Combination Chemotherapy With or Without PSC 833, Peripheral Stem Cell Transplantation, and/or Interleukin-2 in Treating Patients With Acute Myeloid Leukemia

June 3, 2013 updated by: National Cancer Institute (NCI)

Phase III Randomized Study of Induction Chemotherapy With or Without MDR-Modulation With PSC-833 (NSC # 648265, IND # 41121) Followed by Cytogenetic Risk-Adapted Intensification Therapy Followed by Immunotherapy With rIL-2 (NSC # 373364, IND # 1969) vs. Observation in Previously Untreated Patients With AML < 60 Years

Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. PSC 833 may increase the effectiveness of chemotherapy by making cancer cells more sensitive to the drugs. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. Interleukin-2 may stimulate a person's white blood cells to kill cancer cells. This randomized phase III trial is studying giving combination chemotherapy together with PSC 833 followed by a peripheral stem cell transplant with or without interleukin-2 to see how well it works compared to combination chemotherapy alone followed by a peripheral stem cell transplant with or without interleukin-2 in treating patients with acute myeloid leukemia.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. To determine whether the addition of PSC-833 (valspodar) to induction chemotherapy improves disease-free survival and overall survival for patients with acute myeloid leukemia (AML) < 60 years.

II. To determine whether post-consolidation immunotherapy with low-dose continuous/intermittent high-dose bolus subcutaneous recombinant interleukin-2 (rIL-2) (aldesleukin) improves disease-free survival and overall survival in patients with AML < 60 years in first complete remission (CR).

SECONDARY OBJECTIVES:

I. To continue to evaluate the effectiveness of three courses of high-dose ARA-C (HiDAC) (cytarabine) as curative consolidation chemotherapy in patients with core binding factor (CBF) leukemias.

II. To continue to establish the use of intensive post-remission chemotherapy with PSCT or a novel intensification sequence consisting of HiDAC/high-dose etoposide/G-CSF (filgrastim) followed by two cycles of HiDAC in patients in CR with unfavorable cytogenetics.

III. To correlate the rate of relapse and toxicity with busulfan pharmacokinetics when busulfan and etoposide are used prior to autologous stem cell transplantation for AML patients in first CR.

OUTLINE: This is a randomized, multicenter study.

INDUCTION THERAPY: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1-3. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of cytarabine IV continuously on days 1-5 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1 and 2.

ARM II: Patients receive PSC 833 IV continuously on days 1-3 and cytarabine, daunorubicin, and etoposide as in arm I. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of PSC 833 IV continuously on days 1 and 2 and cytarabine, daunorubicin, and etoposide as in arm I.

INTENSIFICATION THERAPY: Patients in complete remission receive intensification therapy. Therapy begins no earlier than 2 weeks and no later than 4 weeks after complete remission is attained. Patients are stratified according to cytogenetics (favorable [t(8;21)(q22;q22) or inv(16)(p13;q22) or t(16;16)(p13;q22)] vs unfavorable [all other karyotypes]).

FAVORABLE: Patients receive high-dose cytarabine (HiDAC) IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats no earlier than 28 days after the prior course and no later than 14 days after hematopoietic recovery for two more courses.

UNFAVORABLE: Patients are further divided into two groups based on ability to receive peripheral blood stem cell transplantation (PBSCT) (yes vs no).

PBSCT GROUP: Patients receive etoposide IV continuously and HiDAC IV over 2 hours every 12 hours on days 1-4. Patients also receive filgrastim (G-CSF) subcutaneously (SC) daily beginning on day 14 and continuing until peripheral blood stem cell (PBSC) collection is completed. Patients who are not able to undergo PBSCT after HiDAC/etoposide continue treatment in the non-PBSCT group. At least 4 weeks after HiDAC/etoposide recovery, patients receive oral busulfan every 6 hours on days -7 to -4 and etoposide IV over 4 hours on day -3 prior to PBSCT. Patients receive autologous PBSC infusion on day 0. Patients also receive G-CSF SC beginning on day 0 and continuing until hematopoietic recovery.

NON-PBSCT GROUP: Patients receive etoposide, HiDAC, and G-CSF as in the PBSCT group. After hematopoietic recovery, patients then receive HiDAC IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats no earlier than 28 days after prior course and no later than 14 days after hematopoietic recovery for one more course.

IMMUNOTHERAPY: Patients are again randomized to 1 of 2 treatment arms.

ARM I: Patients begin therapy no later than 120 days after the first day of the last course of HiDAC treatment OR day 0 of PBSCT. Patients receive low-dose interleukin-2 (IL-2) SC on days 1-14, 19-28, 33-42, 47-56, 61-70, and 75-90. In addition, patients receive high-dose IL-2 SC on days 15-17, 29-31, 43-45, 57-59, and 71-73.

ARM II: Patients are observed and receive no further therapy.

Patients are followed at 1 month, every 2 months for 2 years, every 6 months for 2 years, and then annually for 6 years.

PROJECTED ACCRUAL: A total of 720 patients will be accrued for this study within 4 years.

Study Type

Interventional

Enrollment (Actual)

720

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Illinois
      • Chicago, Illinois, United States, 60606
        • Cancer and Leukemia Group B

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

15 years to 59 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Unequivocal histologic diagnosis of AML (> 20% blasts in the bone marrow based on the World Health Organization [WHO] and/or French-American-British Cooperative group [FAB] classifications), excluding M3 (acute promyelocytic leukemia); patients with antecedent myelodysplasia are eligible for treatment on this trial only if there was no bone marrow biopsy showing myelodysplastic syndrome (MDS) > 3 months prior to enrollment; patients with therapy-related MDS or therapy-related AML or a chronic myeloproliferative disorder are not eligible

  • No prior treatment for leukemia or myelodysplasia with four permissible exceptions:

    • Emergency leukapheresis
    • Emergency treatment for hyperleukocytosis with hydroxyurea
    • Cranial radiation therapy (RT) for central nervous system (CNS) leukostasis (one dose only)
    • Growth factor/cytokine support

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Induction Arm I
Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1-3. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of cytarabine IV continuously on days 1-5 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1 and 2.
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Drug: cytarabine
Given IV
Other Names:
  • Cytosar-U
  • cytosine arabinoside
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
Drug: daunorubicin hydrochloride
Given IV
Other Names:
  • Cerubidin
  • Cerubidine
  • RP-13057
  • daunomycin hydrochloride
  • daunorubicin
Experimental: Induction Arm II
Patients receive PSC 833 IV continuously on days 1-3 and cytarabine, daunorubicin, and etoposide as in arm I. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of PSC 833 IV continuously on days 1 and 2 and cytarabine, daunorubicin, and etoposide as in arm I.
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Drug: cytarabine
Given IV
Other Names:
  • Cytosar-U
  • cytosine arabinoside
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
Drug: daunorubicin hydrochloride
Given IV
Other Names:
  • Cerubidin
  • Cerubidine
  • RP-13057
  • daunomycin hydrochloride
  • daunorubicin
Drug: valspodar
Given IV
Other Names:
  • Amdray
  • PSC 833
Experimental: Intensification Favorable
Patients receive HiDAC IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats no earlier than 28 days after the prior course and no later than 14 days after hematopoietic recovery for two more courses.
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Drug: cytarabine
Given IV
Other Names:
  • Cytosar-U
  • cytosine arabinoside
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
Experimental: Intensification Unfavorable PBSCT Group
Patients receive etoposide IV continuously and HiDAC IV over 2 hours every 12 hours on days 1-4. Patients also receive G-CSF SC daily beginning on day 14 and continuing until PBSC collection is completed. Patients who are not able to undergo PBSCT after HiDAC/etoposide continue treatment in the non-PBSCT group. At least 4 weeks after HiDAC/etoposide recovery, patients receive oral busulfan every 6 hours on days -7 to -4 and etoposide IV over 4 hours on day -3 prior to PBSCT. Patients receive autologous PBSC infusion on day 0. Patients also receive G-CSF SC beginning on day 0 and continuing until hematopoietic recovery.
Drug: busulfan
Given orally
Other Names:
  • BSF
  • BU
  • Misulfan
  • Mitosan
  • Myeloleukon
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Drug: cytarabine
Given IV
Other Names:
  • Cytosar-U
  • cytosine arabinoside
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
Biological: filgrastim
Given SC
Other Names:
  • G-CSF
  • Neupogen
Procedure: autologous hematopoietic stem cell transplantation
Undergo autologous PBSCT
Procedure: peripheral blood stem cell transplantation
Undergo autologous PBSCT
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Experimental: Intensification Unfavorable Non-PBSCT Group
Patients receive etoposide, HiDAC, and G-CSF as in the PBSCT group. After hematopoietic recovery, patients then receive HiDAC IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats no earlier than 28 days after prior course and no later than 14 days after hematopoietic recovery for one more course.
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Drug: cytarabine
Given IV
Other Names:
  • Cytosar-U
  • cytosine arabinoside
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
Biological: filgrastim
Given SC
Other Names:
  • G-CSF
  • Neupogen
Experimental: Immunotherapy Arm I
Patients begin therapy no later than 120 days after the first day of the last course of HiDAC treatment OR day 0 of PBSCT. Patients receive low-dose IL-2 SC on days 1-14, 19-28, 33-42, 47-56, 61-70, and 75-90. In addition, patients receive high-dose IL-2 SC on days 15-17, 29-31, 43-45, 57-59, and 71-73.
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Biological: aldesleukin
Given SC
Other Names:
  • Proleukin
  • IL-2
  • recombinant human interleukin-2
  • recombinant interleukin-2
Active Comparator: Immunotherapy Arm II
Patients are observed and receive no further therapy.
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Other: clinical observation
Undergo clinical observation
Other Names:
  • observation

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease-free survival
Time Frame: Up to 10 years
An unstratified logrank test for the induction treatment comparison and a stratified logrank test for the post-remission treatment comparison will be the primary statistical methods used for treatment comparisons.
Up to 10 years
Overall survival
Time Frame: Up to 10 years
An unstratified logrank test for the induction treatment comparison and a stratified logrank test for the post-remission treatment comparison will be the primary statistical methods used for treatment comparisons.
Up to 10 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Estimates of disease-free survival curves
Time Frame: Up to 10 years
Up to 10 years
Estimates of overall survival curves
Time Frame: Up to 10 years
Up to 10 years
Toxicities and adverse events assessed using National Cancer Institute (NCI) Common Toxicity Criteria (CTC)
Time Frame: Up to 10 years
Will be tabulated.
Up to 10 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Jonathan Kolitz, Cancer and Leukemia Group B

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2000

Primary Completion (Actual)

June 1, 2005

Study Registration Dates

First Submitted

October 4, 2000

First Submitted That Met QC Criteria

January 26, 2003

First Posted (Estimate)

January 27, 2003

Study Record Updates

Last Update Posted (Estimate)

June 4, 2013

Last Update Submitted That Met QC Criteria

June 3, 2013

Last Verified

June 1, 2013

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2012-02824
  • U10CA031946 (U.S. NIH Grant/Contract)
  • CALGB-19808

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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