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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Biological: filgrastim
* Biological: sargramostim
* Drug: cytarabine
* Drug: daunorubicin hydrochloride
* Drug: zosuquidar trihydrochloride
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zosuquidar<br>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<br>* 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.<br>* Other names: granulocyte colony-stimulating factor, r-metHuG-CSF;Biological: sargramostim<br>* 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.<br>* Other names: Leukine, NSC # 617589;Drug: cytarabine<br>* 100 mg/m²/day by continuous intravenous infusion for 7 days (days 1-7).<br>* Other names: Cytosar-U, Ara-C, Arabinosyl, cytosine arabinoside.;Drug: daunorubicin hydrochloride<br>* 45 mg/m²/day by 10 - 15 minute intravenous infusion for 3 days (days 1, 2, and 3).<br>* Other names: Daunomycin, Rubidomycin, Cerubidine.;Drug: zosuquidar trihydrochloride<br>* 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.<br>* Other names: Multi drug resistance modulator, MDR, LY335979;|
| Active Comparator: Placebo<br>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<br>* 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.<br>* Other names: granulocyte colony-stimulating factor, r-metHuG-CSF;Biological: sargramostim<br>* 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.<br>* Other names: Leukine, NSC # 617589;Drug: cytarabine<br>* 100 mg/m²/day by continuous intravenous infusion for 7 days (days 1-7).<br>* Other names: Cytosar-U, Ara-C, Arabinosyl, cytosine arabinoside.;Drug: daunorubicin hydrochloride<br>* 45 mg/m²/day by 10 - 15 minute intravenous infusion for 3 days (days 1, 2, and 3).<br>* Other names: Daunomycin, Rubidomycin, Cerubidine.;Drug: Placebo<br>* 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.<br>* Other names: Baxter Infuvite Adult;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Time from randomization to death. Patients alive at last follow-up were censored. | Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually thereafter | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Time from randomization to the earlier of disease progression or death. Patients alive and progression-free at last follow-up were censored. | Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually thereafter | 
| Response | 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. | Assessed at the end of induction | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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)