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

Trial Information

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).

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.