease recurred within 6 months

- Disease to be treated by regional therapy must be distal to the planned site of
tourniquet placement

- Bidimensionally measurable disease by caliper or a radiological method as defined by
the RECIST criteria modified for cutaneous lesions

- Photo documentation required

- Patients with a single lesion must have archived tumor tissue available for
study analysis

- No history of tumors with clinically significant evidence of active bleeding (e.g.,
gross hemoptysis, hematemesis, hematuria, melena, or bleeding superficial tumor)
within the past 12 weeks

- No stage IV disease

- No cerebral metastases

PATIENT CHARACTERISTICS:

- ECOG/Zubrod performance status 0-1

- Serum creatinine ≤ 1.5 mg/dL

- WBC ≥ 3,000/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 10 g/dL

- Bilirubin normal

- AST and ALT ≤ 2.5 times normal

- Must have a palpable femoral/axillary pulse in the affected extremity

- No uncontrolled seizures or clinically significant CNS disorders

- No psychiatric condition or diminished capacity that could preclude study compliance
or giving informed consent

- No history of allergic reactions and/or hypersensitivity to melphalan

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No history of other malignancies except adequately treated basal cell or squamous
cell carcinoma of the skin; curatively treated carcinoma in situ of the uterine
cervix, prostate cancer, or superficial bladder cancer; or other curatively treated
solid tumors with no evidence of disease for ≥ 5 years

- No stroke or other major tissue injury within the past 4 weeks

- No other uncontrolled serious chronic disease or condition that, in the
investigator's opinion, could preclude study compliance or follow-up

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from prior therapy

- More than 4 weeks since prior major surgery

- Wound healing adequate since last major surgery

- More than 4 weeks since prior antineoplastic therapy, radiotherapy, or any other
investigational drug

- More than 7 days since prior antimicrobial agents (i.e., antibiotic, antifungal, or
antiviral agents) for active infection or infectious symptoms

- No drugs that are known to cause enhanced glutathione depletion (e.g., acetaminophen)
for 7 days before, during, and for 7 days after buthionine sulfoximine (BSO)
administration

- No cephalosporin antibiotics for 7 days before, during, and for 7 days after BSO
administration

Type of Study:

Interventional

Study Design:

Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of melphalan when administered as an isolated limb infusion in combination with a systemic infusion of buthionine sulfoximine (BSO)

Safety Issue:

Yes

Principal Investigator

Douglas S. Tyler, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke Cancer Institute

Authority:

United States: Food and Drug Administration

Study ID:

Pro00001793

NCT ID:

NCT00661336

Start Date:

April 2008

Completion Date:

Related Keywords:

  • Melanoma (Skin)
  • stage III melanoma
  • recurrent melanoma
  • Melanoma

Name

Location

Duke Comprehensive Cancer CenterDurham, North Carolina  27710
M. D. Anderson Cancer Center at University of TexasHouston, Texas  77030-4009