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

NCT00046930 | Completed Phase 3 Results DMC

• 3 other identifiers: CDR0000257122E3999U10CA021115
• Study Type: interventional
• Target: 449
• Locations: 2 countries
• Sites: 92

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.

Conditions

Leukemia; Myelodysplastic Syndromes

Keywords

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)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Progression-free Survival (PFS)

  Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually thereafter

• Response

  Assessed at the end of induction

Study Arms (2)

Zosuquidar

EXPERIMENTAL

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; Biological: sargramostim; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: zosuquidar trihydrochloride

Placebo

ACTIVE COMPARATOR

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; Biological: sargramostim; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: Placebo

Interventions

filgrastim BIOLOGICAL

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.

Also known as: Neupogen, recombinant-methionyl human granulocyte-colony stimulating factor,, granulocyte colony-stimulating factor, r-metHuG-CSF

Placebo; Zosuquidar

sargramostim BIOLOGICAL

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.

Also known as: Granulocyte-macrophage colony stimulating factor, rHu GM-CSF,, Leukine, NSC # 617589

Placebo; Zosuquidar

cytarabine DRUG

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

Also known as: Cytosar-U, Ara-C, Arabinosyl, cytosine arabinoside.

Placebo; Zosuquidar

daunorubicin hydrochloride DRUG

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

Also known as: Daunomycin, Rubidomycin, Cerubidine.

Placebo; Zosuquidar

zosuquidar trihydrochloride DRUG

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.

Also known as: Multi drug resistance modulator, MDR, LY335979

Zosuquidar

Placebo DRUG

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.

Also known as: Baxter Infuvite Adult

Placebo

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%

You may not qualify if:

• 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

Sponsors & Collaborators

• Eastern Cooperative Oncology Group: lead
• National Cancer Institute (NCI): collaborator
• Eli Lilly and Company: collaborator
• Kanisa Pharmaceuticals: collaborator

Study Sites (92)

CCOP - Mayo Clinic Scottsdale Oncology Program

Scottsdale, Arizona, 85259, United States

Location

Aurora Presbyterian Hospital

Aurora, Colorado, 80012, United States

Location

Boulder Community Hospital

Boulder, Colorado, 80301, United States

Location

Penrose Cancer Center at Penrose Hospital

Colorado Springs, Colorado, 80933, United States

Location

Porter Adventist Hospital

Denver, Colorado, 80210, United States

Location

Presbyterian - St. Luke's Medical Center

Denver, Colorado, 80218, United States

Location

St. Joseph Hospital

Denver, Colorado, 80218, United States

Location

Rose Medical Center

Denver, Colorado, 80220, United States

Location

CCOP - Colorado Cancer Research Program, Incorporated

Denver, Colorado, 80224-2522, United States

Location

Swedish Medical Center

Englewood, Colorado, 80110, United States

Location

Sky Ridge Medical Center

Lone Tree, Colorado, 80124, United States

Location

Hope Cancer Care Center at Longmont United Hospital

Longmont, Colorado, 80502, United States

Location

St. Mary-Corwin Regional Medical Center

Pueblo, Colorado, 81004, United States

Location

North Suburban Medical Center

Thornton, Colorado, 80229, United States

Location

University of Florida Shands Cancer Center

Gainesville, Florida, 32610, United States

Location

Baptist Cancer Institute - Jacksonville

Jacksonville, Florida, 32207, United States

Location

Mayo Clinic - Jacksonville

Jacksonville, Florida, 32224-9980, United States

Location

Watson Clinic, LLC

Lakeland, Florida, 33805, United States

Location

H. Lee Moffitt Cancer Center and Research Institute at University of South Florida

Tampa, Florida, 33612, United States

Location

MBCCOP-Medical College of Georgia Cancer Center

Augusta, Georgia, 30912, United States

Location

Hematology and Oncology Associates

Chicago, Illinois, 60611, United States

Location

Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Chicago, Illinois, 60611, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Decatur Memorial Hospital Cancer Care Institute

Decatur, Illinois, 62526, United States

Location

Evanston Northwestern Health Care - Evanston Hospital

Evanston, Illinois, 60201, United States

Location

Regional Cancer Center at Memorial Medical Center

Springfield, Illinois, 62781-0001, United States

Location

Carle Cancer Center at Carle Foundation Hospital

Urbana, Illinois, 61801, United States

Location

Indiana University Cancer Center

Indianapolis, Indiana, 46202, United States

Location

Methodist Cancer Center at Methodist Hospital

Indianapolis, Indiana, 46202, United States

Location

McFarland Clinic, P.C.

Ames, Iowa, 50010, United States

Location

Siouxland Hematology-Oncology Associates

Sioux City, Iowa, 51101, United States

Location

St. Luke's Regional Medical Center

Sioux City, Iowa, 51104, United States

Location

Cancer Center of Kansas - Chanute

Chanute, Kansas, 66720, United States

Location

Cancer Center of Kansas - Dodge City

Dodge City, Kansas, 67801, United States

Location

Cancer Center of Kansas - Kingman

Kingman, Kansas, 67068, United States

Location

Southwest Medical Center

Liberal, Kansas, 67901, United States

Location

Cancer Center of Kansas - Newton

Newton, Kansas, 67114, United States

Location

Pratt Cancer Center of Kansas

Pratt, Kansas, 67124, United States

Location

Cancer Center of Kansas - Salina

Salina, Kansas, 67042, United States

Location

Cancer Center of Kansas - Wellington

Wellington, Kansas, 67152, United States

Location

Associates in Womens Health

Wichita, Kansas, 67203, United States

Location

Cancer Center of Kansas, P.A.

Wichita, Kansas, 67208, United States

Location

Cancer Center of Kansas, P.A. - Wichita

Wichita, Kansas, 67214, United States

Location

CCOP - Wichita

Wichita, Kansas, 67214, United States

Location

Via Christi Cancer Center at Via Christi Regional Medical Center

Wichita, Kansas, 67214, United States

Location

Wesley Medical Center

Wichita, Kansas, 67214, United States

Location

Cancer Center of Kansas - Winfield

Winfield, Kansas, 67156, United States

Location

Tufts - New England Medical Center

Boston, Massachusetts, 02111, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Baystate Regional Cancer Program at D'Amour Center for Cancer Care

Springfield, Massachusetts, 01199, United States

Location

CCOP - Michigan Cancer Research Consortium

Ann Arbor, Michigan, 48100, United States

Location

St. Joseph Mercy Cancer Center at St. Joseph Mercy Hospital

Ann Arbor, Michigan, 48106-0995, United States

Location

Borgess Medical Center

Kalamazoo, Michigan, 49001, United States

Location

Bronson Methodist Hospital

Kalamazoo, Michigan, 49007, United States

Location

West Michigan Cancer Center

Kalamazoo, Michigan, 49007, United States

Location

Fairview Ridges Hospital

Burnsville, Minnesota, 55337, United States

Location

Mercy and Unity Cancer Center at Mercy Hospital

Coon Rapids, Minnesota, 55433, United States

Location

Fairview Southdale Hospital

Edina, Minnesota, 55435, United States

Location

Mercy and Unity Cancer Center at Unity Hospital

Fridley, Minnesota, 55432, United States

Location

Virginia Piper Cancer Institute at Abbott-Northwestern Hospital

Minneapolis, Minnesota, 55403, United States

Location

Hubert H. Humphrey Cancer Center at North Memorial Medical Center

Robbinsdale, Minnesota, 55422, United States

Location

Mayo Clinic Cancer Center

Rochester, Minnesota, 55905, United States

Location

CCOP - Metro-Minnesota

Saint Louis Park, Minnesota, 55416, United States

Location

Park Nicollet Clinic

Saint Louis Park, Minnesota, 55416, United States

Location

United Hospital

Saint Paul, Minnesota, 55102, United States

Location

Ridgeview Medical Center

Waconia, Minnesota, 55387, United States

Location

University Medical Center of Southern Nevada

Las Vegas, Nevada, 89102, United States

Location

CCOP - Southern Nevada Cancer Research Foundation

Las Vegas, Nevada, 89106, United States

Location

CCOP - Northern New Jersey

Hackensack, New Jersey, 07601, United States

Location

Booker Cancer Center at Riverview Medical Center

Red Bank, New Jersey, 07701, United States

Location

NYU Cancer Institute at New York University Medical Center

New York, New York, 10016, United States

Location

Albert Einstein Cancer Center at Albert Einstein College of Medicine

The Bronx, New York, 10461, United States

Location

Leo W. Jenkins Cancer Center at Pitt County Memorial Hospital

Greenville, North Carolina, 27858, United States

Location

Aultman Hospital Cancer Center at Aultman Health Foundation

Canton, Ohio, 44710, United States

Location

Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University

Cleveland, Ohio, 44106, United States

Location

MetroHealth's Cancer Care Center at MetroHealth Medical Center

Cleveland, Ohio, 44109, United States

Location

St. Luke's Hospital Cancer Center

Bethlehem, Pennsylvania, 18015, United States

Location

Geisinger Medical Center

Danville, Pennsylvania, 17822-2001, United States

Location

Penn State Cancer Institute at Milton S. Hershey Medical Center

Hershey, Pennsylvania, 17033-0850, United States

Location

Abramson Cancer Center of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Hillman Cancer Center at University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, 15213, United States

Location

Guthrie Medical Center - Sayre

Sayre, Pennsylvania, 18840, United States

Location

Hematology and Oncology Associates

Scranton, Pennsylvania, 18510, United States

Location

Geisinger Medical Group

State College, Pennsylvania, 16801, United States

Location

Geisinger Wyoming Valley Medical Center

Wilkes-Barre, Pennsylvania, 18711, United States

Location

Sioux Valley Hospital and University of South Dakota Medical Center

Sioux Falls, South Dakota, 57104, United States

Location

University of Virginia Cancer Center

Charlottesville, Virginia, 22908, United States

Location

Mary Babb Randolph Cancer Center at West Virginia University Hospitals

Morgantown, West Virginia, 26506, United States

Location

Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center

La Crosse, Wisconsin, 54601, United States

Location

University of Wisconsin Comprehensive Cancer Center

Madison, Wisconsin, 53792, United States

Location

Marshfield Clinic - Marshfield Center

Marshfield, Wisconsin, 54449, United States

Location

Rambam Medical Center

Haifa, Israel

Location

Related Publications (3)

• 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.

  RESULT

• 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.

  PMID: 37185873 DERIVED

• 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.

  PMID: 20716770 DERIVED

MeSH Terms

Conditions

Leukemia; Myelodysplastic Syndromes; Leukemia, Monocytic, Acute; Leukemia, Erythroblastic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Anemia, Refractory, with Excess of Blasts; Congenital Abnormalities

Interventions

Filgrastim; Granulocyte Colony-Stimulating Factor; sargramostim; Colony-Stimulating Factors; Cytarabine; Daunorubicin; zosuquidar trihydrochloride

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Leukemia, Myeloid; Myeloproliferative Disorders; Anemia, Refractory; Anemia; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides

Results Point of Contact

• Title: Study Statistician
• Organization: ECOG Statistical Office

617-632-3012

Study Officials

• Larry D. Cripe, MD

  Indiana University Melvin and Bren Simon Cancer Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 3, 2002
• First Posted: January 27, 2003
• Study Start: September 17, 2002
• Primary Completion: June 1, 2009
• Last Updated: July 5, 2023
• Results First Posted: September 6, 2010

Record last verified: 2023-06

Locations

IL (1); US (91)