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

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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

Study Description
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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.


Condition or disease Intervention/treatment Phase
Leukemia Myelodysplastic Syndromes Biological: filgrastim Biological: sargramostim Drug: cytarabine Drug: daunorubicin hydrochloride Drug: zosuquidar trihydrochloride Drug: Placebo Phase 3

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 449 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : July 2002
Actual Primary Completion Date : June 2009

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
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.
 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
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.
 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: 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


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.


Eligibility Criteria
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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00046930


Locations
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Sponsors and Collaborators
Eastern Cooperative Oncology Group
National Cancer Institute (NCI)
Eli Lilly and Company
Kanisa Pharmaceuticals
Investigators
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Study Chair: Larry D. Cripe, MD Indiana University Melvin and Bren Simon Cancer Center
More Information
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Publications of Results:
Cripe LD, Li X, Litzow M, et al.: A randomized, placebo-controlled, double blind trial of the MDR modulator, zosuquidar, during conventional induction and post-remission therapy for Pts > 60 years of age with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS): ECOG 3999. [Abstract] Blood 108 (11): A-423, 2006.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Layout table for additonal information
Responsible Party: Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier: NCT00046930    
Obsolete Identifiers: NCT00046046
Other Study ID Numbers: CDR0000257122
E3999 ( Other Identifier: Eastern Cooperative Oncology Group )
U10CA021115 ( U.S. NIH Grant/Contract )
First Posted: January 27, 2003    Key Record Dates
Results First Posted: September 6, 2010
Last Update Posted: June 26, 2015
Last Verified: June 2015
Keywords provided by Eastern Cooperative Oncology Group:
adult acute monocytic leukemia (M5b)
adult acute erythroid leukemia (M6)
adult acute megakaryoblastic leukemia (M7)
adult acute myeloblastic leukemia with maturation (M2)
adult acute myeloblastic leukemia without maturation (M1)
adult acute myelomonocytic leukemia (M4)
adult acute monoblastic leukemia (M5a)
refractory anemia with excess blasts in transformation
refractory anemia with excess blasts
 secondary acute myeloid leukemia
untreated adult acute myeloid leukemia
de novo myelodysplastic syndromes
adult acute minimally differentiated myeloid leukemia (M0)
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Anemia
Myelodysplastic Syndromes
Anemia, Refractory
Anemia, Refractory, with Excess of Blasts
Neoplasms by Histologic Type
Neoplasms
Hematologic Diseases
Bone Marrow Diseases
Precancerous Conditions
Cytarabine
Daunorubicin
 Molgramostim
Lenograstim
Sargramostim
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Adjuvants, Immunologic
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors