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

This study has been completed.
Sponsor:
Information provided by:
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00002925
First received: November 1, 1999
Last updated: November 29, 2012
Last verified: March 2011
  Purpose

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 Intervention Phase
Leukemia
Drug: ara-C
Drug: Daunorubicin
Drug: Etoposide
Drug: PSC-833
Biological: Aldesleukin
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Enrollment: 410
Study Start Date: February 1997
Study Completion Date: June 2010
Primary Completion Date: November 2003 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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

Ages Eligible for Study:   15 Years to 59 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00002925

  Show 33 Study Locations
Sponsors and Collaborators
Investigators
Study Chair: Jonathan E. Kolitz, MD Don Monti Comprehensive Cancer Center at North Shore University Hospital
  More Information

Additional Information:
Publications:
Marcucci G, Baldus CD, Ruppert AS, et al.: Overexpression of the ERG gene is an adverse prognostic factor in acute myeloid leukemia (AML) with normal cytogenetics (NC): a Cancer and Leukemia Group B study (CALGB). [Abstract] Blood 106 (11): A-335, 2005.
Marcucci G, Radmacher MD, Ruppert AS, et al.: Independent validation of prognostic relevance of a previously reported gene-expression signature in acute myeloid leukemia (AML) with normal cytogenetics (NC): a Cancer and Leukemia Group B (CALGB) study. [Abstract] Blood 106 (11): A-755, 2005.
Kolitz JE, George SL, Barrier R, et al.: Treatment of core binding factor (CBF) acute myeloid leukemia (AML) with post-remission high-dose cytarabine (HiDAC): results from CALGB 9621. [Abstract] Blood 102 (11 Pt 1): A-612, 2003.
Kolitz JE, George SL, Barrier R, et al.: A novel post-remission consolidation regimen for patients with acute myeloid leukemia (AML) < 60 years old with normal or unfavorable cytogenetics: results from CALGB 9621. [Abstract] Blood 102 (11 Pt 1): A-609, 2003.
Kolitz JE, George SL, Hurd D, et al.: Parallel phase I trials of multi-drug resistance (MDR) modulation with PSC-833 in untreated patients (PTS) with acute myeloid leukemia (AML) less than 60 years old: preliminary results of CALGB 9621. Blood 94(suppl 1): A-1705, 384a, 1999.
Kolitz JE, Georg SL, Hurd D, et al.: Cytogenetic risk-adapted intensification followed by immunotherapy with recombinant interleukin-2 (rIL-2) in patients (PTS) less than 60 years old with acute myeloid leukemia (AML) in first complete remission (CR): preliminary results of CALGB 9621. Blood 94(suppl 1): A-2582, 579a, 1999.
Langer C, Maharry K, Mrózek K, et al.: Low Meningioma 1 (MN1) gene expression to predict outcome in cytogenetically normal acute myeloid leukemia (CN-AML): A Cancer and Leukemia Group B (CALGB) study. [Abstract] J Clin Oncol 26 (Suppl 15): A-7011, 2008.
Langer C, Ruppert, AS, Radmacher MD, et al.: High BAALC expression associates with other molecular prognostic markers, poor outcome and a distinct gene expression signature in cytogenetically normal acute myeloid leukemia (CN AML): a Cancer and Leukemia Group B (CALGB) study. [Abstract] J Clin Oncol 25 (Suppl 18): A-7013, 360s, 2007.
Marcucci G, Maharry K, Radmacher MD, et al.: Gene and microRNA (miRNA) expression signatures and prognostic significance of CEBPA mutations in cytogenetically normal (CN) acute myeloid leukemia (AML) with high-risk molecular features: a Cancer and Leukemia Group B (CALGB) study . [Abstract] Blood 110 (11): A-104, 2007.
Metzeler KH, Hummel M, Bloomfield CD, et al.: An 86-probe gene expression signature can predict survival in AML with normal karyotype independently of FLT3 ITD and NPM1 mutation status: a collaborative study from the AMLCG and CALGB study groups. [Abstract] Blood 110 (11): A-596, 2007.
Sekeres MA, Dodge RK, Bloomfield CD, et al.: Racial differences in prognostic factors and outcome in acute myeloid leukemia (AML): a Cancer and Leukemia Group B (CALGB) study. [Abstract] Blood 100 (11 Pt 1): A-323, 2002.

Responsible Party: Monica M Bertagnolli, MD, Cancer and Leukemia Group B
ClinicalTrials.gov Identifier: NCT00002925     History of Changes
Other Study ID Numbers: CDR0000065333, U10CA031946, CLB-9621
Study First Received: November 1, 1999
Last Updated: November 29, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):
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)

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms
Neoplasms by Histologic Type
Daunorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses
Topoisomerase II Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on October 23, 2014