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

Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00046930
• Other study ID #: CDR0000257122
• Secondary ID: E3999U10CA021115
• Status: Completed
• Phase: Phase 3
• Start date: September 17, 2002

Study information

• Verified date: June 2023
• Source: Eastern Cooperative Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Other known NCT identifiers

• NCT00046046

Recruitment information / eligibility

• Status: Completed
• Enrollment: 449
• Est. primary completion date: June 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Anemia
• Anemia, Refractory, with Excess of Blasts
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndromes
• Preleukemia

Intervention

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.
• 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.

Drug:
• cytarabine
100 mg/m²/day by continuous intravenous infusion for 7 days (days 1-7).
• daunorubicin hydrochloride
45 mg/m²/day by 10 - 15 minute intravenous infusion for 3 days (days 1, 2, and 3).
• 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.
• 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.

Locations

Country	Name	City	State
Israel	Rambam Medical Center	Haifa
United States	McFarland Clinic, P.C.	Ames	Iowa
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	MBCCOP-Medical College of Georgia Cancer Center	Augusta	Georgia
United States	Aurora Presbyterian Hospital	Aurora	Colorado
United States	St. Luke's Hospital Cancer Center	Bethlehem	Pennsylvania
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Tufts - New England Medical Center	Boston	Massachusetts
United States	Boulder Community Hospital	Boulder	Colorado
United States	Albert Einstein Cancer Center at Albert Einstein College of Medicine	Bronx	New York
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Aultman Hospital Cancer Center at Aultman Health Foundation	Canton	Ohio
United States	Cancer Center of Kansas - Chanute	Chanute	Kansas
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Hematology and Oncology Associates	Chicago	Illinois
United States	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
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	Penrose Cancer Center at Penrose Hospital	Colorado Springs	Colorado
United States	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Decatur Memorial Hospital Cancer Care Institute	Decatur	Illinois
United States	CCOP - Colorado Cancer Research Program, Incorporated	Denver	Colorado
United States	Porter Adventist Hospital	Denver	Colorado
United States	Presbyterian - St. Luke's Medical Center	Denver	Colorado
United States	Rose Medical Center	Denver	Colorado
United States	St. Joseph Hospital	Denver	Colorado
United States	Cancer Center of Kansas - Dodge City	Dodge City	Kansas
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Swedish Medical Center	Englewood	Colorado
United States	Evanston Northwestern Health Care - Evanston Hospital	Evanston	Illinois
United States	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota
United States	University of Florida Shands Cancer Center	Gainesville	Florida
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	Penn State Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Indiana University Cancer Center	Indianapolis	Indiana
United States	Methodist Cancer Center at Methodist Hospital	Indianapolis	Indiana
United States	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida
United States	Mayo Clinic - Jacksonville	Jacksonville	Florida
United States	Borgess Medical Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Cancer Center of Kansas - Kingman	Kingman	Kansas
United States	Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	Watson Clinic, LLC	Lakeland	Florida
United States	CCOP - Southern Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	University Medical Center of Southern Nevada	Las Vegas	Nevada
United States	Southwest Medical Center	Liberal	Kansas
United States	Sky Ridge Medical Center	Lone Tree	Colorado
United States	Hope Cancer Care Center at Longmont United Hospital	Longmont	Colorado
United States	University of Wisconsin Comprehensive Cancer Center	Madison	Wisconsin
United States	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin
United States	Virginia Piper Cancer Institute at Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Mary Babb Randolph Cancer Center at West Virginia University Hospitals	Morgantown	West Virginia
United States	NYU Cancer Institute at New York University Medical Center	New York	New York
United States	Cancer Center of Kansas - Newton	Newton	Kansas
United States	Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Hillman Cancer Center at University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania
United States	Pratt Cancer Center of Kansas	Pratt	Kansas
United States	St. Mary-Corwin Regional Medical Center	Pueblo	Colorado
United States	Booker Cancer Center at Riverview Medical Center	Red Bank	New Jersey
United States	Hubert H. Humphrey Cancer Center at North Memorial Medical Center	Robbinsdale	Minnesota
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota
United States	Park Nicollet Clinic	Saint Louis Park	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Cancer Center of Kansas - Salina	Salina	Kansas
United States	Guthrie Medical Center - Sayre	Sayre	Pennsylvania
United States	CCOP - Mayo Clinic Scottsdale Oncology Program	Scottsdale	Arizona
United States	Hematology and Oncology Associates	Scranton	Pennsylvania
United States	Siouxland Hematology-Oncology Associates	Sioux City	Iowa
United States	St. Luke's Regional Medical Center	Sioux City	Iowa
United States	Sioux Valley Hospital and University of South Dakota Medical Center	Sioux Falls	South Dakota
United States	Baystate Regional Cancer Program at D'Amour Center for Cancer Care	Springfield	Massachusetts
United States	Regional Cancer Center at Memorial Medical Center	Springfield	Illinois
United States	Geisinger Medical Group	State College	Pennsylvania
United States	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida	Tampa	Florida
United States	North Suburban Medical Center	Thornton	Colorado
United States	Carle Cancer Center at Carle Foundation Hospital	Urbana	Illinois
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Cancer Center of Kansas - Wellington	Wellington	Kansas
United States	Associates in Womens Health	Wichita	Kansas
United States	Cancer Center of Kansas, P.A.	Wichita	Kansas
United States	Cancer Center of Kansas, P.A. - Wichita	Wichita	Kansas
United States	CCOP - Wichita	Wichita	Kansas
United States	Via Christi Cancer Center at Via Christi Regional Medical Center	Wichita	Kansas
United States	Wesley Medical Center	Wichita	Kansas
United States	Geisinger Wyoming Valley Medical Center	Wilkes-Barre	Pennsylvania
United States	Cancer Center of Kansas - Winfield	Winfield	Kansas

Sponsors (4)

Lead Sponsor	Collaborator
Eastern Cooperative Oncology Group	Eli Lilly and Company, Kanisa Pharmaceuticals, National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Israel, 

References & Publications (1)

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) o

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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