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Daunorubicin & Cytarabine +/- Zosuquidar inTreating Older Patients With Newly Diagnosed Acute Myeloid Leukemia or Refractory Anemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00046930
Recruitment Status : Completed
First Posted : January 27, 2003
Results First Posted : September 6, 2010
Last Update Posted : June 26, 2015
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Eli Lilly and Company
Kanisa Pharmaceuticals
Information provided by (Responsible Party):
Eastern Cooperative Oncology Group

Tracking Information
First Submitted Date  ICMJE October 3, 2002
First Posted Date  ICMJE January 27, 2003
Results First Submitted Date  ICMJE August 17, 2010
Results First Posted Date  ICMJE September 6, 2010
Last Update Posted Date June 26, 2015
Study Start Date  ICMJE July 2002
Actual Primary Completion Date June 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 21, 2011)
Overall Survival (OS) [ Time Frame: Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually thereafter ]
Time from randomization to death. Patients alive at last follow-up were censored.
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00046930 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 21, 2011)
  • Progression-free Survival (PFS) [ Time Frame: Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually thereafter ]
    Time from randomization to the earlier of disease progression or death. Patients alive and progression-free at last follow-up were censored.
  • Response [ Time Frame: Assessed at the end of induction ]
    Number of eligible participants in each response category. Categories, based on peripheral blood counts and bone marrow aspirate and biopsy, include complete remission (CR), partial remission (PR), morphologic complete remission (MCR), and relapse.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Daunorubicin & Cytarabine +/- Zosuquidar inTreating Older Patients With Newly Diagnosed Acute Myeloid Leukemia or Refractory Anemia
Official Title  ICMJE A Randomized, Placebo-Controlled, Double Blind, Trial of the Administration of the MDR Modulator, Zosuquidar Trihydrochloride (LY335979), During Conventional Induction and Post-Remission Therapy in Patients Greater Than 60 Years of Age With Newly Diagnosed Acute Myeloid Leukemia, Refractory Anemia With Excess Blasts in Transformation or High-Risk Refractory Anemia With Excess Blasts
Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Zosuquidar trihydrochloride, a modulator of multidrug resistance (MDR), may help daunorubicin and cytarabine kill more cancer cells by making cancer cells more sensitive to the drugs. It is not yet known whether daunorubicin and cytarabine are more effective with or without zosuquidar trihydrochloride in treating acute myeloid leukemia or anemia.

PURPOSE: This randomized phase III trial is studying how well giving zosuquidar trihydrochloride together with daunorubicin and cytarabine works compared to daunorubicin and cytarabine alone in treating older patients with newly diagnosed acute myeloid leukemia or anemia that has not responded to previous treatment.

Detailed Description

OBJECTIVES:

  • Compare the overall survival and progression-free survival of elderly patients with newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts (RAEB) in transformation, or high-risk RAEB treated with daunorubicin and cytarabine with or without zosuquidar trihydrochloride.
  • Compare the complete remission rate of patients treated with these regimens.
  • Compare the toxicity of these regimens in these patients.
  • Compare the systemic exposure of daunorubicin and cytarabine in patients treated with zosuquidar trihydrochloride vs placebo.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to age (60-69 years vs 70 years and over), disease (refractory anemia with excess blasts [RAEB] vs RAEB in transformation or acute myeloid leukemia [AML]), and disease type (de novo vs secondary). Patients are randomized to 1 of 2 treatment arms.

  • Induction:

    • Arm I: Patients receive daunorubicin via intravenous (IV) infusion over 10-15 minutes and zosuquidar trihydrochloride IV over 6 hours on days 1-3. Patients also receive cytarabine IV continuously on days 1-7.
    • Arm II: Patients receive daunorubicin and cytarabine as in arm I. Patients also receive placebo IV over 6 hours on days 1-3.

Beginning on day 12, patients who achieve aplasia receive filgrastim (G-CSF) or sargramostim (GM-CSF) subcutaneously (SC) or IV daily until blood counts recover. Patients who have evidence of persistent AML are eligible to receive a second identical course of induction chemotherapy.

  • Consolidation I (beginning within 8 weeks after documentation of complete remission [CR] or measurable remission [MR]): Patients who achieve a CR or MR receive cytarabine IV over 1 hour once or twice daily on days 1-6 and GM-CSF or G-CSF SC or IV beginning on day 7 and continuing until blood counts recover.
  • Consolidation II: Patients who have maintained peripheral blood evidence of a remission receive daunorubicin, cytarabine, and zosuquidar trihydrochloride or placebo as in induction chemotherapy. Patients also receive GM-CSF or G-CSF SC or IV beginning on day 8 or after last cytarabine dose and continuing until blood counts recover.

Patients are followed monthly for 1 year, every 2 months for 1 year, every 3 months for 1 year, and then every 6 months for 2 years.

PROJECTED ACCRUAL: Approximately 450 patients (225 per treatment arm) accrued over 4.1 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Leukemia
  • Myelodysplastic Syndromes
Intervention  ICMJE
  • Biological: filgrastim
    250 μg/m2/day by either intravenous or subcutaneous injection starting day 12, provided marrow aplasia is achieved, through recovery of absolute neutrophil count (ANC) to > 500 cells/μl, sustained for 3 consecutive days. The dose may be rounded to the nearest vial size.
    Other Names:
    • Neupogen, recombinant-methionyl human granulocyte-colony stimulating factor,
    • granulocyte colony-stimulating factor, r-metHuG-CSF
  • Biological: sargramostim
    5 μg/kg/day by either intravenous or subcutaneous injection starting day 12, provided marrow aplasia is achieved, through recovery of absolute neutrophil count (ANC) to > 500 cells/μl, sustained for 3 consecutive days. The dose may be rounded to the nearest vial size.
    Other Names:
    • Granulocyte-macrophage colony stimulating factor, rHu GM-CSF,
    • Leukine, NSC # 617589
  • Drug: cytarabine
    100 mg/m²/day by continuous intravenous infusion for 7 days (days 1-7).
    Other Name: Cytosar-U, Ara-C, Arabinosyl, cytosine arabinoside.
  • Drug: daunorubicin hydrochloride
    45 mg/m²/day by 10 - 15 minute intravenous infusion for 3 days (days 1, 2, and 3).
    Other Name: Daunomycin, Rubidomycin, Cerubidine.
  • Drug: zosuquidar trihydrochloride

    Zosuquidar 550 mg/day by continuous intravenous infusion through a central venous catheter over approximately 6 hours on days 1, 2, and 3.

    The infusion will begin approximately one hour prior to daunorubicin on days 1, 2 and 3.

    Other Name: Multi drug resistance modulator, MDR, LY335979
  • Drug: Placebo

    Placebo 550 mg/day by continuous intravenous infusion through a central venous catheter over approximately 6 hours on days 1, 2, and 3.

    The infusion will begin approximately one hour prior to daunorubicin on days 1, 2 and 3. Placebo consisted of a 1:1000 dilution of Infuvite, appropriately colored.

    Other Name: Baxter Infuvite Adult
Study Arms  ICMJE
  • Experimental: Zosuquidar
    Induction treatment with daunorubicin, cytarabine and zosuquidar (details provided in Intervention section), followed by consolidation with Cytarabine (1500 mg/m2 every 12 hours for 6 days), then additional consolidation with the same regimen as received during induction.
    Interventions:
    • Biological: filgrastim
    • Biological: sargramostim
    • Drug: cytarabine
    • Drug: daunorubicin hydrochloride
    • Drug: zosuquidar trihydrochloride
  • Active Comparator: Placebo
    Induction treatment with daunorubicin, cytarabine and placebo (details provided in Intervention section), followed by consolidation with Cytarabine (1500 mg/m2 every 12 hours for 6 days), then additional consolidation with the same regimen as received during induction.
    Interventions:
    • Biological: filgrastim
    • Biological: sargramostim
    • Drug: cytarabine
    • Drug: daunorubicin hydrochloride
    • Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 17, 2010)
449
Original Enrollment  ICMJE Not Provided
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date June 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

One of the following disorders:

  • Acute myeloid leukemia (AML), defined as >30% myeloblasts on the marrow aspirate or peripheral blood differential and any French-American-British (FAB) subtype except M3 (i.e., acute promyelocytic leukemia)
  • Refractory anemia with excess blasts (RAEB), defined as 11-20% myeloblasts on bone marrow aspirate or peripheral blood differential, provided there are other criteria for high-risk disease
  • Refractory anemia with excess blasts in transformation (RAEB-T), defined as 21-30% myeloblasts on bone marrow aspirate or peripheral blood differential
  • Participants may have secondary AML
  • Age greater than 60 years
  • ECOG performance status of 0 to 3
  • Total serum bilirubin < 3 mg/dL
  • Serum creatinine < 2 mg/dL
  • Cardiac ejection fraction of > 45%

Exclusion Criteria:

  • Blastic transformation of chronic myelogenous leukemia
  • CNS leukemia
  • Prior chemotherapy for AML, with the exception of hydroxyurea
  • For women: pregnant or breast feeding
  • Other malignancy for which participant is currently receiving treatment
  • Concurrent treatment with other colony-stimulating factors
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Israel,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00046930
Other Study ID Numbers  ICMJE CDR0000257122
E3999 ( Other Identifier: Eastern Cooperative Oncology Group )
U10CA021115 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Eastern Cooperative Oncology Group
Study Sponsor  ICMJE Eastern Cooperative Oncology Group
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Eli Lilly and Company
  • Kanisa Pharmaceuticals
Investigators  ICMJE
Study Chair: Larry D. Cripe, MD Indiana University Melvin and Bren Simon Cancer Center
PRS Account Eastern Cooperative Oncology Group
Verification Date June 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP