Trial Information

A Pilot Clinical Trial of Mitomycin C Modulation of Multidrug Resistance Proteins and a Phase I Evaluation of Mitomycin C and Mitoxantrone in Patients With Acute Myelogenous Leukemia

OBJECTIVES: I. Determine whether a single mitomycin C treatment will suppress expression of
one or more proteins associated with the multidrug resistance phenotype in leukemia cells of
patients with refractory acute myelogenous leukemia. II. Determine the maximum tolerated
dose of a combination of mitomycin C followed 72 hours later by a single dose of
mitoxantrone in patients with acute myelogenous leukemia with GM-CSF support. III. Determine
the toxicity profile and pharmokinetics for these combinations of mitomycin C and
mitoxantrone. IV. Determine the ability of this regimen to induce complete response in
patients with primary resistant or refractory acute myelogenous leukemia.

OUTLINE: Patients receive mitomycin C by IV bolus on day 1 of treatment. Patients receive
mitoxantrone beginning on day 4. One patient each is entered at the first and second dose
levels. Dose escalation of mitoxantrone continues in the absence of toxicity. If the patient
experiences toxicity at level 1 or 2, then 2 additional patients are entered at that tier.
Three patients are entered at all subsequent tiers. At these tiers, if no toxicity is
observed, escalation continues. If 1 of the 3 patients experiences toxicity, an additional 3
patients are enrolled at the same dose. If none of these additional patients experiences
toxicity, escalation continues; however, if 1 patient has toxicity, the trial is stopped. If
2 or more have toxicities, the dose is de-escalated. If 2 or more of the original 3 patients
have toxicities, the dose is de-escalated. On day 15, patients are treated with sargramostim
(GM-CSF) intravenously over 4 hours if the bone marrow is free of residual leukemia; GM-CSF
treatment continues until the ANC is greater than 1,500/mm3 for 3 consecutive days.

PROJECTED ACCRUAL: For the pilot study of mitomycin C modulation of multidrug resistance
proteins, 12 patients will be accrued. For the phase I study of mitomycin C and
mitoxantrone, at least 17 patients will be entered.