Daunorubicin & Cytarabine +/- Zosuquidar inTreating Older Patients With Newly Diagnosed Acute Myeloid Leukemia or Refractory Anemia
NCT ID: NCT00046930
Last Updated: 2023-07-05
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
449 participants
INTERVENTIONAL
2002-09-17
Brief Summary
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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.
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Detailed Description
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* 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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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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.
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.
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.
cytarabine
100 mg/m²/day by continuous intravenous infusion for 7 days (days 1-7).
daunorubicin hydrochloride
45 mg/m²/day by 10 - 15 minute intravenous infusion for 3 days (days 1, 2, and 3).
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.
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.
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.
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.
cytarabine
100 mg/m²/day by continuous intravenous infusion for 7 days (days 1-7).
daunorubicin hydrochloride
45 mg/m²/day by 10 - 15 minute intravenous infusion for 3 days (days 1, 2, and 3).
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.
Interventions
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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.
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.
cytarabine
100 mg/m²/day by continuous intravenous infusion for 7 days (days 1-7).
daunorubicin hydrochloride
45 mg/m²/day by 10 - 15 minute intravenous infusion for 3 days (days 1, 2, and 3).
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.
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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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
60 Years
ALL
No
Sponsors
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National Cancer Institute (NCI)
NIH
Eli Lilly and Company
INDUSTRY
Kanisa Pharmaceuticals
INDUSTRY
Eastern Cooperative Oncology Group
NETWORK
Responsible Party
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Principal Investigators
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Larry D. Cripe, MD
Role: STUDY_CHAIR
Indiana University Melvin and Bren Simon Cancer Center
Locations
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CCOP - Mayo Clinic Scottsdale Oncology Program
Scottsdale, Arizona, United States
Aurora Presbyterian Hospital
Aurora, Colorado, United States
Boulder Community Hospital
Boulder, Colorado, United States
Penrose Cancer Center at Penrose Hospital
Colorado Springs, Colorado, United States
Porter Adventist Hospital
Denver, Colorado, United States
Presbyterian - St. Luke's Medical Center
Denver, Colorado, United States
St. Joseph Hospital
Denver, Colorado, United States
Rose Medical Center
Denver, Colorado, United States
CCOP - Colorado Cancer Research Program, Incorporated
Denver, Colorado, United States
Swedish Medical Center
Englewood, Colorado, United States
Sky Ridge Medical Center
Lone Tree, Colorado, United States
Hope Cancer Care Center at Longmont United Hospital
Longmont, Colorado, United States
St. Mary-Corwin Regional Medical Center
Pueblo, Colorado, United States
North Suburban Medical Center
Thornton, Colorado, United States
University of Florida Shands Cancer Center
Gainesville, Florida, United States
Baptist Cancer Institute - Jacksonville
Jacksonville, Florida, United States
Mayo Clinic - Jacksonville
Jacksonville, Florida, United States
Watson Clinic, LLC
Lakeland, Florida, United States
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
Tampa, Florida, United States
MBCCOP-Medical College of Georgia Cancer Center
Augusta, Georgia, United States
Hematology and Oncology Associates
Chicago, Illinois, United States
Robert H. Lurie Comprehensive Cancer Center at Northwestern University
Chicago, Illinois, United States
Rush University Medical Center
Chicago, Illinois, United States
Decatur Memorial Hospital Cancer Care Institute
Decatur, Illinois, United States
Evanston Northwestern Health Care - Evanston Hospital
Evanston, Illinois, United States
Regional Cancer Center at Memorial Medical Center
Springfield, Illinois, United States
Carle Cancer Center at Carle Foundation Hospital
Urbana, Illinois, United States
Indiana University Cancer Center
Indianapolis, Indiana, United States
Methodist Cancer Center at Methodist Hospital
Indianapolis, Indiana, United States
McFarland Clinic, P.C.
Ames, Iowa, United States
Siouxland Hematology-Oncology Associates
Sioux City, Iowa, United States
St. Luke's Regional Medical Center
Sioux City, Iowa, United States
Cancer Center of Kansas - Chanute
Chanute, Kansas, United States
Cancer Center of Kansas - Dodge City
Dodge City, Kansas, United States
Cancer Center of Kansas - Kingman
Kingman, Kansas, United States
Southwest Medical Center
Liberal, Kansas, United States
Cancer Center of Kansas - Newton
Newton, Kansas, United States
Pratt Cancer Center of Kansas
Pratt, Kansas, United States
Cancer Center of Kansas - Salina
Salina, Kansas, United States
Cancer Center of Kansas - Wellington
Wellington, Kansas, United States
Associates in Womens Health
Wichita, Kansas, United States
Cancer Center of Kansas, P.A.
Wichita, Kansas, United States
Cancer Center of Kansas, P.A. - Wichita
Wichita, Kansas, United States
CCOP - Wichita
Wichita, Kansas, United States
Via Christi Cancer Center at Via Christi Regional Medical Center
Wichita, Kansas, United States
Wesley Medical Center
Wichita, Kansas, United States
Cancer Center of Kansas - Winfield
Winfield, Kansas, United States
Tufts - New England Medical Center
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
Baystate Regional Cancer Program at D'Amour Center for Cancer Care
Springfield, Massachusetts, United States
CCOP - Michigan Cancer Research Consortium
Ann Arbor, Michigan, United States
St. Joseph Mercy Cancer Center at St. Joseph Mercy Hospital
Ann Arbor, Michigan, United States
Borgess Medical Center
Kalamazoo, Michigan, United States
Bronson Methodist Hospital
Kalamazoo, Michigan, United States
West Michigan Cancer Center
Kalamazoo, Michigan, United States
Fairview Ridges Hospital
Burnsville, Minnesota, United States
Mercy and Unity Cancer Center at Mercy Hospital
Coon Rapids, Minnesota, United States
Fairview Southdale Hospital
Edina, Minnesota, United States
Mercy and Unity Cancer Center at Unity Hospital
Fridley, Minnesota, United States
Virginia Piper Cancer Institute at Abbott-Northwestern Hospital
Minneapolis, Minnesota, United States
Hubert H. Humphrey Cancer Center at North Memorial Medical Center
Robbinsdale, Minnesota, United States
Mayo Clinic Cancer Center
Rochester, Minnesota, United States
CCOP - Metro-Minnesota
Saint Louis Park, Minnesota, United States
Park Nicollet Clinic
Saint Louis Park, Minnesota, United States
United Hospital
Saint Paul, Minnesota, United States
Ridgeview Medical Center
Waconia, Minnesota, United States
University Medical Center of Southern Nevada
Las Vegas, Nevada, United States
CCOP - Southern Nevada Cancer Research Foundation
Las Vegas, Nevada, United States
CCOP - Northern New Jersey
Hackensack, New Jersey, United States
Booker Cancer Center at Riverview Medical Center
Red Bank, New Jersey, United States
NYU Cancer Institute at New York University Medical Center
New York, New York, United States
Albert Einstein Cancer Center at Albert Einstein College of Medicine
The Bronx, New York, United States
Leo W. Jenkins Cancer Center at Pitt County Memorial Hospital
Greenville, North Carolina, United States
Aultman Hospital Cancer Center at Aultman Health Foundation
Canton, Ohio, United States
Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University
Cleveland, Ohio, United States
MetroHealth's Cancer Care Center at MetroHealth Medical Center
Cleveland, Ohio, United States
St. Luke's Hospital Cancer Center
Bethlehem, Pennsylvania, United States
Geisinger Medical Center
Danville, Pennsylvania, United States
Penn State Cancer Institute at Milton S. Hershey Medical Center
Hershey, Pennsylvania, United States
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, United States
Hillman Cancer Center at University of Pittsburgh Cancer Institute
Pittsburgh, Pennsylvania, United States
Guthrie Medical Center - Sayre
Sayre, Pennsylvania, United States
Hematology and Oncology Associates
Scranton, Pennsylvania, United States
Geisinger Medical Group
State College, Pennsylvania, United States
Geisinger Wyoming Valley Medical Center
Wilkes-Barre, Pennsylvania, United States
Sioux Valley Hospital and University of South Dakota Medical Center
Sioux Falls, South Dakota, United States
University of Virginia Cancer Center
Charlottesville, Virginia, United States
Mary Babb Randolph Cancer Center at West Virginia University Hospitals
Morgantown, West Virginia, United States
Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center
La Crosse, Wisconsin, United States
University of Wisconsin Comprehensive Cancer Center
Madison, Wisconsin, United States
Marshfield Clinic - Marshfield Center
Marshfield, Wisconsin, United States
Rambam Medical Center
Haifa, , Israel
Countries
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References
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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.
Foran JM, Sun Z, Lai C, Fernandez HF, Cripe LD, Ketterling RP, Racevskis J, Luger SM, Paietta E, Lazarus HM, Zhang Y, Bennett JM, Levine RL, Rowe JM, Litzow MR, Tallman MS. Obesity in adult acute myeloid leukemia is not associated with inferior response or survival even when dose capping anthracyclines: An ECOG-ACRIN analysis. Cancer. 2023 Aug 15;129(16):2479-2490. doi: 10.1002/cncr.34807. Epub 2023 Apr 25.
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. doi: 10.1182/blood-2010-04-277269. Epub 2010 Aug 17.
Other Identifiers
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E3999
Identifier Type: OTHER
Identifier Source: secondary_id
CDR0000257122
Identifier Type: -
Identifier Source: org_study_id
NCT00046046
Identifier Type: -
Identifier Source: nct_alias
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