Dasatinib (BMS-354835) Versus Imatinib Mesylate in Subjects With Chronic Myeloid Leukemia

A Randomized Multi-Center Open Label Study of BMS-354825 vs. Imatinib Mesylate (Gleevec) 800 mg/d in Subjects With Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukemia Who Have Disease That is Resistant to Imatinib at a Dose at 400 - 600 mg/d

The primary purpose of this study is to estimate the major cytogenetic response rates of BMS-354825 and imatinib (800 mg/d) in subjects with chronic phase, Philadelphia chromosome positive, chronic myeloid leukemia (PH+ CML) with disease resistant to imatinib at a dose of 400-600 mg/d.

Study Overview

• Status: Completed
• Conditions: Chronic Myeloid Leukemia; Philadelphia-Positive Myeloid Leukemia
• Intervention / Treatment: Drug: Dasatinib; Drug: Imatinib

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Local Institution
  • Cordoba, Argentina
    • Local Institution
• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia
      • Local Institution
    • St. Leonards, New South Wales, Australia
      • Local Institution
  • Queensland
    • South Brisbane, Queensland, Australia
      • Local Institution
  • South Australia
    • Adelaide, South Australia, Australia
      • Local Institution
  • Western Australia
    • Perth, Western Australia, Australia
      • Local Institution
• Austria
  • Wein, Austria
    • Local Institution
• Belgium
  • B-Leuven, Belgium
    • Local Institution
  • Brugge, Belgium
    • Local Institution
  • Bruxelles, Belgium
    • Local Institution
  • Charleroi, Belgium
    • Local Institution
  • Edegem, Belgium
    • Local Institution
  • Yvoir, Belgium
    • Local Institution
• Brazil
  • Rio De Janeiro, Brazil
    • Local Institution
  • Sao Paulo, Brazil
    • Local Institution
  • Parana
    • Curitiba, Parana, Brazil
      • Local Institution
• Canada
  • Alberta
    • Edmonton, Alberta, Canada
      • Local Institution
  • British Columbia
    • Vancouver, British Columbia, Canada
      • Local Institution
  • Ontario
    • Toronto, Ontario, Canada
      • Local Institution
  • Quebec
    • Montreal, Quebec, Canada
      • Local Institution
• China
  • Beijing, China
    • Local Institution
  • Shanghai, China
    • Local Institution
• Denmark
  • Aarhus, Denmark
    • Local Institution
• Estonia
  • Tallin, Estonia
    • Local Institution
• Finland
  • Helsinki, Finland
    • Local Institution
• France
  • Lille, France
    • Local Institution
  • Lyon Cedex 03, France
    • Local Institution
  • Nantes, France
    • Local Institution
  • Paris, France
    • Local Institution
  • Pessac, France
    • Local Institution
  • Poitiers, France
    • Local Institution
  • Strasbourg Cedex, France
    • Local Institution
• Germany
  • Dresden, Germany
    • Local Institution
  • Groenkloof, Germany
    • Local Institution
  • Hamburg, Germany
    • Local Institution
  • Leipzig, Germany
    • Local Institution
  • Mainz, Germany
    • Local Institution
  • Mannheim, Germany
    • Local Institution
• Hungary
  • Budapest, Hungary
    • Local Institution
• Ireland
  • Dublin, Ireland
    • Local Institution
• Israel
  • Ramat-Gan, Israel
    • Local Institution
• Italy
  • Bari, Italy
    • Local Institution
  • Bologna, Italy
    • Local Institution
  • Milano, Italy
    • Local Institution
  • Napoli, Italy
    • Local Institution
  • Orbassano, Italy
    • Local Institution
  • Roma, Italy
    • Local Institution
• Korea, Republic of
  • Kyunggi-Do, Korea, Republic of
    • Local Institution
• Norway
  • Trondheim, Norway
    • Local Institution
• Peru
  • Lima, Peru
    • Local Institution
• Philippines
  • Quezon City, Philippines
    • Local Institution
• Poland
  • Katowice, Poland
    • Local Institution
  • Krakow, Poland
    • Local Institution
  • Lublin, Poland
    • Local Institution
  • Warsaw, Poland
    • Local Institution
• Puerto Rico
  • San Juan, Puerto Rico
    • Local Institution
• Russian Federation
  • Moscow, Russian Federation
    • Local Institution
  • St. Petersburg, Russian Federation
    • Local Institution
• Singapore
  • Singapore, Singapore
    • Local Institution
• South Africa
  • Free State
    • Bloemfontein, Free State, South Africa
      • Local Institution
  • Gauteng
    • Parktown, Gauteng, South Africa
      • Local Institution
    • Soweto, Gauteng, South Africa
      • Local Institution
• Spain
  • Barcelona, Spain
    • Local Institution
  • Madrid, Spain
    • Local Institution
• Sweden
  • Gothenburg, Sweden
    • Local Institution
  • Lund, Sweden
    • Local Institution
  • Stockholm, Sweden
    • Local Institution
  • Umea, Sweden
    • Local Institution
  • Uppsala, Sweden
    • Local Institution
• Switzerland
  • Basel, Switzerland
    • Local Institution
  • Bellinzona, Switzerland
    • Local Institution
• Taiwan
  • Taipei, Taiwan
    • Local Institution
  • Taoyuan, Taiwan
    • Local Institution
• Thailand
  • Bangkok, Thailand
    • Local Institution
• United Kingdom
  • Central
    • Glasglow, Central, United Kingdom
      • Local Institution
  • Greater London
    • London, Greater London, United Kingdom
      • Local Institution
  • Tyne and Wear
    • Newcastle, Tyne and Wear, United Kingdom
      • Local Institution
• United States
  • Alabama
    • Birmingham, Alabama, United States
      • Local Institution
  • California
    • Anaheim, California, United States
      • Local Institution
    • Bakersfield, California, United States
      • Local Institution
    • Fullerton, California, United States
      • Local Institution
    • Loma Linda, California, United States
      • Local Institution
    • Los Angeles, California, United States
      • Local Institution
    • Monterey Park, California, United States
      • Local Institution
    • San Diego, California, United States
      • Local Institution
    • Santa Barbara, California, United States
      • Local Institution
    • Santa Maria, California, United States
      • Local Institution
    • Stanford, California, United States
      • Local Institution
    • Vallejo, California, United States
      • Local Institution
  • Colorado
    • Aurora, Colorado, United States
      • Local Institution
  • Connecticut
    • Hartford, Connecticut, United States
      • Local Institution
  • District of Columbia
    • Washington, District of Columbia, United States
      • Local Institution
  • Florida
    • Jacksonville, Florida, United States
      • Local Institution
    • Tampa, Florida, United States
      • Local Institution
  • Georgia
    • Athens, Georgia, United States
      • Local Institution
    • Atlanta, Georgia, United States
      • Local Institution
    • Lawrenceville, Georgia, United States
      • Local Institution
    • Tucker, Georgia, United States
      • Local Institution
  • Illinois
    • Chicago, Illinois, United States
      • Local Institution
    • Peoria, Illinois, United States
      • Local Institution
  • Indiana
    • Indianapolis, Indiana, United States
      • Local Institution
  • Kansas
    • Kansas City, Kansas, United States
      • Local Institution
  • Kentucky
    • Lexington, Kentucky, United States
      • Local Institution
  • Massachusetts
    • Boston, Massachusetts, United States
      • Local Institution
  • Minnesota
    • Minneapolis, Minnesota, United States
      • Local Institution
    • Rochester, Minnesota, United States
      • Local Institution
  • Missouri
    • Columbia, Missouri, United States
      • Local Institution
    • Kansas City, Missouri, United States
      • Local Institution
    • St. Louis, Missouri, United States
      • Local Institution
  • Nebraska
    • Omaha, Nebraska, United States
      • Local Institution
  • New Jersey
    • Hackensack, New Jersey, United States
      • Local Institution
    • Morristown, New Jersey, United States
      • Local Institution
    • New Brunswick, New Jersey, United States
      • Local Institution
  • North Carolina
    • Cary, North Carolina, United States
      • Local Institution
    • Chapel Hill, North Carolina, United States
      • Local Institution
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • Local Institution
    • Tulsa, Oklahoma, United States
      • Local Institution
  • Oregon
    • Portland, Oregon, United States
      • Local Institution
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States
      • Local Institution
  • South Carolina
    • Greenville, South Carolina, United States
      • Local Institution
  • Tennessee
    • Nashville, Tennessee, United States
      • Local Institution
  • Texas
    • Dallas, Texas, United States
      • Local Institution
    • Fort Worth, Texas, United States
      • Local Institution
    • Houston, Texas, United States
      • Local Institution
    • San Antonio, Texas, United States
      • Local Institution
    • Tyler, Texas, United States
      • Local Institution
  • Virginia
    • Norfolk, Virginia, United States
      • Local Institution
  • Washington
    • Seattle, Washington, United States
      • Local Institution
    • Spokane, Washington, United States
      • Local Institution
    • Vancouver, Washington, United States
      • Local Institution

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men and women, 18 years of age or older.
• Subjects with Chronic Phase Ph+ CML.
• Subjects have not been treated with imatinib at a dose >600 mg/day.
• Subjects developed resistance to disease while receiving an imatinib dose 400-600 mg/day.
• Able to tolerate imatinib at the highest dose the subject had received in the past.
• Demonstrate adequate renal and hepatic function.
• Women of childbearing potential must have a negative serum or urine pregnancy test, must be using an adequate method of contraception.

Exclusion Criteria:

• Women who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period for a least 1 month before and at least 3 months after the completion of the study.
• Women using a prohibited contraceptive method.
• Women who are pregnant or breastfeeding.
• Men whose sexual partners are women who are of childbearing potential, and who are unwilling or unable to use an acceptable method to avoid pregnancy of his partner for the entire study period as outlined above.
• Prior treatment with imatinib at a dose >600 mg/day.
• Subjects who have previously identified specific BCR-ABL mutations.
• Previous diagnosis of accelerated phase or blast crisis CML.
• Intolerance to imatinib at any dose.
• Subjects who are eligible and willing to undergo transplantation during the screening period.
• Serious uncontrolled medical disorder or active infection.
• Uncontrolled or significant cardiovascular disease.
• Uncontrolled hypertension.
• Dementia or altered mental status.
• Evidence of organ dysfunction.
• Use of imatinib within 7 days.
• Use of interferon or cytarabine within 14 days.
• Use of a targeted small molecule anticancer agent within 14 days.
• Subjects taking certain medications that are accepted to have a risk of causing Torsades de Pointes.
• Subjects taking medications that irreversibly inhibit platelet function or anticoagulants.
• Prior therapy with BMS-354825.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1; Active Comparator	Drug: Dasatinib; Tablets, oral, 20 mg and 50mg, twice daily, up to 96 weeks; Other Names: BMS-354825; Sprycel
EXPERIMENTAL: 2; Active Comparator	Drug: Imatinib; Tablets, Oral, 400mg and 100mg, twice daily, up to 96 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Major Cytogenetic Response (MCyR) at Week 12	Cytogenetic response was based on the prevalence of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase on a bone marrow sample (aspirate/biopsy). MCyR was defined as Complete CyR (CCyR; 0% Ph+ cells in metaphase in bone marrow) or Partial CyR (PCyR; >0% to 35% Ph+ cells in metaphase in bone marrow).	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MCyR at Any Time Prior to Crossover	Cytogenetic response was based on the prevalence of Ph+ metaphases among cells in metaphase on a bone marrow sample (aspirate/biopsy). MCyR was defined as CCyR (0% Ph+ cells in metaphase in bone marrow) or PCyR (>0% to 35% Ph+ cells in metaphase in bone marrow).	Baseline (within 4 weeks of Day 1), every 12 weeks until crossover or off-study timepoints. Restricted to precrossover measurements.
Duration of MCyR at 12 Months and 18 Months	Percentage of participants who achieved MCyR and did not progress at 12 and 18 months.	12 months, 18 months
Duration of MCyR at 24 Months	Percentage of participants who achieved MCyR and did not progress at 24 months.	24 Months
Time to MCyR Prior to Crossover	Median time from first dosing date to date of MCyR	Baseline (within 4 weeks of Day 1), every 12 weeks, at crossover or off-study timepoints; restricted to precrossover measurements.
Complete Hematologic Response (CHR) at Any Time Prior to Crossover	Participants achieving CHR prior to crossover. CHR=all of the following criteria: white blood cell count ≤ institutional upper limit of normal; platelets < 450,000/mm³; no blasts or promyelocytes in peripheral blood; < 5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils ≤ 20%; no extramedullary involvement. Confirmed CHR is defined as CHR maintained at least 4 weeks after first documented at ≥ Day 14. Failure to maintain criteria of CHR was defined by 2 or more consecutive records of non-response.	Baseline (within 4 weeks of Day 1), weekly until Week 12 and then every 12 weeks until crossover or off-study; restricted to precrossover measurements.
Duration of Complete Hematologic Response (CHR)	Percentage of participants who achieved CHR and did not progress at specified time points. CHR=all of the following criteria: white blood cell count ≤ institutional upper limit of normal; platelets < 450,000/mm³; no blasts or promyelocytes in peripheral blood; < 5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils ≤ 20%; no extramedullary involvement. Confirmed CHR is defined as CHR maintained at least 4 weeks after first documented at ≥ Day 14. Failure to maintain criteria of CHR was defined by 2 or more consecutive records of non-response.	12 months, 24 months
Time to CHR Prior to Crossover	Median time from first dosing date to date of CHR. CHR=all of the following criteria: white blood cell count ≤ institutional upper limit of normal; platelets < 450,000/mm³; no blasts or promyelocytes in peripheral blood; < 5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils ≤ 20%; no extramedullary involvement. Confirmed CHR is defined as CHR maintained at least 4 weeks after first documented at ≥ Day 14. Failure to maintain criteria of CHR was defined by 2 or more consecutive records of non-response.	Baseline (within 4 weeks of Day 1), weekly until Week 12, then every 12 weeks until crossover or off-study; restricted to precrossover measurements.
Major Molecular Response (MMR)	Number of participants Achieving MMR. MMR is defined as ≤3 log reduction (ie, international ratio ≤0.1), in BCR-ABL levels from the standardized baseline value of BCR-ABL: Control Gene ratio. The international ratio is obtained by multiplying BCR-ABL: Control gene ratio by the lab-specific conversion factor.	Pretreatment, then after every 4 weeks for 12 weeks, then after every 12 week period out to 2 years; restricted to precrossover measurements.
CHR After Crossover	Participants achieving CHR after crossover. CHR=all of the following criteria: white blood cell count ≤ institutional upper limit of normal; platelets < 450,000/mm³; no blasts or promyelocytes in peripheral blood; < 5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils ≤ 20%; no extramedullary involvement. Confirmed CHR is defined as CHR maintained at least 4 weeks after first documented at ≥ Day 14. Failure to maintain criteria of CHR was defined by 2 or more consecutive records of non-response.	Weekly for 12 weeks, then after every 12 week period out to 2 years; restricted to postcrossover measurements.
Cytogenetic Response After Crossover	Cytogenetic response was based on the prevalence of Ph+ metaphases among cells in metaphase on a bone marrow sample (aspirate/biopsy). MCyR was defined as Complete CyR (0% Ph+ cells in metaphase in bone marrow) or Partial CyR (>0% to 35% Ph+ cells in metaphase in bone marrow).	every 12 week period out to 2 years and off-study timepoints; restricted to postcrossover measurements
Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths and Hematologic Toxicities Prior to Crossover	AE=any new untoward medical occurrence or worsening of a pre-existing medical condition regardless of causal relationship with treatment. SAE=any untoward medical occurrence at any dose that: results in death; is life-threatening; requires or prolongs inpatient hospitalization; results in persistent or significant disability; is cancer; is congenital anomaly/birth defect; results in drug dependency/abuse; is an important medical event. Graded by National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. (1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening/disabling, 5=Death)	Continuously from baseline through 2 years
Health-Related Quality of Life Prior to Crossover	Health-related quality of life as measured by Functional Assessment of Cancer Therapy-General (FACT-G). FACT-G=27 questions in 4 domains: physical, social/family, emotional, & functional well-being (PWB, SWB, EWB, FWB). Higher scores=better health-related quality of life. Total Score change of 7 or more=minimal clinical important change; PWB, EWB, & FWB score change of 3 or more, & SWB score change of 2 or more=minimal clinical important change.	Every 4 weeks for the first 24 weeks, then every 12 weeks for the remainder of treatment. Last questionnaire was to be completed at first follow-up visit after off-study date.
Blood Sample Collection for Pharmacokinetic (PK) Analysis of Dasatinib	Number of participants from which blood samples were collected for population PK studies.	Day 8: pretreatment trough sample, a sample between 30 minutes and 3 hours following treatment, a sample between 5 and 8 hours following treatment, and a sample at 12 hours, prior to the next dose.

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Muller MC, Cortes JE, Kim DW, Druker BJ, Erben P, Pasquini R, Branford S, Hughes TP, Radich JP, Ploughman L, Mukhopadhyay J, Hochhaus A. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood. 2009 Dec 3;114(24):4944-53. doi: 10.1182/blood-2009-04-214221. Epub 2009 Sep 24.
• Kantarjian H, Pasquini R, Levy V, Jootar S, Holowiecki J, Hamerschlak N, Hughes T, Bleickardt E, Dejardin D, Cortes J, Shah NP. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R). Cancer. 2009 Sep 15;115(18):4136-47. doi: 10.1002/cncr.24504.

Study record dates

Study Major Dates

• Study Start: February 1, 2005
• Primary Completion (ACTUAL): August 1, 2006
• Study Completion (ACTUAL): March 1, 2008

Study Registration Dates

• First Submitted: February 15, 2005
• First Submitted That Met QC Criteria: February 15, 2005
• First Posted (ESTIMATE): February 16, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): August 10, 2010
• Last Update Submitted That Met QC Criteria: August 3, 2010
• Last Verified: June 1, 2010

More Information

Terms related to this study

• Keywords: Chronic Phase Philadelphia chromosome Positive (Ph+) chronic myeloid leukemia
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Chromosome Aberrations; Translocation, Genetic; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate; Dasatinib
• Other Study ID Numbers: CA180-017