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

Sponsor:	Eastern Cooperative Oncology Group
Collaborators:	National Cancer Institute (NCI) Eli Lilly and Company Kanisa Pharmaceuticals
Information provided by:	Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier:	NCT00046930

Purpose

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	Intervention	Phase
Leukemia Myelodysplastic Syndromes	Biological: filgrastim Biological: sargramostim Drug: cytarabine Drug: daunorubicin hydrochloride Drug: zosuquidar trihydrochloride Drug: Placebo	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:

MedlinePlus related topics: Acute Myeloid Leukemia Anemia Cancer Leukemia Myelodysplastic Syndromes

Drug Information available for: Cytarabine hydrochloride Daunorubicin Daunorubicin hydrochloride Granulocyte-macrophage colony-stimulating factor Filgrastim Sargramostim Lenograstim Granulocyte colony-stimulating factor Zosuquidar Zosuquidar Trihydrochloride Cytarabine

U.S. FDA Resources

Further study details as provided by Eastern Cooperative Oncology Group:

Primary Outcome Measures:

Overall Survival (OS) [ Time Frame: Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually thereafter ] [ Designated as safety issue: No ]
Time from randomization to death. Patients alive at last follow-up were censored.

Secondary Outcome Measures:

Progression-free Survival (PFS) [ Time Frame: Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually thereafter ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
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.

Enrollment:	449
Study Start Date:	July 2002
Primary Completion Date:	June 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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

Arms

Assigned Interventions

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

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.

Eligibility

Ages Eligible for Study:	60 Years and older
Genders Eligible for Study:	Both
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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00046930

Show 92 Study Locations

Sponsors and Collaborators

Eastern Cooperative Oncology Group

National Cancer Institute (NCI)

Eli Lilly and Company

Kanisa Pharmaceuticals

Investigators

Study Chair:

Larry D. Cripe, MD

Indiana University Melvin and Bren Simon Cancer Center

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

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.

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

Cripe LD, Uno H, Paietta EM, Litzow MR, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Luger S, Tallman MS. Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999. Blood. 2010 Nov 18;116(20):4077-85. Epub 2010 Aug 17.

Responsible Party:	Group Chair, Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier:	NCT00046930 History of Changes
Obsolete Identifiers:	NCT00046046
Other Study ID Numbers:	CDR0000257122, E3999, U10CA021115
Study First Received:	October 3, 2002
Results First Received:	August 17, 2010
Last Updated:	June 21, 2011
Health Authority:	United States: Food and Drug Administration

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:

Anemia
Anemia, Refractory
Anemia, Refractory, with Excess of Blasts
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Myelodysplastic Syndromes
Preleukemia
Anemia, Aplastic
Hematologic Diseases
Bone Marrow Diseases
Neoplasms by Histologic Type
Neoplasms
Precancerous Conditions
Cytarabine

Daunorubicin
Lenograstim
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Adjuvants, Immunologic

ClinicalTrials.gov processed this record on February 12, 2012