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

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).