A Study of Dasatinib in Chronic Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia

Study Overview
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Brief Summary
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The objective is to evaluate the cytogenetic response to Dasatinib (BMS-354825) administered for 24 weeks in subjects with Imatinib resistant or intolerant chronic phase chronic myeloid leukemia (CML) once daily (QD) or twice daily. (BID)

Official Title
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A Randomized, Multicenter, Open-label Phase II Study of Dasatinib (BMS-354825) Administered Orally at a Dose of 50mg Twice Daily or 100mg Once Daily in Subjects With Chronic Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia Who Are Resistant or Intolerant to Imatinib

Conditions
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Myeloid Leukemia, Chronic

Intervention / Treatment
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* Drug: Dasatinib
* Drug: dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Philadelphia chromosome positive or bcr-abl gene positive Chronic phase Chronic Myelogenous Leukemia (CML) subjects must have primary or acquired resistance to Imatinib mesylate or have intolerance of imatinib mesylate Performance status (general conditions) specified by the Eastern Cooperative Oncology Group: 0-2 Men and women, ages 20 to 75 Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 3 months after the study in such a manner that the risk of pregnancy is minimized Exclusion Criteria: Subjects who are eligible and willing to undergo transplantation at pre-study Women who are pregnant or breastfeeding Uncontrolled or significant cardiovascular disease History of significant bleeding disorder unrelated to CML Adequate hepatic function Adequate renal function Medication that increases bleeding risk Medication that changes heart rhythms Subjects who are compulsory detained for legal reasons or treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: Dasatinib<br>* tablets, Oral, 100 mg, once daily<br>* Other names: BMS-354825;|
| Experimental: B<br> | Drug: dasatinib<br>* tablets, Oral, 50 mg, twice daily<br>* Other names: BMS-354825;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | Cytogenetic responses (CyR) are based on the percentage of Philadelphia-positive (Ph+) metaphases among at least 20 metaphase cells in each bone marrow (BM) sample. The criteria for cytogenetic responses are as follows. Best CyR is defined as the best response obtained at any time during the study. Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR; 0 Ph+ Cells in Metaphase in BM), and Partial Cytogenetic Response (PCyR; 1 - 35 Ph+ Cells in Metaphase in BM). | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations, and Deaths During Treatment | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. Related AE=relationship of certain, probable, possible, or missing. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in the development of drug dependency or drug abuse, is an important medical event. | Throughout study period to last observation. Dosing period=6 months; if beneficial, medication may continue in the extension period (ending in January 2009). Last observation=30 days past last dosing day or the discontinuation day. | 
| Complete Hematologic Response (CHR) in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | 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. A confirmed CHR (cCHR) is obtained when all above criteria are maintained for at least 28 days after they are first met. All hematologic responses can begin only 14 days after the dosing start date. | Week 24 | 
| Time to Major Cytogenetic Response (MCyR) | Time to MCyR is defined as the time from first dose of Dasatinib (BMS-354825) until the first day criteria for CCyR or PCyR, whichever occurs first, are first met. MCyR = a complete and a partial cytogenetic response (CyR), based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow sample. Percentage of Ph+ Cells in Metaphase in bone marrow: Complete Cytogenetic Response (CCyR) = 0; Partial Cytogenetic Response (PCyR) 1 - 35 | time from first dose of Dasatinib (BMS-354825) until the first day criteria for CCyR or PCyR, whichever occurs first, are first met | 
| Pharmacokinetics of Dasatinib (BMS-354825) as Characterized by Population Pharmacokinetics | Blood sample collection for pharmacokinetic (PK) analysis that will contribute to PK modeling. | Six or more peripheral blood samples were collected at any visit after Day 7, pre-dose and 5 - 8 hours after dose administration. | 
| Duration of MCyR | The duration of MCyR will be measured from the first day all criteria are met for CCyR or PCyR until the date of progressed disease (PD) or death. Subjects who neither progress nor die will be censored on the date of their last cytogenetic assessment.MCyR = a complete and a partial cytogenetic response (CyR), based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow sample. Percentage of Philadelphia-positive (Ph+) Cells in Metaphase in bone marrow: Complete Cytogenetic Response (CCyR) = 0; Partial Cytogenetic Response (PCyR) 1 - 35 | from the first day all criteria are met for CCyR or PCyR until the date of progressed disease (PD) or death | 
| Time to CHR | Time to CHR = time from first dose of Dasatinib until the first day CHR criteria are met (provided subjects achieved a cCHR). CHR=all of the following criteria: white blood cell count ≤ 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. A confirmed CHR (cCHR) is obtained when all above criteria are maintained for at least 28 days after they are first met. All hematologic responses can begin only 14 days after the dosing start date. | time from first dose of Dasatinib (BMS-354825) until the first day CHR criteria are met | 
| Duration of CHR | The duration of CHR were measured from the first day all criteria were first met for CHR (provided subjects achieved a cCHR), until the date PD is first reported or until death. Subjects who neither progress nor die were censored on the date of their last hematologic assessment. | measured from the first day all criteria were first met for CHR (provided subjects achieved a cCHR), until the date PD is first reported or until death | 
| Progression-Free Survival (PFS) | Progressed disease=achieving a CHR & subsequently no longer meeting criteria consistently over a consecutive 2-week period after starting maximum dose; no CHR after receiving maximum dose & increase in white blood cell count (doubling of count from lowest value to >20,000/mm3 or an increase by >50,000/mm3 on 2 assessments done ≥2 weeks apart); meeting the criteria of accelerated or blastic phase chronic myeloid leukemia at any time; having an MCyR & subsequently no longer meeting the criteria for MCyR after starting maximum dose; or having a >=30% absolute increase in number of Ph+ metaphases. | time from first dose of Dasatinib (BMS-354825) until the first day criteria for CCyR or PCyR, whichever occurs first, are first met | 
| Expression of BCR-ABL Gene Mutations of RNA (mRNA) | Number of participants with positive (>= 2.0 log copies/mg) and negative (<2.0 log copies/mg) expression of mRNA at Baseline and at end of study. | Baseline and at the end of long term extension period (The enrollment period was followed by an extension period until the launch of dasatinib in Japan, January 2009.) | 
| Mutational Spectrum of BCR-ABL | Number of participants with a particular BCR-ABL mutation at Baseline and End-of-Study. | Baseline and at the end of long term extension period (The enrollment period was followed by an extension period until the launch of dasatinib in Japan, January 2009.) | 
| Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at End of Study | Cytogenetic response (CyR) as reflected in the major cytogenetic response was determined by bone marrow (BM) aspirates and are based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each BM sample. Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR; 0 Ph+ Cells in Metaphase in BM), or Partial Cytogenetic Response (PCyR; 1 - 35 Ph+ Cells in Metaphase in BM). | Baseline and at the end of long term extension period (The enrollment period was followed by an extension period until the launch of dasatinib in Japan, January 2009.) | 
| Hematologic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at End of Study | 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. A confirmed CHR (cCHR) is obtained when all above criteria are maintained for at least 28 days after they are first met. All hematologic responses can begin only 14 days after the dosing start date. | Baseline and at the end of long term extension period (The enrollment period was followed by an extension period until the launch of dasatinib in Japan, January 2009.) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Imatinib resistant or intolerant chronic phase CML