Irofulven in Treating Children With Recurrent or Refractory Solid Tumors

OBJECTIVES:

I. Determine the maximum tolerated dose and dose limiting toxicity of 6-hydroxymethylacylfulvene (MGI-114) in pediatric patients with recurrent or refractory solid tumors.

II. Determine the incidence and severity of other toxic effects of MGI-114. III. Determine a safe and tolerable dose of MGI-114 to be used in phase II studies.

IV. Determine the pharmacokinetics of MGI-114 in these patients. V. Determine preliminary evidence of antitumor activity of MGI-114 against recurrent or refractory pediatric solid tumors.

OUTLINE: This is a dose escalation study. If the dose limiting toxicity is myelosuppression in stratum 1, then stratum 1 is closed and stratum 2 opens.

Stratum 2 consists of the following: patients receiving no more than 2 prior chemotherapy regimens; patients who have not received prior central axis radiation or bone marrow transplantation; and patients with no known bone marrow involvement. Patients receive intravenous 6-hydroxymethylacylfulvene over 10 minutes daily for 5 days. The course is repeated every 28 days unless disease progression or unacceptable toxic effects are observed. Patients with stable or responding disease may receive up to 1 year of therapy. If dose limiting toxicity occurs in 2 of 6 patients at a given dose level, then dose escalation ceases and the next lower dose is declared the maximum tolerated dose. Dose escalation will not occur until all patients within a cohort have been observed for 28 days from day 1 of therapy. Patients are followed until death.

DISEASE CHARACTERISTICS:

• Histologically or cytologically proven recurrent or refractory solid tumors
• No leukemia
• Patients with brain tumors are not eligible until the first 2 patients at each dose level are evaluable for toxicity

PATIENT CHARACTERISTICS:

• Age: 21 and under
• Performance status: Karnofsky 50-100% Lansky play scale 50-100% (for infants)
• Life expectancy: At least 8 weeks
• Absolute neutrophil count at least 1,000/mm3
• Hemoglobin at least 9 g/dL
• Platelet count at least 75,000/mm3
• Bilirubin less than 1.5 mg/dL
• SGPT less than 5 times upper limit of normal
• Creatinine normal for age OR GFR at least 70 mL/min
• Cardiac shortening fraction at least 27% OR institutional normal OR cardiac ejection fraction greater than 50% OR institutional normal
• Neurologic deficits in patients with CNS tumors must be stable for at least 2 weeks
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 6 months after the study
• No uncontrolled infection

PRIOR CONCURRENT THERAPY:

• At least 1 week since prior growth factor therapy and recovered
• At least 6 months since prior bone marrow transplantation and no evidence of graft versus host disease
• At least 2 weeks since prior myelosuppressive chemotherapy and recovered
• At least 6 weeks since prior nitrosourea and recovered
• At least 2 weeks on stable dexamethasone for patients with CNS tumors
• No concurrent chemotherapy
• At least 2 weeks since prior palliative radiotherapy (small port)
• At least 6 months since prior substantial bone marrow radiation
• At least 6 months since total abdominal, pelvic, chest, mantle, and Y ports radiotherapy
• No other concurrent anticancer therapy or investigational agents