Clinical trial NCT00002925: Combination Chemotherapy Plus PSC 833 Followed by Interleukin-2 in Treating Patients With Acute Myelogenous Leukemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Leukemia
Keywords: untreated adult acute myeloid leukemia
adult acute erythroid leukemia (M6)
adult acute myeloblastic leukemia without maturation (M1)
adult acute myeloblastic leukemia with maturation (M2)
adult acute myelomonocytic leukemia (M4)
adult acute monoblastic leukemia (M5a)
adult acute megakaryoblastic leukemia (M7)
adult acute monocytic leukemia (M5b)
adult acute minimally differentiated myeloid leukemia (M0)
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2004-07-19
Enrollment: 410
Sex: ALL
Minimum age (years): 15
Maximum age (years): 59
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: DISEASE CHARACTERISTICS: Histologically proven acute myelogenous leukemia, except M3

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

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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California San Diego Cancer Center
state: California
city: San Francisco
country: United States
facility: UCSF Cancer Center and Cancer Research Institute
state: California
city: Wilmington
country: United States
facility: CCOP - Christiana Care Health Services
state: Delaware
city: Washington
country: United States
facility: Walter Reed Army Medical Center
state: District of Columbia
city: Miami Beach
country: United States
facility: CCOP - Mount Sinai Medical Center
state: Florida
city: Chicago
country: United States
facility: University of Illinois at Chicago Health Sciences Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Cancer Research Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Baltimore
country: United States
facility: Marlene & Stewart Greenebaum Cancer Center, University of Maryland
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Memorial Medical Center
state: Massachusetts
city: Columbia
country: United States
facility: Ellis Fischel Cancer Center - Columbia
state: Missouri
city: Saint Louis
country: United States
facility: Barnes-Jewish Hospital
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: CCOP - Southern Nevada Cancer Research Foundation
state: Nevada
city: Lebanon
country: United States
facility: Norris Cotton Cancer Center
state: New Hampshire
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Manhasset
country: United States
facility: CCOP - North Shore University Hospital
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital - Cornell Campus
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center, NY
state: New York
city: Syracuse
country: United States
facility: CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.
state: New York
city: Syracuse
country: United States
facility: State University of New York - Upstate Medical University
state: New York
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center, UNC
state: North Carolina
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Winston-Salem
country: United States
facility: CCOP - Southeast Cancer Control Consortium
state: North Carolina
city: Winston-Salem
country: United States
facility: Comprehensive Cancer Center of Wake Forest University Baptist Medical Center
state: North Carolina
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: University of Tennessee, Memphis Cancer Center
state: Tennessee
city: Burlington
country: United States
facility: Vermont Cancer Center
state: Vermont
city: Richmond
country: United States
facility: MBCCOP - Massey Cancer Center
state: Virginia
Study officials:
affiliation: Don Monti Comprehensive Cancer Center at North Shore University Hospital
name: Jonathan E. Kolitz, MD
role: STUDY_CHAIR
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