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

Chronic Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00103844
• Other study ID #: CA180-017
• Status: Completed
• Phase: Phase 2
• First received: February 15, 2005
• Last updated: August 3, 2010
• Start date: February 2005
• Est. completion date: March 2008

Study information

• Verified date: June 2010
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 150
• Est. completion date: March 2008
• Est. primary completion date: August 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Myeloid Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Philadelphia Chromosome
• Philadelphia-Positive Myeloid Leukemia

Intervention

Drug:
• Dasatinib
Tablets, oral, 20 mg and 50mg, twice daily, up to 96 weeks
• Imatinib
Tablets, Oral, 400mg and 100mg, twice daily, up to 96 weeks

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  China,  Denmark,  Estonia,  Finland,  France,  Germany,  Hungary,  Ireland,  Israel,  Italy,  Korea, Republic of,  Norway,  Peru,  Philippines,  Poland,  Puerto Rico,  Russian Federation,  Singapore,  South Africa,  Spain,  Sweden,  Switzerland,  Taiwan,  Thailand,  United Kingdom, 

References & Publications (2)

Kantarjian H, Pasquini R, Lévy 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. — View Citation

Müller 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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.	No
Secondary	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	No
Secondary	Duration of MCyR at 24 Months	Percentage of participants who achieved MCyR and did not progress at 24 months.	24 Months	No
Secondary	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.	No
Secondary	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.	No
Secondary	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	No
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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	No
Secondary	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	Yes
Secondary	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.	No
Secondary	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.	No

External Links

•   BMS Clinical Trials Disclosure
•   For FDA Safety Alerts and Recalls refer to the following link www.fda.gov/MEDWATCH/safety.htm