Study of Dasatinib in Patients With Chronic Phase Chronic Myeloid Leukemia and a Suboptimal Response to Imatinib

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy of dasatinib with that of high-dose (800-mg) imatinib in participants with chronic phase chronic myeloid leukemia who achieved only a suboptimal response after at least 3 months of monotherapy with 400-mg imatinib. The safety of these treatments will also be evaluated.

Detailed Description
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Participants were randomized 2:1 to dasatinib or high-dose imatinib, respectively. Randomization was stratified by a suboptimal response, defined as a hematologic response less than a complete hematologic response after at least 3 months of monotherapy with 400-mg imatinib; a cytogenic response (CgR) less than a partial CgR (PCgR) after at least 6 months of monotherapy with 400-mg; a PCgR after at least 12 months of monotherapy with 400-mg imatinib; or less than a major molecular response with a complete CgR after at least 18 months of monotherapy with 400-mg imatinib. Participants received either dasatinib or imatinib for 12 months or until disease progression, unacceptable toxicity, consent withdrawal, or study discontinuation. After 12 months, who had a confirmed major molecular response and were still receiving dasatinib, 100 mg, or imatinib, 800 mg, were eligible to extend treatment for an additional 12 months. Participants permanently discontinuing treatment before 12 months were considered treatment failures and withdrawn from the study.

Official Title
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An Open-label, Randomized Study of Dasatinib vs High-dose (800-mg) Imatinib in the Treatment of Subjects With Chronic Phase Chronic Myeloid Leukemia Who Have Had a Suboptimal Response After at Least 3 Months of Therapy With 400 mg Imatinib

Conditions
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Leukemia, Myeloid, Chronic

Intervention / Treatment
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* Drug: Imatinib
* Drug: Dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic phase Ph^+ chronic myeloid leukemia (CML) demonstrating only a suboptimal response, defined as a hematologic response that is less than a complete hematologic response after at least 3 months of monotherapy with imatinib, 400 mg; a cytogenic response (CgR) that is less than a partial CgR (PCgR) after at least 6 months of monotherapy with imatinib, 400 mg; a PCgR after at least 12 months of monotherapy with imatinib, 400 mg; or less than a major molecular response with a complete CgR after at least 18 months of monotherapy with imatinib, 400 mg. Either gender Age of 18 years or older Exclusion Criteria: Previous diagnosis of accelerated phase or blast crisis CML Uncontrolled or significant cardiovascular disease History of significant bleeding disorder unrelated to CML Concurrent malignancies Intolerance of imatinib, 400 mg Prior treatment with imatinib at a dose higher than 400 mg Prior stem cell transplantation and/or high-dose chemotherapy for CML

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dasatinib<br>Participants with chronic phase chronic myeloid leukemia (CML) who had only a suboptimal response after at least 3 months of therapy with imatinib, 400 mg. | Drug: Dasatinib<br>* Dasatinib tablets administered orally at a dose of 100 mg once daily.<br>|
| Active Comparator: Imatinib<br>Participants with chronic phase CML who had only a suboptimal response after at least 3 months of therapy with imatinib, 400 mg. | Drug: Imatinib<br>* Imatinib tablets administered orally at a dose of 400 mg twice daily. Each 400- mg dose to be taken with a meal and a large glass of water.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Chronic Phase Chronic Myeloid Leukemia Who Have a Major Molecular Response (MMolR) | MMolR is defined as reduction in transcript levels of the breakpoint cluster region (BCR)-V-abl Abelson murine leukemia viral oncogene homolog 1 (ABL) gene of at least 3 log. The BCR-ABL gene has a role in the production of a mutated protein that converts bone marrow stem cells from normal to leukemic. | At 12 months from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Death as Outcome, Adverse Events (AEs), Treatment-related AEs, Serious Adverse Events (SAEs), Treatment-related SAEs, and AEs Leading to Discontinuation | AE=any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with treatment. SAE=any untoward medical occurrence that at any dose results in death, persistent or significant disability/incapacity, drug dependency, or drug abuse; prolongs inpatient hospitalization; or is life-threatening, a congenital anomaly/birth defect, or an important medical event. Treatment related=possibly, probably, or certainly related to and of unknown relationship to study treatment. | Months 1 to 12, continuously, and Months 12 to 24, continuously | 
| Percentage of Participants With On-study AEs of Special Interest | GI=gastrointestinal. AE=any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with treatment. Grade 1=mild; Grade 2=moderate; Grade 3=severe and undesirable; Grade 4=life-threatening or disabling; Grade 5=death. Percentages based on the number of participants with a specific grade at baseline. Participants without on-study test values for a particular laboratory analyte are not included in the reporting of that analyte. | Months 1 to 12, continuously, and Months 12 to 24, continuously | 
| Median Time to MMolR | Time to MMolR is defined as the time from first treatment dose until measurement criteria are first met for MMolR. MMolR is defined as a reduction in transcript levels of the BCR-ABL gene of at least 3 log from baseline. | At 3, 6, 9, and 12 months from baseline | 
| Percentage of Participants With Complete Cytogenetic Response | Cytogenetic response is based on the prevalence of Ph+ metaphases among cells in metaphase in a bone marrow sample. | At 6 and 12 months from baseline | 
| Median Time to Treatment Failure | Time to treatment failure is defined as the time in days from randomization to progressive disease documented by the investigator, to death from any cause without prior progression, or to early treatment discontinuation for any reason, whichever occurs first. Participants without disease progression or who do not die and complete the 12-month study treatment are censored on the date of their last molecular, cytogenetic, or hematologic assessment. | Randomization to disease progression, death, or discontinuation (to 12 months) | 
| Median Time to Progression-free Survival | Progression-free survival is defined as the time in days from randomization to progressive disease documented by the investigator or to death from any cause without prior progression. Participants without progressive disease or who do not die and complete the 12-month treatment are censored on the date of their last molecular, cytogenetic, or hematologic assessment. | Randomization to disease progression or death (to 12 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic phase CML, with a suboptimal response after treatment with imatinib