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

Phase 2

Completed

Conditions: Chronic Myeloid Leukemia
Philadelphia-Positive Myeloid Leukemia

Interventions: Drug: Dasatinib

Registration Number: NCT00101660

Lead Sponsor: Bristol-Myers Squibb

Brief 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 387

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

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Dasatinib, 70 mg twice daily (BID)	Dasatinib	Dasatanib, 70 mg twice daily (BID), with dose escalation to 90 mg BID was allowed for participants who showed evidence of progression or lack of response. Up to 2 dose reductions were allowed for intolerance.

Primary Outcome Measures

Name	Time	Method
Number of Imatinib-resistant Participants With Major Cytogenetic Response (MCyR)	2 years	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.

Secondary Outcome Measures

Name	Time	Method
Number of Imatinib-intolerant Participants With MCyR	Baseline to 2 years	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.
Percentage of Participants Who Achieved MCyR and Did Not Progress at 12 and 24 Months	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.
Median Time From First Dosing Date to Date of MCyR	Baseline (within 4 weeks of Day 1) and every 12 weeks	MCyR is the combination of CCyR-0% Ph+ metaphases and PCyR - 1% to 35% Ph+ metaphases.
Number of Participants With Complete Hematologic Response (CHR)	Baseline (within 72 hours of start of therapy), weekly until Week 12, every 3 months until off-study	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.
Percentage of Participants Who Acheived CHR and Did Not Progress at 12 Months and 24 Months	12 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.
Median Time From First Dosing Until CHR	Baseline (within 72 hours of start of therapy), weekly until Week 12, every 3 months until off-study	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.
Number of Participants With Major Molecular Response (MMR)	Baseline to 2 years	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.
Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) Questionnaire Scores	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.	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.
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	Continuously, from baseline through 2 years	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)
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	Continuously, from baseline through 2 years	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)
Blood Sample Collection for Pharmacokinetic (PK) Analysis of Dasatinib	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.	Blood samples were collected for PK to be included in separate population PK analyses.