Combination Chemotherapy in Treating Patients With Stage III or Stage IV Melanoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. PURPOSE: Phase I/II trial to study the effectiveness of combination chemotherapy consisting of acetaminophen plus carmustine in treating patients who have stage III or stage IV melanoma.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose (MTD) and the optimal biologic dose (OBD) of high-dose acetaminophen when given alone, and the MTD of carmustine when given with acetaminophen at the OBD in patients with metastatic melanoma (Phase I closed to accrual 3/7/2001). Determine the dose of acetaminophen that results in maximal depletion of intracellular glutathione in these patients. Assess the antitumor activity of high-dose acetaminophen in these patients. Assess the toxicity and antitumor activity of carmustine when administered with high-dose acetaminophen in these patients. OUTLINE: This is a dose-escalation study. Phase I: (closed to accrual 3/7/2001) Patients receive a single oral dose of acetaminophen, then acetylcysteine IV over 20 hours, beginning 6-8 hours after the acetaminophen. This treatment is repeated 3 weeks later. On day 1 of the first treatment, patients also receive carmustine IV over 1 hour, before the acetylcysteine. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients each receive escalating doses of acetaminophen to determine the optimal biological dose (OBD). The OBD is defined as the lowest dose at or preceding the maximum tolerated dose (MTD) that results in maximal depletion of glutathione. The MTD is defined as the dose at which no more than 1 to 6 patients experience dose-limiting toxicity (DLT). Once the OBD is established for acetaminophen, cohorts of 3-6 patients each receive escalating doses of carmustine. The MTD is defined as for acetaminophen. Dose escalation does not proceed until all patients are observed for 6 weeks after receiving carmustine. Once the OBD for acetaminophen and MTD for carmustine are determined, 3 more patients are treated at 3 week intervals instead of 6 weeks. If no DLT is observed, this is the dose and schedule for the phase II portion of the study. Phase II: A cohort of 14 patients receives oral acetaminophen and acetylcysteine IV every 3 weeks. Another cohort of 14 patients receives oral acetaminophen and acetylcysteine IV, then oral acetaminophen, carmustine IV, and acetylcysteine IV 3 weeks later. Patients continue therapy in the absence of disease progression or unacceptable toxicity. PROJECTED ACCRUAL: A total of 30-80 patients will be accrued for this study within 40 months.

Official Title
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Phase I-II Trial of High-Dose Acetaminophen With Carmustine in Patients With Metastatic Melanoma

Conditions
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Melanoma (Skin)

Intervention / Treatment
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* Drug: acetaminophen
* Drug: acetylcysteine
* Drug: carmustine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed stage IV melanoma or stage III melanoma not potentially curable by surgery Phase I: (closed to accrual 3/7/2001) measurable or evaluable disease required Phase II: At least 2 measurable subcutaneous or cutaneous metastases that are accessible for biopsy PATIENT CHARACTERISTICS: Age: Over 18 Performance status: Karnofsky 60-100% Life expectancy: Not specified Hematopoietic: WBC at least 4,000/mm^3 Hemoglobin at least 9 g/dL Platelet count at least 100,000/mm^3 No active bleeding Hepatic: AST less than 1.5 times upper limit of normal (ULN) Alkaline phosphatase less than 1.5 times ULN PT/PTT within normal range Renal: Not specified Pulmonary: No interstitial lung disease or unexplained interstitial infiltrates on chest x-ray No chronic obstructive pulmonary disease No asthma requiring treatment Other: No active infection requiring antimicrobial drugs Not pregnant or nursing Fertile patients must use effective barrier contraception No allergies to acetaminophen or acetylcysteine PRIOR CONCURRENT THERAPY: Biologic therapy: At least 4 weeks since prior immunotherapy Chemotherapy: At least 4 weeks since prior chemotherapy (6 weeks for mitomycin) No prior nitrosoureas No prior hepatic perfusions with chemotherapy Endocrine therapy: No concurrent oral contraceptives Radiotherapy: At least 4 weeks since prior radiotherapy Surgery: Not specified Other: No concurrent vitamin, mineral, or garlic supplements At least 7 days since prior garlic or alcohol No concurrent treatment with medications known to affect P450 hepatic enzymes No concurrent treatment with calcium channel blockers

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: acetaminophen|nan|
|Drug: acetylcysteine|nan|
|Drug: carmustine|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III melanoma, stage IV melanoma, recurrent melanoma