Neoplasms

Symptoms and General Pathology

All Conditions

Blood and Lymph Conditions

Diseases and Abnormalities at or Before Birth

Rare Diseases

Neoplasm Metastasis

Syndrome

Leukemia

Congenital Abnormalities

Anemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Anemia, Refractory, with Excess of Blasts

Anemia, Refractory

Leukemia, Myelomonocytic, Acute

Leukemia, Monocytic, Acute

Leukemia, Erythroblastic, Acute

Leukemia, Megakaryoblastic, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Bone Marrow Diseases

Precancerous Conditions

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Myelodysplastic Syndrome With Excess Blasts

Acute Monoblastic Leukemia

Acute Myelomonocytic Leukemia

Acute Erythroid Leukemia

Di Guglielmo's Syndrome

Acute Megakaryoblastic Leukemia

Acute Myeloblastic Leukemia Without Maturation

Acute Myeloblastic Leukemia With Maturation

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Cytarabine

Molgramostim

Sargramostim

Daunorubicin

Lenograstim

Antimetabolites

Antiviral Agents

Immunosuppressive Agents

Immunologic Factors

Adjuvants, Immunologic

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

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.

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.

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.

filgrastim

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.

sargramostim

100 mg/m²/day by continuous intravenous infusion for 7 days (days 1-7).

cytarabine

45 mg/m²/day by 10 - 15 minute intravenous infusion for 3 days (days 1, 2, and 3).

daunorubicin hydrochloride

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.

zosuquidar trihydrochloride

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.

Placebo

Larry D. Cripe, MD

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.

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.

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

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

Time from randomization to death. Patients alive at last follow-up were censored.

Time from randomization to the earlier of disease progression or death. Patients alive and progression-free at last follow-up were censored.

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.

National Cancer Institute (NCI)

Eli Lilly and Company

Kanisa Pharmaceuticals

Eastern Cooperative Oncology Group

In addition to lab assessed as above, clinical events were reported via case report forms at the end of Induction, Consolidation I, and Consolidation II. After the end of treatment, forms were collected every 3 months for 2 years, then every 6 months for 3 years. CTCv2 reports were electronically mapped to CTCAE3.

Induction treatment with daunorubicin, cytarabine and zosuquidar

Zosuquidar Induction

Induction treatment with daunorubicin, cytarabine and placebo

Placebo Induction

Consolidation I

Consolidation with Daunorubicin, Cytarabine and Zosuquidar

Zosuquidar Consolidation II

Consolidation with Daunorubicin, Cytarabine and Placebo

Placebo Consolidation II

Zosuquidar

Total

Age, Continuous

Sex: Female, Male

Study Statistician

The study was designed to have 80% power to detect a non-proportional hazards difference in OS at the one-sided 0.025 significance level of 30.2% vs 39.6%, 12.8% vs 27.1% and 7.0% vs 14.0% at 1 years, 2 years, and full information for zosuquidar and placebo, respectively.

Overall Survival (OS)

Eligible participants, as randomized. Patients who had neither documented progression nor death within 3 months of registration without disease evaluation were excluded.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Daunorubicin & Cytarabine +/- Zosuquidar inTreating Older Patients With Newly Diagnosed Acute Myeloid Leukemia or Refractory Anemia	NCT00046930	Leukemia Myelodysplastic...	filgrastim sargramostim cytarabine daunorubicin hy... zosuquidar trih... Placebo	60 Years -	Eastern Cooperative Oncology Group
Daunorubicin & Cytarabine +/- Zosuquidar inTreating Older Patients With Newly Diagnosed Acute Myeloid Leukemia or Refractory Anemia	NCT00046930	Leukemia Myelodysplastic...	filgrastim sargramostim cytarabine daunorubicin hy... zosuquidar trih... Placebo	60 Years -	Eastern Cooperative Oncology Group

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