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LeukemiaPhase 3NCT00046930

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

A Phase 3 study testing filgrastim, sargramostim and cytarabine in people with Leukemia and Myelodysplastic Syndromes, run by Eastern Cooperative Oncology Group at 92 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 60 years and older
Conditions the study is for
Leukemia, Myelodysplastic Syndromes
What is being tested?
filgrastim, sargramostim and cytarabine
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
449 participants
Where
92 sitesin 2 countries
Study dates
17 Sep 2002to Jun 2009
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 60 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 10Show fewer
  • ECOG performance status of 0 to 3
  • Total serum bilirubin < 3 mg/dL
  • Serum creatinine < 2 mg/dL
  • Cardiac ejection fraction of > 45%

Who cannot join

  • 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

Trial locations and contacts

92 sites in 2 countries.

92 sites in 2 countries

United States91 sites

  • McFarland Clinic, P.C.

    Ames, Iowa, 50010

  • CCOP - Michigan Cancer Research Consortium

    Ann Arbor, Michigan, 48100

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

    Ann Arbor, Michigan, 48106-0995

  • MBCCOP-Medical College of Georgia Cancer Center

    Augusta, Georgia, 30912

  • Aurora Presbyterian Hospital

    Aurora, Colorado, 80012

  • St. Luke's Hospital Cancer Center

    Bethlehem, Pennsylvania, 18015

  • Tufts - New England Medical Center

    Boston, Massachusetts, 02111

  • Beth Israel Deaconess Medical Center

    Boston, Massachusetts, 02215

  • Boulder Community Hospital

    Boulder, Colorado, 80301

  • Fairview Ridges Hospital

    Burnsville, Minnesota, 55337

  • Aultman Hospital Cancer Center at Aultman Health Foundation

    Canton, Ohio, 44710

  • Cancer Center of Kansas - Chanute

    Chanute, Kansas, 66720

  • University of Virginia Cancer Center

    Charlottesville, Virginia, 22908

  • Hematology and Oncology Associates

    Chicago, Illinois, 60611

  • Robert H. Lurie Comprehensive Cancer Center at Northwestern University

    Chicago, Illinois, 60611

  • Rush University Medical Center

    Chicago, Illinois, 60612

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

    Cleveland, Ohio, 44106

  • MetroHealth's Cancer Care Center at MetroHealth Medical Center

    Cleveland, Ohio, 44109

  • Penrose Cancer Center at Penrose Hospital

    Colorado Springs, Colorado, 80933

  • Mercy and Unity Cancer Center at Mercy Hospital

    Coon Rapids, Minnesota, 55433

  • Geisinger Medical Center

    Danville, Pennsylvania, 17822-2001

  • Decatur Memorial Hospital Cancer Care Institute

    Decatur, Illinois, 62526

  • Porter Adventist Hospital

    Denver, Colorado, 80210

  • Presbyterian - St. Luke's Medical Center

    Denver, Colorado, 80218

  • St. Joseph Hospital

    Denver, Colorado, 80218

  • Rose Medical Center

    Denver, Colorado, 80220

  • CCOP - Colorado Cancer Research Program, Incorporated

    Denver, Colorado, 80224-2522

  • Cancer Center of Kansas - Dodge City

    Dodge City, Kansas, 67801

  • Fairview Southdale Hospital

    Edina, Minnesota, 55435

  • Swedish Medical Center

    Englewood, Colorado, 80110

  • Evanston Northwestern Health Care - Evanston Hospital

    Evanston, Illinois, 60201

  • Mercy and Unity Cancer Center at Unity Hospital

    Fridley, Minnesota, 55432

  • University of Florida Shands Cancer Center

    Gainesville, Florida, 32610

  • Leo W. Jenkins Cancer Center at Pitt County Memorial Hospital

    Greenville, North Carolina, 27858

  • CCOP - Northern New Jersey

    Hackensack, New Jersey, 07601

  • Penn State Cancer Institute at Milton S. Hershey Medical Center

    Hershey, Pennsylvania, 17033-0850

  • Indiana University Cancer Center

    Indianapolis, Indiana, 46202

  • Methodist Cancer Center at Methodist Hospital

    Indianapolis, Indiana, 46202

  • Baptist Cancer Institute - Jacksonville

    Jacksonville, Florida, 32207

  • Mayo Clinic - Jacksonville

    Jacksonville, Florida, 32224-9980

  • Borgess Medical Center

    Kalamazoo, Michigan, 49001

  • Bronson Methodist Hospital

    Kalamazoo, Michigan, 49007

  • West Michigan Cancer Center

    Kalamazoo, Michigan, 49007

  • Cancer Center of Kansas - Kingman

    Kingman, Kansas, 67068

  • Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center

    La Crosse, Wisconsin, 54601

  • Watson Clinic, LLC

    Lakeland, Florida, 33805

  • University Medical Center of Southern Nevada

    Las Vegas, Nevada, 89102

  • CCOP - Southern Nevada Cancer Research Foundation

    Las Vegas, Nevada, 89106

  • Southwest Medical Center

    Liberal, Kansas, 67901

  • Sky Ridge Medical Center

    Lone Tree, Colorado, 80124

  • Hope Cancer Care Center at Longmont United Hospital

    Longmont, Colorado, 80502

  • University of Wisconsin Comprehensive Cancer Center

    Madison, Wisconsin, 53792

  • Marshfield Clinic - Marshfield Center

    Marshfield, Wisconsin, 54449

  • Virginia Piper Cancer Institute at Abbott-Northwestern Hospital

    Minneapolis, Minnesota, 55403

  • Mary Babb Randolph Cancer Center at West Virginia University Hospitals

    Morgantown, West Virginia, 26506

  • NYU Cancer Institute at New York University Medical Center

    New York, New York, 10016

  • Cancer Center of Kansas - Newton

    Newton, Kansas, 67114

  • Abramson Cancer Center of the University of Pennsylvania

    Philadelphia, Pennsylvania, 19104

  • Hillman Cancer Center at University of Pittsburgh Cancer Institute

    Pittsburgh, Pennsylvania, 15213

  • Pratt Cancer Center of Kansas

    Pratt, Kansas, 67124

  • St. Mary-Corwin Regional Medical Center

    Pueblo, Colorado, 81004

  • Booker Cancer Center at Riverview Medical Center

    Red Bank, New Jersey, 07701

  • Hubert H. Humphrey Cancer Center at North Memorial Medical Center

    Robbinsdale, Minnesota, 55422

  • Mayo Clinic Cancer Center

    Rochester, Minnesota, 55905

  • CCOP - Metro-Minnesota

    Saint Louis Park, Minnesota, 55416

  • Park Nicollet Clinic

    Saint Louis Park, Minnesota, 55416

  • United Hospital

    Saint Paul, Minnesota, 55102

  • Cancer Center of Kansas - Salina

    Salina, Kansas, 67042

  • Guthrie Medical Center - Sayre

    Sayre, Pennsylvania, 18840

  • CCOP - Mayo Clinic Scottsdale Oncology Program

    Scottsdale, Arizona, 85259

  • Hematology and Oncology Associates

    Scranton, Pennsylvania, 18510

  • Siouxland Hematology-Oncology Associates

    Sioux City, Iowa, 51101

  • St. Luke's Regional Medical Center

    Sioux City, Iowa, 51104

  • Sioux Valley Hospital and University of South Dakota Medical Center

    Sioux Falls, South Dakota, 57104

  • Regional Cancer Center at Memorial Medical Center

    Springfield, Illinois, 62781-0001

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

    Springfield, Massachusetts, 01199

  • Geisinger Medical Group

    State College, Pennsylvania, 16801

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

    Tampa, Florida, 33612

  • Albert Einstein Cancer Center at Albert Einstein College of Medicine

    The Bronx, New York, 10461

  • North Suburban Medical Center

    Thornton, Colorado, 80229

  • Carle Cancer Center at Carle Foundation Hospital

    Urbana, Illinois, 61801

  • Ridgeview Medical Center

    Waconia, Minnesota, 55387

  • Cancer Center of Kansas - Wellington

    Wellington, Kansas, 67152

  • Associates in Womens Health

    Wichita, Kansas, 67203

  • Cancer Center of Kansas, P.A.

    Wichita, Kansas, 67208

  • Cancer Center of Kansas, P.A. - Wichita

    Wichita, Kansas, 67214

  • CCOP - Wichita

    Wichita, Kansas, 67214

  • Via Christi Cancer Center at Via Christi Regional Medical Center

    Wichita, Kansas, 67214

  • Wesley Medical Center

    Wichita, Kansas, 67214

  • Geisinger Wyoming Valley Medical Center

    Wilkes-Barre, Pennsylvania, 18711

  • Cancer Center of Kansas - Winfield

    Winfield, Kansas, 67156

Other trials in United States

Israel1 site

  • Rambam Medical Center

    Haifa

Other trials in Israel

About this study

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

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.

Read the 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.

Being tested
filgrastim, sargramostim, cytarabine, daunorubicin hydrochloride, zosuquidar trihydrochloride
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)
Medical subject headings
Leukemia, Myelodysplastic Syndromes, Leukemia, Monocytic, Acute, Leukemia, Erythroblastic, Acute, Leukemia, Megakaryoblastic, Acute, Leukemia, Myeloid, Acute, Leukemia, Myelomonocytic, Acute, Anemia, Refractory, with Excess of Blasts

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • filgrastimBiological

    Also called Neupogen, recombinant-methionyl human granulocyte-colony stimulating factor,, granulocyte colony-stimulating factor, r-metHuG-CSF

    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.

  • sargramostimBiological

    Also called Granulocyte-macrophage colony stimulating factor, rHu GM-CSF,, Leukine, NSC # 617589

    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.

  • cytarabineDrug

    Also called Cytosar-U, Ara-C, Arabinosyl, cytosine arabinoside.

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

  • daunorubicin hydrochlorideDrug

    Also called Daunomycin, Rubidomycin, Cerubidine.

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

  • zosuquidar trihydrochlorideDrug

    Also called Multi drug resistance modulator, MDR, LY335979

    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.

  • PlaceboDrug

    Also called Baxter Infuvite Adult

    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.

Study groups in NCT00046930
Study groupRoleWhat they receive
ZosuquidarExperimentalInduction 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.
Receives: Biological: filgrastim; Biological: sargramostim; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: zosuquidar trihydrochloride
PlaceboActive comparatorInduction 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.
Receives: Biological: filgrastim; Biological: sargramostim; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall Survival (OS)

    Time from randomization to death. Patients alive at last follow-up were censored.

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

Secondary outcomes (2)

  1. 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.

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

  2. 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.

    Measured: Assessed at the end of induction

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Jan 2003 (estimated)
  2. Study start17 Sep 2002
  3. Primary completionJun 2009

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
449 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00046930
Sponsor's protocol ID
CDR0000257122
Other IDs
E3999, U10CA021115
Status last verified
Jun 2023
First submitted
3 Oct 2002
Last updated
5 Jul 2023
Data monitoring committee
Yes

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.

  • 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.

    PubMed 37185873

  • 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.

    PubMed 20716770

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing filgrastim, sargramostim and cytarabine in people with Leukemia and Myelodysplastic Syndromes, run by Eastern Cooperative Oncology Group at 92 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 92 sites in United States, Israel. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 6 Sep 2010). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Survival (OS) (time frame: Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually thereafter). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00046930, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jul 2023.

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