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


Phase 2
18 Years
N/A
Not Enrolling
Both
Melanoma (Skin)

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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.

Inclusion Criteria


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

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Principal Investigator

Paul B. Chapman, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center

Authority:

United States: Federal Government

Study ID:

97-124

NCT ID:

NCT00003346

Start Date:

November 1997

Completion Date:

February 2003

Related Keywords:

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

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021