RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Some cancers may become resistant to chemotherapy drugs. Combining PSC 833 with chemotherapy may reduce resistance to the drugs and allow the cancer cells to be killed. Interleukin-2 may stimulate a person's white blood cells to kill leukemia cells.

PURPOSE: Phase I/II trial to study the effectiveness of combination chemotherapy plus PSC 833 followed by additional chemotherapy or peripheral stem cell transplantation and interleukin-2 in treating patients with untreated acute myelogenous leukemia.

Condition	Treatment or Intervention	Phase
untreated adult acute myeloid leukemia adult acute differentiated monocytic leukemia (M5b) adult acute myeloblastic leukemia without maturation (M1) adult acute minimally differentiated myeloid leukemia (M0) adult acute poorly differentiated monocytic leukemia (M5a) adult acute erythroleukemia (M6) adult acute myelomonocytic leukemia (M4) adult acute myeloblastic leukemia with maturation (M2) adult acute megakaryocytic leukemia (M7)	Drug: busulfan  Drug: cytarabine  Drug: daunorubicin  Drug: etoposide  Drug: filgrastim  Drug: interleukin-2  Drug: PSC 833	Phase I Phase II

Further Study Details: 

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.

PROTOCOL 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 220 patients will be accrued into this study within 36 months.

Ages Eligible for Study:  15 Years   -   59 Years

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Histologically proven acute myelogenous leukemia, except M3

--Prior/Concurrent Therapy--

• Biologic therapy: No prior biologic therapy; No prior treatment for leukemia except leukapheresis
• Chemotherapy: No prior chemotherapy except hydroxyurea which may be used for emergency therapy of hyperleukocytosis
• Endocrine therapy: Not specified
• Radiotherapy: Prior cranial radiation therapy allowed for CNS leukostasis
• Surgery: Not specified

--Patient Characteristics--

• Age: 15 to 59
• Performance status: Not specified
• Life expectancy: Not specified
• Hematopoietic: No prior hematologic malignancy, myeloproliferative disorder, myelodysplastic syndrome, or paroxysmalnocturnal hemoglobinuria; No unexplained cytopenias greater than 3 months in duration
• Hepatic: Not specified
• Renal: Not specified

California
      UCSF Cancer Center and Cancer Research Institute, San Francisco,  California,  94115-0128,  United States
      University of California San Diego Cancer Center, La Jolla,  California,  92093-0658,  United States
Delaware
      CCOP - Christiana Care Health Services, Wilmington,  Delaware,  19899,  United States
District of Columbia
      Walter Reed Army Medical Center, Washington,  District of Columbia,  20307-5000,  United States
Florida
      CCOP - Mount Sinai Medical Center, Miami Beach,  Florida,  33140,  United States
Illinois
      University of Chicago Cancer Research Center, Chicago,  Illinois,  60637,  United States
      University of Illinois at Chicago Health Sciences Center, Chicago,  Illinois,  60612,  United States
Iowa
      University of Iowa Hospitals and Clinics, Iowa City,  Iowa,  52242,  United States
Maryland
      Marlene & Stewart Greenebaum Cancer Center, University of Maryland, Baltimore,  Maryland,  21201,  United States
Massachusetts
      Dana-Farber Cancer Institute, Boston,  Massachusetts,  02115,  United States
      University of Massachusetts Memorial Medical Center, Worcester,  Massachusetts,  01655,  United States
Missouri
      Barnes-Jewish Hospital, Saint Louis,  Missouri,  63110,  United States
      Ellis Fischel Cancer Center - Columbia, Columbia,  Missouri,  65203,  United States
Nebraska
      University of Nebraska Medical Center, Omaha,  Nebraska,  68198-3330,  United States
Nevada
      CCOP - Southern Nevada Cancer Research Foundation, Las Vegas,  Nevada,  89106,  United States
New Hampshire
      Norris Cotton Cancer Center, Lebanon,  New Hampshire,  03756,  United States
New York
      CCOP - North Shore University Hospital, Manhasset,  New York,  11030,  United States
      CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C., Syracuse,  New York,  13210,  United States
      Memorial Sloan-Kettering Cancer Center, New York,  New York,  10021,  United States
      Mount Sinai Medical Center, NY, New York,  New York,  10029,  United States
      New York Presbyterian Hospital - Cornell Campus, New York,  New York,  10021,  United States
      North Shore University Hospital, Manhasset,  New York,  11030,  United States
      Roswell Park Cancer Institute, Buffalo,  New York,  14263-0001,  United States
      State University of New York - Upstate Medical University, Syracuse,  New York,  13210,  United States
North Carolina
      CCOP - Southeast Cancer Control Consortium, Winston Salem,  North Carolina,  27104-4241,  United States
      Comprehensive Cancer Center of Wake Forest University Baptist Medical Center, Winston Salem,  North Carolina,  27157-1082,  United States
      Duke Comprehensive Cancer Center, Durham,  North Carolina,  27710,  United States
      Lineberger Comprehensive Cancer Center, UNC, Chapel Hill,  North Carolina,  27599-7295,  United States
Rhode Island
      Rhode Island Hospital, Providence,  Rhode Island,  02903,  United States
South Carolina
      Medical University of South Carolina, Charleston,  South Carolina,  29425-0721,  United States
Tennessee
      University of Tennessee, Memphis Cancer Center, Memphis,  Tennessee,  38163,  United States
Vermont
      Vermont Cancer Center, Burlington,  Vermont,  05401-3498,  United States
Virginia
      MBCCOP - Massey Cancer Center, Richmond,  Virginia,  23298-0037,  United States

Study chairs or principal investigators

Jonathan Eliahu Kolitz,  Study Chair,  Cancer and Leukemia Group B   

Study ID Numbers:  CDR0000065333; CLB-9621
Record last reviewed:  July 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002925
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08