Trial Information

Phase III Randomized Study of Induction Chemotherapy With or Without MDR-Modulation With PSC-833 (NSC # 648265, IND # 41121) Followed by Cytogenetic Risk-Adapted Intensification Therapy Followed by Immunotherapy With rIL-2 (NSC # 373364, IND # 1969) vs. Observation in Previously Untreated Patients With AML < 60 Years

PRIMARY OBJECTIVES:

I. To determine whether the addition of PSC-833 (valspodar) to induction chemotherapy
improves disease-free survival and overall survival for patients with acute myeloid leukemia
(AML) < 60 years.

II. To determine whether post-consolidation immunotherapy with low-dose
continuous/intermittent high-dose bolus subcutaneous recombinant interleukin-2 (rIL-2)
(aldesleukin) improves disease-free survival and overall survival in patients with AML < 60
years in first complete remission (CR).

SECONDARY OBJECTIVES:

I. To continue to evaluate the effectiveness of three courses of high-dose ARA-C (HiDAC)
(cytarabine) as curative consolidation chemotherapy in patients with core binding factor
(CBF) leukemias.

II. To continue to establish the use of intensive post-remission chemotherapy with PSCT or a
novel intensification sequence consisting of HiDAC/high-dose etoposide/G-CSF (filgrastim)
followed by two cycles of HiDAC in patients in CR with unfavorable cytogenetics.

III. To correlate the rate of relapse and toxicity with busulfan pharmacokinetics when
busulfan and etoposide are used prior to autologous stem cell transplantation for AML
patients in first CR.

OUTLINE: This is a randomized, multicenter study.

INDUCTION THERAPY: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV over 5-10
minutes followed by etoposide IV over 2 hours on days 1-3. Patients with 20% or greater bone
marrow cellularity and greater than 5% leukemia blasts at the end of the first course
receive a second course of cytarabine IV continuously on days 1-5 and daunorubicin IV over
5-10 minutes followed by etoposide IV over 2 hours on days 1 and 2.

ARM II: Patients receive PSC 833 IV continuously on days 1-3 and cytarabine, daunorubicin,
and etoposide as in arm I. Patients with 20% or greater bone marrow cellularity and greater
than 5% leukemia blasts at the end of the first course receive a second course of PSC 833 IV
continuously on days 1 and 2 and cytarabine, daunorubicin, and etoposide as in arm I.

INTENSIFICATION THERAPY: Patients in complete remission receive intensification therapy.
Therapy begins no earlier than 2 weeks and no later than 4 weeks after complete remission is
attained. Patients are stratified according to cytogenetics (favorable [t(8;21)(q22;q22) or
inv(16)(p13;q22) or t(16;16)(p13;q22)] vs unfavorable [all other karyotypes]).

FAVORABLE: Patients receive high-dose cytarabine (HiDAC) IV over 3 hours every 12 hours on
days 1, 3, and 5. Treatment repeats no earlier than 28 days after the prior course and no
later than 14 days after hematopoietic recovery for two more courses.

UNFAVORABLE: Patients are further divided into two groups based on ability to receive
peripheral blood stem cell transplantation (PBSCT) (yes vs no).

PBSCT GROUP: Patients receive etoposide IV continuously and HiDAC IV over 2 hours every 12
hours on days 1-4. Patients also receive filgrastim (G-CSF) subcutaneously (SC) daily
beginning on day 14 and continuing until peripheral blood stem cell (PBSC) collection is
completed. Patients who are not able to undergo PBSCT after HiDAC/etoposide continue
treatment in the non-PBSCT group. At least 4 weeks after HiDAC/etoposide recovery, patients
receive oral busulfan every 6 hours on days -7 to -4 and etoposide IV over 4 hours on day -3
prior to PBSCT. Patients receive autologous PBSC infusion on day 0. Patients also receive
G-CSF SC beginning on day 0 and continuing until hematopoietic recovery.

NON-PBSCT GROUP: Patients receive etoposide, HiDAC, and G-CSF as in the PBSCT group. After
hematopoietic recovery, patients then receive HiDAC IV over 3 hours every 12 hours on days
1, 3, and 5. Treatment repeats no earlier than 28 days after prior course and no later than
14 days after hematopoietic recovery for one more course.

IMMUNOTHERAPY: Patients are again randomized to 1 of 2 treatment arms.

ARM I: Patients begin therapy no later than 120 days after the first day of the last course
of HiDAC treatment OR day 0 of PBSCT. Patients receive low-dose interleukin-2 (IL-2) SC on
days 1-14, 19-28, 33-42, 47-56, 61-70, and 75-90. In addition, patients receive high-dose
IL-2 SC on days 15-17, 29-31, 43-45, 57-59, and 71-73.

ARM II: Patients are observed and receive no further therapy.

Patients are followed at 1 month, every 2 months for 2 years, every 6 months for 2 years,
and then annually for 6 years.

PROJECTED ACCRUAL: A total of 720 patients will be accrued for this study within 4 years.