Clinical trial NCT00046930: Daunorubicin & Cytarabine +/- Zosuquidar inTreating Older Patients With Newly Diagnosed Acute Myeloid Leukemia or Refractory Anemia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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)
Lead sponsor: Eastern Cooperative Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: Eli Lilly and Company
name: Kanisa Pharmaceuticals
First posted: 2003-01-27
Enrollment: 449
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually thereafter
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually thereafter
measure: Response
timeFrame: Assessed at the end of induction
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: CCOP - Mayo Clinic Scottsdale Oncology Program
state: Arizona
city: Aurora
country: United States
facility: Aurora Presbyterian Hospital
state: Colorado
city: Boulder
country: United States
facility: Boulder Community Hospital
state: Colorado
city: Colorado Springs
country: United States
facility: Penrose Cancer Center at Penrose Hospital
state: Colorado
city: Denver
country: United States
facility: Porter Adventist Hospital
state: Colorado
city: Denver
country: United States
facility: Presbyterian - St. Luke's Medical Center
state: Colorado
city: Denver
country: United States
facility: St. Joseph Hospital
state: Colorado
city: Denver
country: United States
facility: Rose Medical Center
state: Colorado
city: Denver
country: United States
facility: CCOP - Colorado Cancer Research Program, Incorporated
state: Colorado
city: Englewood
country: United States
facility: Swedish Medical Center
state: Colorado
city: Lone Tree
country: United States
facility: Sky Ridge Medical Center
state: Colorado
city: Longmont
country: United States
facility: Hope Cancer Care Center at Longmont United Hospital
state: Colorado
city: Pueblo
country: United States
facility: St. Mary-Corwin Regional Medical Center
state: Colorado
city: Thornton
country: United States
facility: North Suburban Medical Center
state: Colorado
city: Gainesville
country: United States
facility: University of Florida Shands Cancer Center
state: Florida
city: Jacksonville
country: United States
facility: Baptist Cancer Institute - Jacksonville
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Lakeland
country: United States
facility: Watson Clinic, LLC
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
state: Florida
city: Augusta
country: United States
facility: MBCCOP-Medical College of Georgia Cancer Center
state: Georgia
city: Chicago
country: United States
facility: Hematology and Oncology Associates
state: Illinois
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center at Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital Cancer Care Institute
state: Illinois
city: Evanston
country: United States
facility: Evanston Northwestern Health Care - Evanston Hospital
state: Illinois
city: Springfield
country: United States
facility: Regional Cancer Center at Memorial Medical Center
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center at Carle Foundation Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: Methodist Cancer Center at Methodist Hospital
state: Indiana
city: Ames
country: United States
facility: McFarland Clinic, P.C.
state: Iowa
city: Sioux City
country: United States
facility: Siouxland Hematology-Oncology Associates
state: Iowa
city: Sioux City
country: United States
facility: St. Luke's Regional Medical Center
state: Iowa
city: Chanute
country: United States
facility: Cancer Center of Kansas - Chanute
state: Kansas
city: Dodge City
country: United States
facility: Cancer Center of Kansas - Dodge City
state: Kansas
city: Kingman
country: United States
facility: Cancer Center of Kansas - Kingman
state: Kansas
city: Liberal
country: United States
facility: Southwest Medical Center
state: Kansas
city: Newton
country: United States
facility: Cancer Center of Kansas - Newton
state: Kansas
city: Pratt
country: United States
facility: Pratt Cancer Center of Kansas
state: Kansas
city: Salina
country: United States
facility: Cancer Center of Kansas - Salina
state: Kansas
city: Wellington
country: United States
facility: Cancer Center of Kansas - Wellington
state: Kansas
city: Wichita
country: United States
facility: Associates in Womens Health
state: Kansas
city: Wichita
country: United States
facility: Cancer Center of Kansas, P.A.
state: Kansas
city: Wichita
country: United States
facility: Cancer Center of Kansas, P.A. - Wichita
state: Kansas
city: Wichita
country: United States
facility: CCOP - Wichita
state: Kansas
city: Wichita
country: United States
facility: Via Christi Cancer Center at Via Christi Regional Medical Center
state: Kansas
city: Wichita
country: United States
facility: Wesley Medical Center
state: Kansas
city: Winfield
country: United States
facility: Cancer Center of Kansas - Winfield
state: Kansas
city: Boston
country: United States
facility: Tufts - New England Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Regional Cancer Program at D'Amour Center for Cancer Care
state: Massachusetts
city: Ann Arbor
country: United States
facility: CCOP - Michigan Cancer Research Consortium
state: Michigan
city: Ann Arbor
country: United States
facility: St. Joseph Mercy Cancer Center at St. Joseph Mercy Hospital
state: Michigan
city: Kalamazoo
country: United States
facility: Borgess Medical Center
state: Michigan
city: Kalamazoo
country: United States
facility: Bronson Methodist Hospital
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Burnsville
country: United States
facility: Fairview Ridges Hospital
state: Minnesota
city: Coon Rapids
country: United States
facility: Mercy and Unity Cancer Center at Mercy Hospital
state: Minnesota
city: Edina
country: United States
facility: Fairview Southdale Hospital
state: Minnesota
city: Fridley
country: United States
facility: Mercy and Unity Cancer Center at Unity Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: Virginia Piper Cancer Institute at Abbott-Northwestern Hospital
state: Minnesota
city: Robbinsdale
country: United States
facility: Hubert H. Humphrey Cancer Center at North Memorial Medical Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Saint Louis Park
country: United States
facility: CCOP - Metro-Minnesota
state: Minnesota
city: Saint Louis Park
country: United States
facility: Park Nicollet Clinic
state: Minnesota
city: Saint Paul
country: United States
facility: United Hospital
state: Minnesota
city: Waconia
country: United States
facility: Ridgeview Medical Center
state: Minnesota
city: Las Vegas
country: United States
facility: University Medical Center of Southern Nevada
state: Nevada
city: Las Vegas
country: United States
facility: CCOP - Southern Nevada Cancer Research Foundation
state: Nevada
city: Hackensack
country: United States
facility: CCOP - Northern New Jersey
state: New Jersey
city: Red Bank
country: United States
facility: Booker Cancer Center at Riverview Medical Center
state: New Jersey
city: Bronx
country: United States
facility: Albert Einstein Cancer Center at Albert Einstein College of Medicine
state: New York
city: New York
country: United States
facility: NYU Cancer Institute at New York University Medical Center
state: New York
city: Greenville
country: United States
facility: Leo W. Jenkins Cancer Center at Pitt County Memorial Hospital
state: North Carolina
city: Canton
country: United States
facility: Aultman Hospital Cancer Center at Aultman Health Foundation
state: Ohio
city: Cleveland
country: United States
facility: Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth's Cancer Care Center at MetroHealth Medical Center
state: Ohio
city: Bethlehem
country: United States
facility: St. Luke's Hospital Cancer Center
state: Pennsylvania
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Cancer Institute at Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Abramson Cancer Center of the University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Hillman Cancer Center at University of Pittsburgh Cancer Institute
state: Pennsylvania
city: Sayre
country: United States
facility: Guthrie Medical Center - Sayre
state: Pennsylvania
city: Scranton
country: United States
facility: Hematology and Oncology Associates
state: Pennsylvania
city: State College
country: United States
facility: Geisinger Medical Group
state: Pennsylvania
city: Wilkes-Barre
country: United States
facility: Geisinger Wyoming Valley Medical Center
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Sioux Valley Hospital and University of South Dakota Medical Center
state: South Dakota
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
city: Morgantown
country: United States
facility: Mary Babb Randolph Cancer Center at West Virginia University Hospitals
state: West Virginia
city: La Crosse
country: United States
facility: Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Comprehensive Cancer Center
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Clinic - Marshfield Center
state: Wisconsin
city: Haifa
country: Israel
facility: Rambam Medical Center
Study officials:
affiliation: Indiana University Melvin and Bren Simon Cancer Center
name: Larry D. Cripe, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.