Dasatinib in Imatinib Resistant/Intolerant Chinese CML (Chronic and Advanced Phase) Subjects

Study Overview
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Brief Summary
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The primary objective of this study is to estimate the major cytogenetic response (MCyR) rate to Dasatinib in subjects with CP CML, complete and overall hematologic response (CHR and OHR) rate in subjects with AD CML or Ph+ ALL who have primary or acquired resistance to imatinib, or are intolerant of imatinib, when administered at 100 mg QD (Chronic CML) or 70mg BID (AP CML and Ph+ALL).

Official Title
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A Phase II Study to Determine the Activity of Dasatinib Administered Orally (PO) at a Dose of 100 mg Once Daily (QD) in Chronic Phase Chronic Myelogenous Leukemia (CML), at a Dose of 70 mg Twice Daily (BID) in Advanced Phase Chronic Myelogenous Leukemia (CML) Chinese Subjects Who Are Resistant to or Intolerant of Imatinib Mesylate (Gleevec®)

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Dasatinib


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: Signed Written Informed Consent Men and women, ages 18 years of age or older Subjects with Chronic Phase (CP) or Advanced Disease (AD) chronic myeloid leukemia (CML)/Ph+ Acute Lymphoblastic Leukemia (Ph+ ALL) Subjects resistant/intolerant to imatinib Subjects presenting: Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0-2 Adequate hepatic function Adequate renal function Sodium, Potassium, Magnesium, Phosphorus, Calcium higher or equal than the lower limit of normal range Exclusion Criteria: Women of child bearing potential who are not using adequate birth control Women who are pregnant or breastfeeding Subjects eligible for stem cell transplantation Serious uncontrolled medical disorder or active infection Uncontrolled or significant cardiovascular disease Concurrent incurable malignancy other than CML Subjects who received imatinib, interferon, cytarabine within 7 days or other antineoplastic agents other than hydroxyurea within 14 days before dasatinib, Dasatinib in the past History of significant bleeding unrelated to 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Dasatinib<br>* Tablets, Oral, 70 mg BID (AD CML) or 100 mg QD (Chronic CML), once or twice daily dependent on disease stage, until subjects meet discontinuation (DC) criteria for study<br>* Other names: BMS-354825;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Chronic Phase Chronic Myeloid Leukemia (CP - CML) Participants With Major Cytogenetic Response (MCyR) | Major Cytogenetic Response (MCyR) is defined as Complete Cytogenetic Response (CCyR) or Partial Cytogenetic Response (PCyR). CCyR: 0% Ph-chromosome-positive cells in metaphase in bone marrow [BM] PCyR: 1-35% Ph-chromosome-positive cells in metaphase in [BM]. | From first dose up to approximately 12 months of follow up after dasatinib treatment (data cut-off date: 18-Jun-2010) | 
| Percentage of Participants With Complete, Major, and Overall Hematologic Response (CHR, MaHR, & OHR) in Advanced Disease Chronic Myeloid Leukemia (AD CML) and Blast Phase CML/Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) | Major hematologic response: (MaHR) = complete hematologic response (CHR) + no evidence of leukemia (NEL). CHR=white blood cells (WBC) ≤upper limit of normal (ULN); absolute neutrophil count (ANC) ≥1,000/mm3; platelets ≥100,000/mm3; no blasts/promyelocytes, <20% basophils & <5% myelocytes+metamyelocytes in peripheral blood (PB); BM blasts ≤5%; no extra-medullary involvement/hepatomegaly/splenomegaly. NEL=CHR except platelets ≥20,000/mm3 & <100,000/mm3; ANC >500/mm3 & <1,000/mm3. Overall hematologic response (OHR)=CHR+NEL+ return to chronic phase (RTC=<15% blasts in BM and PB; <30% blasts+promyelocytes in BM & PB; <20% basophils in PB; no extra-medullar disease other than spleen & liver) | From first dose up to approximately 12 months of follow up after dasatinib treatment (data cut-off date: 18-Jun-2010) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Chronic Phase Chronic Myeloid Leukemia (CP - CML) Participants With Complete Hematologic Response (CHR) | Complete Hematologic Response (CHR) is obtained when all the following criteria are met: WBC ≤ institutional ULN; platelets ≤ 450,000/mm3; ≤20% basophils in peripheral blood; no blasts or promyelocytes in PB cells; < 5% myelocytes plus metamyelocytes in PB cells; no extra-medullary involvement including no hepatomegaly or splenomegaly. | From first dose up to approximately 12 months of follow up after dasatinib treatment (data cut-off date: 18-Jun-2010) | 
| Time to Major Cytogenetic Response (MCyR) in Chronic Phase Chronic Myeloid Leukemia (CP - CML) Participants | Time to MCyR is defined as the time from the first dosing date until day criteria were first met for CCyR or PCyR, whichever occurred first. Major Cytogenetic Response (MCyR) is defined as Complete Cytogenetic Response (CCyR: 0% Ph-chromosome-positive cells in metaphase in BM) or Partial Cytogenetic Response (PCyR: 1-35% Ph-chromosome-positive cells in metaphase in BM). | From first dose up to the day criteria were first met for CCyR or PCyR, whichever occurred first. (Up to approximately 12 months of follow up after dasatinib treatment [data cut-off date: 18-Jun-2010]) | 
| Duration of Major Cytogenetic Response (MCyR) in Chronic Phase Chronic Myeloid Leukemia (CP - CML) Participants | The duration of time from when the first day all criteria are met for CCyR or PCyR until the date of progression or death. Participants who neither progress nor die will be censored on the date of their last cytogenetic assessment. The duration of MCyR will be estimated via the Kaplan-Meier product-limit method. Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR: 0% Ph-chromosome-positive cells in metaphase in BM) or Partial Cytogenetic Response (PCyR: 1-35% Ph-chromosome-positive cells in metaphase in BM). | From first dose until the date of progression or death. (Up to approximately 12 months of follow up after dasatinib treatment [data cut-off date: 18-Jun-2010]) | 
| Progression-free Survival Among CP CML Participants | Progression-free survival is defined as the time from first dosing date until the time progressive disease (PD) is first documented. Participants who die without a reported prior progression will be considered to have progressed on the date of their death. Participants who do not progress nor die will be censored on the date of their last hematologic or cytogenetic assessment, whichever comes last. PFS will be analyzed via the Kaplan-Meier product-limit method. Participants were considered as having PD if they: achieved a hematologic response but subsequently no longer meet the criteria consistently on all assessment over a consecutive 2-week period after starting maximum dose; had no decrease from their baseline percent blasts in PB or BM on all assessments over a 4-week period, or had an increase by at least 50% in PB blast count (absolute) over a 2-week period after starting their maximum (individually-tolerated) dose. | From first dosing date until the time progressive disease (PD) is first documented. (Up to approximately 12 months of follow up after dasatinib treatment [data cut-off date: 18-Jun-2010]) | 
| Time to Complete and Major Hematologic Response (CHR and MaHR) in Advanced Disease Chronic Myeloid Leukemia (AD CML) and Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Participants (Ph+ ALL) | The time from first dose of Dasatinib until the first day CHR or MaHR criteria are met (for all confirmed responses). Time to CHR is computed only for participants whose best response is CHR. Major HR (MaHR) includes CHR or no evidence of leukemia (NEL). Major hematologic response: (MaHR) = complete hematologic response (CHR) + no evidence of leukemia (NEL). CHR=white blood cells (WBC) ≤upper limit of normal (ULN); absolute neutrophil count (ANC) ≥1,000/mm3; platelets ≥100,000/mm3; no blasts/promyelocytes, <20% basophils & <5% myelocytes+metamyelocytes in peripheral blood (PB); BM blasts ≤5%; no extra-medullary involvement/hepatomegaly/splenomegaly. NEL=CHR except platelets ≥20,000/mm3 & <100,000/mm3; ANC >500/mm3 & <1,000/mm3. | From first dose of Dasatinib until the first day CHR criteria are met (for all confirmed responses). (Up to approximately 12 months of follow up after dasatinib treatment [data cut-off date: 18-Jun-2010]) | 
| Duration of CHR Among AD CML and Ph+ ALL Participants | Time from the first day all criteria are met for CHR until the date treatment is discontinued due to progressive disease (PD) or death. Participants who neither progress nor die will be censored on the date of their last assessment. CHR=white blood cells (WBC) ≤ upper limit of normal (ULN); absolute neutrophil count (ANC) ≥1,000/mm3; platelets ≥100,000/mm3; no blasts/promyelocytes, <20% basophils and <5% myelocytes+metamyelocytes in peripheral blood (PB); BM blasts ≤5%; no extra-medullary involvement/hepatomegaly/splenomegaly. PD = Hematologic response achieved but subsequently no longer meet the criteria consistently on all assessment over a 2-week period;, and no decrease from their baseline percent blasts in PB or BM on all assessments over a 4-week period or have an increase by at least 50% in PB blast count (absolute) over a 2-week period. | From first dose until the date of disease progression (PD) or death. (Up to approximately 12 months of follow up after dasatinib treatment [data cut-off date: 18-Jun-2010]) | 
| Duration of MaHR Among AD CML and Ph+ ALL Participants | Time from the first day all criteria are met for CHR or NEL or MaHR until the date of progression or death. Participants who neither progress nor die will be censored on the date of their last assessment. MAHR = CHR or no evidence of leukemia (NEL). CHR=white blood cells (WBC) ≤ upper limit of normal (ULN); absolute neutrophil count (ANC) ≥1,000/mm3; platelets ≥100,000/mm3; no blasts/promyelocytes, <20% basophils and <5% myelocytes+metamyelocytes in peripheral blood (PB); BM blasts ≤5%; no extra-medullary involvement/hepatomegaly/splenomegaly. NEL=CHR except platelets ≥20,000/mm3 and <100,000/mm3; ANC >500/mm3 and <1,000/mm3. Progressive disease (PD) = Hematologic response achieved but subsequently no longer meet the criteria consistently on all assessment over a 2-week period;, and no decrease from their baseline percent blasts in PB or BM on all assessments over a 4-week period or have an increase by at least 50% in PB blast count (absolute) over a 2-week period. | From first dose until the date of disease progression (PD) or death. (Up to approximately 12 months of follow up after dasatinib treatment [data cut-off date: 18-Jun-2010]) | 
| Progression-free Survival Among AD CML and Ph+ ALL Participants | Progression-free survival is defined as the time from first dosing date until the time progressive disease (PD) is first documented. Participants who die without a reported prior progression will be considered to have progressed on the date of their death. Participants who do not progress nor die will be censored on the date of their last hematologic or cytogenetic assessment whichever comes last. PFS will be analyzed via the Kaplan-Meier product-limit method. Progressive disease (PD) = Hematologic response achieved but subsequently no longer meet the criteria consistently on all assessment over a 2-week period;, and no decrease from their baseline percent blasts in PB or BM on all assessments over a 4-week period or have an increase by at least 50% in PB blast count (absolute) over a 2-week period. | From first dose until the time progressive disease (PD) is first documented. (Up to approximately 12 months of follow up after dasatinib treatment [data cut-off date: 18-Jun-2010]) | 
| Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), and Drug-related Fluid Retention AEs of Special Interest | AEs and SAEs considered possibly, probably, or certainly related to study treatment, graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death).SAE= any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization/prolongation of existing hospitalization, results in persistent/significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. | From first dose to 30 days after last dose. (Up to approximately 161 months) | 
| Mean Dasatinib Plasma Concentrations | Mean dasatinib plasma concentrations following 70 mg BID dose in AD CML or Ph+ ALL participants and following 100 mg QD dose in CP CML participants | Day 1 (0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours postdose), Days 6 and 7 (0 hours postdose), Day 8 (0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12 hours postdose), | 
| Mean Maximum Concentration (Cmax) of Dasatinib Following 70 mg BID and 100 QD Dose Administration | Cmax=maximum observed plasma concentration of dasatinib | Day 1 (0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours postdose), Day 8 (0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12 hours postdose) | 
| Mean (Tmax) and (T-Half) of Dasatinib Following 70 mg BID and 100 QD Dose Administration | Tmax=time of maximum observed plasma concentration. T-Half=plasma half-life. | Day 1 (0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours postdose), Day 8 (0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12 hours postdose) | 
| Mean (AUC[0-T]), (AUC[INF]), and (AUC[TAU])of Dasatinib Following 70 mg BID and 100 QD Dose Administration | Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration AUC(0-T)for dasatinib. AUC(INF)=area under the plasma concentration-time curve from time zero extrapolated to infinite time. AUC(TAU)=area under the plasma concentration-time curve for a dosing interval | Day 1 (0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours postdose), Day 8 (0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12 hours postdose) | 
| Mean Oral Clearance (CLo) of Dasatinib Following 70 mg BID and 100 QD Dose Administration |  | Day 1 (0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours postdose), Day 8 (0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12 hours postdose) | 
| Mean Apparent Volume of Distribution (Vz/F) of Dasatinib Following 70 mg BID and 100 QD Dose Administration |  | Day 1 (0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours postdose), Day 8 (0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12 hours postdose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Phase, Advanced Phase chronic myeloid leukemia, Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia