Trial Information

Phase I Study of MDR Modulation With PSC-833 (NSC# 648265) With a Pilot Study of Cytogenetic Risk-Adapted Consolidation Followed by a Phase II Pilot Study of Immunotherapy With RIL-2 (NSC # 373364) in Previously Untreated Patients With AML< 60 Years

OBJECTIVES: I. Determine the maximum tolerated dose (MTD) of daunorubicin when used in
combination with etoposide, cytarabine, and PSC 833 (ADEP), and in combination with
etoposide and cytarabine (ADE) in previously untreated patients with acute myelogenous
leukemia who are less than 60 years. II. Determine the MTD of etoposide when used in
combination with a constant dose of daunorubicin and cytarabine (ADE) in these patients.
III. Determine the feasibility and toxic effects of administering postremission therapy in a
risk adapted fashion, such that patients with favorable cytogenetic findings receive three
intensifications with high dose cytarabine (HiDAC), while average to poor risk patients
receive HiDAC/etoposide/filgrastim (G-CSF) for consolidation therapy and stem cell
mobilization followed by peripheral stem cell (PBSC) transplant using busulfan/etoposide as
the preparative regimen. IV. Determine the feasibility and toxic effects of the
consolidation sequence of HiDAC/etoposide/G-CSF followed by 2 courses of HiDAC in patients
who would otherwise receive PBSC transplant, but are unable to do so for logistical or
institutional reasons. V. Determine the feasibility of intermittent administration of high
dose subcutaneous interleukin-2 (IL-2) in combination with continuous low dose subcutaneous
IL-2 in patients recovering from PBSC transplant or intensive consolidation chemotherapy.

OUTLINE: This is a dose escalation study of daunorubicin in the induction therapy portion,
with a separate dose escalation study of etoposide in the same portion. Patients are treated
with three phases of treatment: induction, intensification, and postremission therapy.
Induction therapy: Patients receive cytarabine IV as a continuous infusion on days 1-7 plus
daunorubicin IV over 30 minutes and etoposide IV over 2 hours on days 1-3 (ADE regimen).
Some patients also receive PSC 833 IV as a continuous infusion on days 1-3 (ADEP regimen).
This course may be repeated 14 days later. Cohorts of 9 patients each receive escalating
doses of daunorubicin until the maximum tolerated dose (MTD) is reached. The MTD is defined
as the dose at which 3 of 9 patients experience dose limiting toxicity. Escalations are
conducted separately for the ADE and ADEP regimens. Other cohorts of 9 patients each receive
escalating doses of etoposide with constant doses of daunorubicin in the ADE regimen. The
MTD is described in the same manner. Intensification therapy: Arm I (patients with certain
genetic characteristics in their leukemia cells): Patients receive 3 additional courses of
cytarabine IV over 3 hours, twice a day, for 3 days. Courses are repeated every 28 days. Arm
II (patients who do not have these genetic characteristics): Patients undergo a peripheral
blood stem cell (PBSC) transplant. Patients first receive high dose cytarabine IV over 2
hours on days 1-4, etoposide IV as a continuous infusion on days 1-4, and filgrastim (G-CSF)
subcutaneously beginning on day 5 until blood counts recover. PBSC are then collected.
Approximately 4-6 weeks later, patients receive oral busulfan 4 times a day on days 1-4 and
etoposide IV over 4 hours on day 5. PBSC are reinfused on day 7. G-CSF is administered
subcutaneously beginning on day 7 until blood cell counts recover. Arm III (patients who
cannot undergo a PBSC transplant): Patients receive cytarabine, etoposide, and G-CSF as in
arm II, then high dose cytarabine as in arm I. Postremission therapy (all patients):
Patients receive low dose interleukin-2 (IL-2) by daily injection for 2 weeks. On day 15,
patients begin receiving intermittent high dose IL-2 three days a week. Patients alternate
these courses of IL-2: 14 days of low dose IL-2, 3 days of high dose IL-2, 1 day of rest,
low dose IL-2 for 10 days, then 3 days of high dose IL-2, then 1 day of rest. This course is
repeated 3 times. Patients then receive another 16 day course of low dose IL-2. Patients are
followed at 1 month, then every 3 months for 2 years, then every 6 months for 2 years, then
annually thereafter.

PROJECTED ACCRUAL: Approximately 410 patients will be accrued into this study within 36
months.