Study of BMS-354825 (Dasatinib) in Patients With Chronic Myeloid Leukemia Who Are Either Resistant or Intolerant to Imatinib

Chronic Myeloid Leukemia Clinical Trial

Official title:

A Phase II Study to Determine the Activity of BMS-354825 in Subjects With Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukemia Who Have Disease That is Resistant to High Dose Imatinib Mesylate (Gleevec) or Who Are Intolerant of Imatinib

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00101660
• Other study ID #: CA180-013
• Status: Completed
• Phase: Phase 2
• First received: January 12, 2005
• Last updated: February 29, 2012
• Start date: February 2005
• Est. completion date: April 2008

Study information

• Verified date: February 2012
• 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 purpose of this study is assess the effects of the investigational drug dasatinib on participants who are in chronic phase Philadelphia chromosome chronic myeloid leukemia and who are either resistant to or intolerant of imatinib. Other purposes of the study are to identify any side effects the drug may produce and to study the level of dasatanib in the blood and assess the efficacy of dasatanib in the treatment of leukemia.

Other known NCT identifiers

• NCT00112801

Recruitment information / eligibility

• Status: Completed
• Enrollment: 387
• Est. completion date: April 2008
• Est. primary completion date: September 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age of 18 years and older.

• Chronic myeloid leukemia (CML)

• Previous treatment with imatinib at a dose of >600 mg/day AND the development of progressive disease while receiving imatinib at that dose, OR

• CML with resistance to imatinib at a dose less than or equal to 600 mg/day with genetic mutation in the BCR-ABL gene that is associated with a high level of resistance to imatinib, OR

• Intolerance to imatinib at any dose

• Adequate organ function

• Women who are able to bear children must have a negative serum or urine pregnancy test. Adequate methods of contraception must be used throughout the study to avoid pregnancy for the entire interval of at least 1 month before and 3 months after completion of the study medication.

Exclusion Criteria:

• Woman 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

• Previous diagnosis of accelerated phase or blast crisis CML.

• Participants who are eligible and willing to undergo transplantation during the screening period

• Uncontrolled or significant cardiovascular disease

• 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

• Use of certain medication that carry a known side effect risk of Torsade de Pointes - Certain medications that irreversibly inhibit platelet function or anticoagulants

• Prior therapy with dasatinib.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group 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; 70 mg BID, depending on response

Locations

Country	Name	City	State
Australia	Local Institution	Adelaide	South Australia
Australia	Local Institution	East Mebourne	Victoria
Australia	Local Institution	Parkville	Victoria
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	Bruxelles
Belgium	Local Institution	Edegem
Belgium	Local Institution	Yvoir
Canada	Local Institution	Montreal	Quebec
Canada	Local Institution	Toronto	Ontario
Canada	Local Institution	Vancouver	British Columbia
Denmark	Local Institution	Aarhus
Finland	Local Institution	Helsinki
France	Local Institution	Lille Cedex
France	Local Institution	Lyon Cedex 03
France	Local Institution	Nantes
France	Local Institution	Paris Cedex 10
France	Local Institution	Pessac
France	Local Institution	Poitiers Cedex
France	Local Institution	Strasbourg Cedex
Germany	Local Institution	Hamburg
Germany	Local Institution	Leipzig
Germany	Local Institution	Mainz
Germany	Local Institution	Mannheim
Ireland	Local Institution	Co Galway	Galway
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
Netherlands	Local Institution	Nijmegen
Netherlands	Local Institution	Rotterdam
Norway	Local Institution	Trondheim
Peru	Local Institution	Lima
Singapore	Local Institution	Singapore
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 Instituion	Basel
United Kingdom	Local Institution	Glasgow	Central
United Kingdom	Local Institution	London	Greater London
United States	Local Institution	Anaheim	California
United States	Local Institution	Atlanta	Georgia
United States	Local Institution	Baltimore	Maryland
United States	Local Institution	Boston	Massachusetts
United States	Local Institution	Chicago	Illinois
United States	Local Institution	Dallas	Texas
United States	Local Institution	Detroit	Michigan
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	Loma Linda	California
United States	Local Institution	Los Angeles	California
United States	Local Institution	Nashville	Tennessee
United States	Local Institution	New Brunswick	New Jersey
United States	Local Institution	New York	New York
United States	Local Institution	Omaha	Nebraska
United States	Local Institution	Philadelphia	Pennsylvania
United States	Local Institution	Pittsburgh	Pennsylvania
United States	Local Institution	Portland	Oregon
United States	Local Institution	San Antonio	Texas
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	Tyler	Texas
United States	Local Institution	Vallejo	California
United States	Local Institution	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Denmark,  Finland,  France,  Germany,  Ireland,  Israel,  Italy,  Korea, Republic of,  Netherlands,  Norway,  Peru,  Singapore,  South Africa,  Spain,  Sweden,  Switzerland,  United Kingdom, 

References & Publications (2)

Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ, Facon T, Goldberg SL, Cervantes F, Niederwieser D, Silver RT, Stone RM, Hughes TP, Muller MC, Ezzeddine R, Countouriotis AM, Shah NP. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007 Mar 15;109(6):2303-9. Epub 2006 Nov 30. Erratum in: Blood. 2007 Sep 1;110(5):1438. — 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 Imatinib-resistant Participants With Major Cytogenetic Response (MCyR)	Cytogenetic response was based on the prevalence of Ph+ metaphases among cells with metaphases in a bone marrow sample. MCyR is the combination of Complete Cytogenetic Response (CCyR)-0% Ph+ metaphases plus Partial Cytogenetic Response (PCyR)-1% to 35% Ph+ metaphases.	2 years	No
Secondary	Number of Imatinib-intolerant Participants With MCyR	Determination of cytogenetic response was based on the prevalence of Ph+ metaphases among cells with metaphases in a bone marrow sample. MCyR is the combination of CCyR-0% Ph+ metaphases and PCyR - 1% to 35% Ph+ metaphases.	Baseline to 2 years	No
Secondary	Percentage of Participants Who Achieved MCyR and Did Not Progress at 12 and 24 Months	Based on the Kaplan-Meier estimate of the duration of response. Determination of cytogenetic response was based on the prevalence of Ph+ metaphases among cells with metaphases in a bone marrow sample. MCyR is the combination of Complete Cytogenetic Response (CCyR)-0% Ph+ metaphases and Partial Cytogenetic Response (PCyR) - 1% to 35% Ph+ metaphases.	12 and 24 Months	No
Secondary	Median Time From First Dosing Date to Date of MCyR	MCyR is the combination of CCyR-0% Ph+ metaphases and PCyR - 1% to 35% Ph+ metaphases.	Baseline (within 4 weeks of Day 1) and every 12 weeks	No
Secondary	Number of Participants With Complete Hematologic Response (CHR)	CHR=all of the following criteria: white blood cell count = institutional upper limit of normal; platelets <450,000/mm^3; no blasts or promyelocytes in peripheral blood; <5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils =20%; no extramedullary involvement. Response, as defined, must be maintained for at least 4 weeks after first documented. A CHR could begin only 14 days after dosing start date.	Baseline (within 72 hours of start of therapy), weekly until Week 12, every 3 months until off-study	No
Secondary	Percentage of Participants Who Acheived CHR and Did Not Progress at 12 Months and 24 Months	Based on the Kaplan-Meier estimate of the duration of response. CHR=all of the following criteria: white blood cell count = institutional upper limit of normal; platelets < 450,000/mm^3; no blasts or promyelocytes in peripheral blood; <5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils =20%; no extramedullary involvement. Response, as defined, must be maintained for at least 4 weeks after first documented. A CHR could begin only 14 days after dosing start date.	12 and 24 months	No
Secondary	Median Time From First Dosing Until CHR	CHR=all of the following criteria: white blood cell count = institutional upper limit of normal; platelets <450,000/mm^3; no blasts or promyelocytes in peripheral blood; <5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils =20%; no extramedullary involvement. Response, as defined, must be maintained for at least 4 weeks after first documented. A CHR could begin only 14 days after dosing start date.	Baseline (within 72 hours of start of therapy), weekly until Week 12, every 3 months until off-study	No
Secondary	Number of Participants With Major Molecular Response (MMR)	MMR is defined as =3 log reduction 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.	Baseline to 2 years	No
Secondary	Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) Questionnaire Scores	Health-related quality of life as measured by FACT-G, which comprises 27 questions in 4 domains: PWB, SWB, EWB, FWB. Total FACT-G score=summation of the 4 subscale scores and ranges from 0 to 108. 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, and SWB score change of 2 or more=minimal clinical important change. Baseline FACT-G measurements can be found in Baseline Characteristics.	Baseline, Day 29, every 4 weeks for the first 24 weeks, then every 12 weeks for the remainder of treatment, after end of treatment. Treatment continued until disease progression or development of toxicity or until other protocol-defined criteria.	No
Secondary	Number of Imitanib-intolerant Participants With Drug-related Adverse Events (AEs), Death Within 30 Days of Last Dose, Death, and AEs Leading to Discontinuation, Serious Adverse Events (SAEs), Grade 3-4 Thrombocytopenia, Grade 4-4 Neutropenia, and Any AE	AE=any new untoward medical occurrence or worsening of a preexisting 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	Number of Imitanib-resistant Participants With Drug-related AEs, Death Within 30 Days of Last Dose, Death, AEs Leading to Discontinuation, SAEs, Grade 3-4 Thrombocytopenia, Grade 3-4 Neutropenia, and Any AE	AE=any new untoward medical occurrence or worsening of a preexisting 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	Blood Sample Collection for Pharmacokinetic (PK) Analysis of Dasatinib	Blood samples were collected for PK to be included in separate population PK analyses.	Day 8 of study; pretreatment through sample between 30 minutes and 3 hours following treatment, a sample between 5 hours 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