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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Chronic Myeloid Leukemia, Philadelphia-Positive Myeloid Leukemia

Intervention / Treatment
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* Drug: Dasatinib
* Drug: Imatinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Active Comparator | Drug: Dasatinib<br>* Tablets, oral, 20 mg and 50mg, twice daily, up to 96 weeks<br>* Other names: BMS-354825;|
| Experimental: 2<br>Active Comparator | Drug: Imatinib<br>* Tablets, Oral, 400mg and 100mg, twice daily, up to 96 weeks<br>|

What is the study measuring?
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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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Phase Philadelphia chromosome Positive (Ph+) chronic myeloid leukemia