Combination Chemotherapy Plus PSC 833 Followed by Interleukin-2 in Treating Patients With Acute Myelogenous Leukemia

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00002925

Collaborator

(none)

410

Enrollment

Locations

Arms

159.9

Duration (Months)

12.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: ara-C Drug: Daunorubicin Drug: Etoposide Drug: PSC-833 Biological: Aldesleukin	Phase 1/Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

410 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Feb 1, 1997

Actual Primary Completion Date :

Nov 1, 2003

Actual Study Completion Date :

Jun 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: ADE	Drug: ara-C Drug: Daunorubicin Drug: Etoposide Biological: Aldesleukin
Experimental: ADEP	Drug: ara-C Drug: Daunorubicin Drug: Etoposide Drug: PSC-833 Biological: Aldesleukin

Arm

Intervention/Treatment

Active Comparator: ADE

Drug: ara-C

Drug: Daunorubicin

Drug: Etoposide

Biological: Aldesleukin

Experimental: ADEP

Drug: ara-C

Drug: Daunorubicin

Drug: Etoposide

Drug: PSC-833

Biological: Aldesleukin

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years to 59 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

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