Trial Information

A Randomized, Placebo-Controlled, Double Blind, Trial of the Administration of the MDR Modulator, Zosuquidar Trihydrochloride (LY335979), During Conventional Induction and Post-Remission Therapy in Patients Greater Than 60 Years of Age With Newly Diagnosed Acute Myeloid Leukemia, Refractory Anemia With Excess Blasts in Transformation or High-Risk Refractory Anemia With Excess Blasts

OBJECTIVES:

- Compare the overall survival and progression-free survival of elderly patients with
newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts (RAEB) in
transformation, or high-risk RAEB treated with daunorubicin and cytarabine with or
without zosuquidar trihydrochloride.

- Compare the complete remission rate of patients treated with these regimens.

- Compare the toxicity of these regimens in these patients.

- Compare the systemic exposure of daunorubicin and cytarabine in patients treated with
zosuquidar trihydrochloride vs placebo.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients
are stratified according to age (60-69 years vs 70 years and over), disease (refractory
anemia with excess blasts [RAEB] vs RAEB in transformation or acute myeloid leukemia [AML]),
and disease type (de novo vs secondary). Patients are randomized to 1 of 2 treatment arms.

- Induction:

- Arm I: Patients receive daunorubicin via intravenous (IV) infusion over 10-15
minutes and zosuquidar trihydrochloride IV over 6 hours on days 1-3. Patients also
receive cytarabine IV continuously on days 1-7.

- Arm II: Patients receive daunorubicin and cytarabine as in arm I. Patients also
receive placebo IV over 6 hours on days 1-3.

Beginning on day 12, patients who achieve aplasia receive filgrastim (G-CSF) or sargramostim
(GM-CSF) subcutaneously (SC) or IV daily until blood counts recover. Patients who have
evidence of persistent AML are eligible to receive a second identical course of induction
chemotherapy.

- Consolidation I (beginning within 8 weeks after documentation of complete remission
[CR] or measurable remission [MR]): Patients who achieve a CR or MR receive cytarabine
IV over 1 hour once or twice daily on days 1-6 and GM-CSF or G-CSF SC or IV beginning
on day 7 and continuing until blood counts recover.

- Consolidation II: Patients who have maintained peripheral blood evidence of a remission
receive daunorubicin, cytarabine, and zosuquidar trihydrochloride or placebo as in
induction chemotherapy. Patients also receive GM-CSF or G-CSF SC or IV beginning on day
8 or after last cytarabine dose and continuing until blood counts recover.

Patients are followed monthly for 1 year, every 2 months for 1 year, every 3 months for 1
year, and then every 6 months for 2 years.

PROJECTED ACCRUAL: Approximately 450 patients (225 per treatment arm) accrued over 4.1
years.