Daunorubicin & Cytarabine +/- Zosuquidar inTreating Older Patients With Newly Diagnosed Acute Myeloid Leukemia or Refractory Anemia
- Conditions
- LeukemiaMyelodysplastic Syndromes
- Interventions
- Biological: filgrastimBiological: sargramostimDrug: cytarabineDrug: daunorubicin hydrochlorideDrug: zosuquidar trihydrochlorideDrug: Placebo
- Registration Number
- NCT00046930
- Lead Sponsor
- Eastern Cooperative Oncology Group
- 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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 449
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%
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Zosuquidar zosuquidar trihydrochloride 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. Zosuquidar filgrastim 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. Zosuquidar sargramostim 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. Zosuquidar daunorubicin hydrochloride 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. Placebo filgrastim 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. Placebo sargramostim 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. Placebo daunorubicin hydrochloride 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. Placebo 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. Zosuquidar cytarabine 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. Placebo cytarabine 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.
- Primary Outcome Measures
Name Time Method Overall Survival (OS) 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
Name Time Method Progression-free Survival (PFS) 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.
Response 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.
Trial Locations
- Locations (91)
Evanston Northwestern Health Care - Evanston Hospital
🇺🇸Evanston, Illinois, United States
CCOP - Metro-Minnesota
🇺🇸Saint Louis Park, Minnesota, United States
Marshfield Clinic - Marshfield Center
🇺🇸Marshfield, Wisconsin, United States
Hillman Cancer Center at University of Pittsburgh Cancer Institute
🇺🇸Pittsburgh, Pennsylvania, United States
Robert H. Lurie Comprehensive Cancer Center at Northwestern University
🇺🇸Chicago, Illinois, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
Tufts - New England Medical Center
🇺🇸Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, 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
Hope Cancer Care Center at Longmont United Hospital
🇺🇸Longmont, Colorado, United States
Hematology and Oncology Associates
🇺🇸Scranton, Pennsylvania, United States
MBCCOP-Medical College of Georgia Cancer Center
🇺🇸Augusta, Georgia, United States
Decatur Memorial Hospital Cancer Care Institute
🇺🇸Decatur, Illinois, United States
Indiana University Cancer Center
🇺🇸Indianapolis, Indiana, United States
Watson Clinic, LLC
🇺🇸Lakeland, Florida, United States
St. Mary-Corwin Regional Medical Center
🇺🇸Pueblo, Colorado, United States
St. Luke's Regional Medical Center
🇺🇸Sioux City, Iowa, United States
Southwest Medical Center
🇺🇸Liberal, Kansas, United States
Via Christi Cancer Center at Via Christi Regional Medical Center
🇺🇸Wichita, Kansas, United States
Regional Cancer Center at Memorial Medical Center
🇺🇸Springfield, Illinois, United States
CCOP - Mayo Clinic Scottsdale Oncology Program
🇺🇸Scottsdale, Arizona, United States
Baptist Cancer Institute - Jacksonville
🇺🇸Jacksonville, Florida, United States
Borgess Medical Center
🇺🇸Kalamazoo, Michigan, United States
Park Nicollet Clinic
🇺🇸Saint Louis Park, Minnesota, United States
Abramson Cancer Center of the University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Mayo Clinic - Jacksonville
🇺🇸Jacksonville, Florida, United States
North Suburban Medical Center
🇺🇸Thornton, Colorado, United States
Fairview Southdale Hospital
🇺🇸Edina, Minnesota, United States
Cancer Center of Kansas - Chanute
🇺🇸Chanute, Kansas, United States
Siouxland Hematology-Oncology Associates
🇺🇸Sioux City, Iowa, United States
Cancer Center of Kansas - Dodge City
🇺🇸Dodge City, Kansas, United States
Cancer Center of Kansas, P.A.
🇺🇸Wichita, Kansas, United States
Cancer Center of Kansas - Newton
🇺🇸Newton, Kansas, United States
Cancer Center of Kansas - Wellington
🇺🇸Wellington, Kansas, United States
Cancer Center of Kansas - Salina
🇺🇸Salina, Kansas, United States
Cancer Center of Kansas - Winfield
🇺🇸Winfield, Kansas, United States
Hubert H. Humphrey Cancer Center at North Memorial Medical Center
🇺🇸Robbinsdale, Minnesota, United States
Leo W. Jenkins Cancer Center at Pitt County Memorial Hospital
🇺🇸Greenville, North Carolina, United States
CCOP - Northern New Jersey
🇺🇸Hackensack, New Jersey, United States
Guthrie Medical Center - Sayre
🇺🇸Sayre, Pennsylvania, United States
Rambam Medical Center
🇮🇱Haifa, Israel
Methodist Cancer Center at Methodist Hospital
🇺🇸Indianapolis, Indiana, United States
Virginia Piper Cancer Institute at Abbott-Northwestern Hospital
🇺🇸Minneapolis, 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
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
Mayo Clinic Cancer Center
🇺🇸Rochester, Minnesota, United States
United Hospital
🇺🇸Saint Paul, Minnesota, United States
Penrose Cancer Center at Penrose Hospital
🇺🇸Colorado Springs, Colorado, United States
Boulder Community Hospital
🇺🇸Boulder, Colorado, United States
Swedish Medical Center
🇺🇸Englewood, Colorado, United States
Associates in Womens Health
🇺🇸Wichita, Kansas, United States
McFarland Clinic, P.C.
🇺🇸Ames, Iowa, United States
Pratt Cancer Center of Kansas
🇺🇸Pratt, Kansas, United States
Cancer Center of Kansas, P.A. - Wichita
🇺🇸Wichita, Kansas, United States
CCOP - Wichita
🇺🇸Wichita, Kansas, United States
Baystate Regional Cancer Program at D'Amour Center for Cancer Care
🇺🇸Springfield, Massachusetts, United States
West Michigan Cancer Center
🇺🇸Kalamazoo, Michigan, United States
Mercy and Unity Cancer Center at Mercy Hospital
🇺🇸Coon Rapids, Minnesota, United States
Mercy and Unity Cancer Center at Unity Hospital
🇺🇸Fridley, Minnesota, United States
Ridgeview Medical Center
🇺🇸Waconia, Minnesota, United States
NYU Cancer Institute at New York University Medical Center
🇺🇸New York, New York, United States
Geisinger Wyoming Valley Medical Center
🇺🇸Wilkes-Barre, Pennsylvania, 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
Carle Cancer Center at Carle Foundation Hospital
🇺🇸Urbana, Illinois, United States
Sky Ridge Medical Center
🇺🇸Lone Tree, Colorado, United States
Cancer Center of Kansas - Kingman
🇺🇸Kingman, Kansas, United States
Geisinger Medical Center
🇺🇸Danville, Pennsylvania, United States
Fairview Ridges Hospital
🇺🇸Burnsville, Minnesota, United States
Aultman Hospital Cancer Center at Aultman Health Foundation
🇺🇸Canton, Ohio, United States
Wesley Medical Center
🇺🇸Wichita, Kansas, United States
Booker Cancer Center at Riverview Medical Center
🇺🇸Red Bank, New Jersey, United States
St. Luke's Hospital Cancer Center
🇺🇸Bethlehem, Pennsylvania, United States
Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center
🇺🇸La Crosse, Wisconsin, United States
Bronson Methodist Hospital
🇺🇸Kalamazoo, Michigan, United States
University of Wisconsin Comprehensive Cancer Center
🇺🇸Madison, Wisconsin, United States
Penn State Cancer Institute at Milton S. Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
Geisinger Medical Group
🇺🇸State College, Pennsylvania, United States
Sioux Valley Hospital and University of South Dakota Medical Center
🇺🇸Sioux Falls, South Dakota, United States
Aurora Presbyterian Hospital
🇺🇸Aurora, Colorado, United States
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
🇺🇸Tampa, Florida, 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
University of Florida Shands Cancer Center
🇺🇸Gainesville, Florida, United States
Albert Einstein Cancer Center at Albert Einstein College of Medicine
🇺🇸Bronx, New York, United States