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

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.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Leukemia
• Intervention / Treatment: Biological: filgrastim; Biological: sargramostim; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: zosuquidar trihydrochloride; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 449
• Phase: Phase 3

Contacts and Locations

Study Locations

• Israel
  • Haifa, Israel
    • Rambam Medical Center
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • CCOP - Mayo Clinic Scottsdale Oncology Program
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Aurora Presbyterian Hospital
    • Boulder, Colorado, United States, 80301
      • Boulder Community Hospital
    • Colorado Springs, Colorado, United States, 80933
      • Penrose Cancer Center at Penrose Hospital
    • Denver, Colorado, United States, 80210
      • Porter Adventist Hospital
    • Denver, Colorado, United States, 80220
      • Rose Medical Center
    • Denver, Colorado, United States, 80218
      • Presbyterian - St. Luke's Medical Center
    • Denver, Colorado, United States, 80218
      • St. Joseph Hospital
    • Denver, Colorado, United States, 80224-2522
      • CCOP - Colorado Cancer Research Program, Incorporated
    • Englewood, Colorado, United States, 80110
      • Swedish Medical Center
    • Lone Tree, Colorado, United States, 80124
      • Sky Ridge Medical Center
    • Longmont, Colorado, United States, 80502
      • Hope Cancer Care Center at Longmont United Hospital
    • Pueblo, Colorado, United States, 81004
      • St. Mary-Corwin Regional Medical Center
    • Thornton, Colorado, United States, 80229
      • North Suburban Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Shands Cancer Center
    • Jacksonville, Florida, United States, 32207
      • Baptist Cancer Institute - Jacksonville
    • Jacksonville, Florida, United States, 32224-9980
      • Mayo Clinic - Jacksonville
    • Lakeland, Florida, United States, 33805
      • Watson Clinic, LLC
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
  • Georgia
    • Augusta, Georgia, United States, 30912
      • MBCCOP-Medical College of Georgia Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60611
      • Hematology and Oncology Associates
    • Chicago, Illinois, United States, 60611
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital Cancer Care Institute
    • Evanston, Illinois, United States, 60201
      • Evanston Northwestern Health Care - Evanston Hospital
    • Springfield, Illinois, United States, 62781-0001
      • Regional Cancer Center at Memorial Medical Center
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center at Carle Foundation Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Cancer Center
    • Indianapolis, Indiana, United States, 46202
      • Methodist Cancer Center at Methodist Hospital
  • Iowa
    • Ames, Iowa, United States, 50010
      • McFarland Clinic, P.C.
    • Sioux City, Iowa, United States, 51104
      • St. Luke's Regional Medical Center
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology-Oncology Associates
  • Kansas
    • Chanute, Kansas, United States, 66720
      • Cancer Center of Kansas - Chanute
    • Dodge City, Kansas, United States, 67801
      • Cancer Center of Kansas - Dodge City
    • Kingman, Kansas, United States, 67068
      • Cancer Center of Kansas - Kingman
    • Liberal, Kansas, United States, 67901
      • Southwest Medical Center
    • Newton, Kansas, United States, 67114
      • Cancer Center of Kansas - Newton
    • Pratt, Kansas, United States, 67124
      • Pratt Cancer Center of Kansas
    • Salina, Kansas, United States, 67042
      • Cancer Center of Kansas - Salina
    • Wellington, Kansas, United States, 67152
      • Cancer Center of Kansas - Wellington
    • Wichita, Kansas, United States, 67214
      • Wesley Medical Center
    • Wichita, Kansas, United States, 67214
      • CCOP - Wichita
    • Wichita, Kansas, United States, 67214
      • Via Christi Cancer Center at Via Christi Regional Medical Center
    • Wichita, Kansas, United States, 67203
      • Associates In Womens Health
    • Wichita, Kansas, United States, 67208
      • Cancer Center of Kansas, P.A.
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas, P.A. - Wichita
    • Winfield, Kansas, United States, 67156
      • Cancer Center of Kansas - Winfield
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02111
      • TUFTS - New England Medical Center
    • Springfield, Massachusetts, United States, 01199
      • Baystate Regional Cancer Program at D'Amour Center for Cancer Care
  • Michigan
    • Ann Arbor, Michigan, United States, 48106-0995
      • St. Joseph Mercy Cancer Center at St. Joseph Mercy Hospital
    • Ann Arbor, Michigan, United States, 48100
      • CCOP - Michigan Cancer Research Consortium
    • Kalamazoo, Michigan, United States, 49007
      • West Michigan Cancer Center
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49001
      • Borgess Medical Center
  • Minnesota
    • Burnsville, Minnesota, United States, 55337
      • Fairview Ridges Hospital
    • Coon Rapids, Minnesota, United States, 55433
      • Mercy and Unity Cancer Center at Mercy Hospital
    • Edina, Minnesota, United States, 55435
      • Fairview Southdale Hospital
    • Fridley, Minnesota, United States, 55432
      • Mercy and Unity Cancer Center at Unity Hospital
    • Minneapolis, Minnesota, United States, 55403
      • Virginia Piper Cancer Institute at Abbott-Northwestern Hospital
    • Robbinsdale, Minnesota, United States, 55422
      • Hubert H. Humphrey Cancer Center at North Memorial Medical Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
    • Saint Louis Park, Minnesota, United States, 55416
      • CCOP - Metro-Minnesota
    • Saint Louis Park, Minnesota, United States, 55416
      • Park Nicollet Clinic
    • Saint Paul, Minnesota, United States, 55102
      • United Hospital
    • Waconia, Minnesota, United States, 55387
      • Ridgeview Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • CCOP - Southern Nevada Cancer Research Foundation
    • Las Vegas, Nevada, United States, 89102
      • University Medical Center of Southern Nevada
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • CCOP - Northern New Jersey
    • Red Bank, New Jersey, United States, 07701
      • Booker Cancer Center at Riverview Medical Center
  • New York
    • Bronx, New York, United States, 10461
      • Albert Einstein Cancer Center at Albert Einstein College of Medicine
    • New York, New York, United States, 10016
      • NYU Cancer Institute at New York University Medical Center
  • North Carolina
    • Greenville, North Carolina, United States, 27858
      • Leo W. Jenkins Cancer Center at Pitt County Memorial Hospital
  • Ohio
    • Canton, Ohio, United States, 44710
      • Aultman Hospital Cancer Center at Aultman Health Foundation
    • Cleveland, Ohio, United States, 44109
      • MetroHealth's Cancer Care Center at MetroHealth Medical Center
    • Cleveland, Ohio, United States, 44106
      • Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18015
      • St. Luke's Hospital Cancer Center
    • Danville, Pennsylvania, United States, 17822-2001
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Cancer Institute at Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Abramson Cancer Center of the University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Hillman Cancer Center at University of Pittsburgh Cancer Institute
    • Sayre, Pennsylvania, United States, 18840
      • Guthrie Medical Center - Sayre
    • Scranton, Pennsylvania, United States, 18510
      • Hematology and Oncology Associates
    • State College, Pennsylvania, United States, 16801
      • Geisinger Medical Group
    • Wilkes-Barre, Pennsylvania, United States, 18711
      • Geisinger Wyoming Valley Medical Center
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • Sioux Valley Hospital and University of South Dakota Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Cancer Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Mary Babb Randolph Cancer Center at West Virginia University Hospitals
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Comprehensive Cancer Center
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic - Marshfield Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: Baxter Infuvite Adult

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Eastern Cooperative Oncology Group
• Collaborators: 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

Publications and helpful links

General 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 17, 2002
• Primary Completion (Actual): June 1, 2009

Study Registration Dates

• First Submitted: October 3, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimated): January 27, 2003

Study Record Updates

• Last Update Posted (Actual): July 5, 2023
• Last Update Submitted That Met QC Criteria: June 20, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: refractory anemia with excess blasts; refractory anemia with excess blasts in transformation; de novo myelodysplastic syndromes; 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); secondary acute myeloid leukemia; untreated adult acute myeloid leukemia; adult acute erythroid leukemia (M6); adult acute megakaryoblastic leukemia (M7); adult acute minimally differentiated myeloid leukemia (M0); adult acute monoblastic leukemia (M5a); adult acute monocytic leukemia (M5b); adult acute myeloblastic leukemia with maturation (M2); adult acute myeloblastic leukemia without maturation (M1); adult acute myelomonocytic leukemia (M4)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Anemia; Anemia, Refractory, with Excess of Blasts; Anemia, Refractory; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Lenograstim; Cytarabine; Daunorubicin; Sargramostim; Molgramostim
• Other Study ID Numbers: CDR0000257122; U10CA021115 (U.S. NIH Grant/Contract); E3999 (Other Identifier: Eastern Cooperative Oncology Group)