Dasatinib (BMS-354825) in Subjects With Myeloid Blast Phase Chronic Myeloid Leukemia Resistant to or Intolerant of Imatinib Mesylate

Study Overview
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Brief Summary
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The purpose of this study is to see what effect an investigational drug (BMS-354825) has on subjects who are currently in the myeloid blast phase of chronic myeloid leukemia (CML) and who are either resistant to or intolerant of imatinib mesylate. Another purpose of the study is to see what side effects this drug may have on subjects.

Official Title
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A Phase II Study of BMS-354825 in Subjects With Myeloid Blast Phase Chronic Myeloid Leukemia Resistant to or Intolerant of Imatinib Mesylate

Conditions
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Chronic Myeloid Leukemia, Blast Crisis

Intervention / Treatment
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* Drug: Dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with myeloid blast phase chronic myeloid leukemia Subjects who are either resistant or intolerant of imatinib mesylate Exclusion Criteria: Subjects who are eligible and willing to undergo transplantation Serious uncontrolled medical disorder or active infection Uncontrolled or significant heart problems, such as congestive heart failure, recent heart attack, etc Subjects receiving medications that may affect heart rhythm Other malignancy/cancer other than CML History of significant bleeding disorder unrelated to CML Pregnant or breastfeeding women (subjects must avoid becoming pregnant) Subjects received imatinib within 7 days, interferon or cytarabine within 14 days, a targeted anticancer medication within 14 days, an antineoplastic agent (other than hydroxyurea or anagrelide) within 28 days, or any other investigation medication in 28 days Subject is receiving medications that affect platelet function or an anticoagulant

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: Non-Randomized
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, twice daily, Until disease progression or intolerable toxicity, switch to the roll-over study or study closure.<br>* Other names: Sprycel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major and Overall Hematologic Response (MaHR and OHR) | MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). Criteria for MaHR are specified in Outcome Measure 2. OHR=best confirmed response of MaHR or minor HR (MiHR). MiHR= <15% blasts in bone marrow and <15% blasts in peripheral blood (PB); <30% blasts + promyelocytes in bone marrow and <30% blasts + promyelocytes in PB; <20% basophils in PB; no extramedullary disease other than spleen and liver. Confirmed hematologic response=response confirmed ≥4 weeks after first documented event with no concomitant use of anagrelide or hydroxyurea. | Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Duration of Major Hematologic Response (MaHR) | MaHR=best confirmed response of CHR or NEL. CHR=white blood cells ≤ institutional upper limit of normal (iULN); absolute neutrophil count (ANC) ≥1000/mm3; platelets ≥100,000/mm3; no blasts/promyelocytes in peripheral blood (PB); bone marrow blasts ≤5%; <5% myelocytes+metamyelocytes in PB; PB basophils ≤ iULN; no extramedullary involvement. NEL=WBC ≤ iULN; no blasts/promyelocytes in PB; bone marrow blasts ≤5%; <5% myelocytes+metamyelocytes in PB; PB basophils ≤ iULN; no extramedullary involvement; at least 1 of the following: ANC ≥500/mm3 & <1000/mm3; platelets ≥20,000/mm3 & <100,000/mm3. | Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment | 
| Median Duration of Overall Hematologic Response (OHR) | OHR=best confirmed response of MaHR or MiHR. MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). Criteria for MaHR are specified in Outcome Measure 2. Criteria for MiHR are specified in Outcome Measure 1. Maintaining a response was defined as no 2 consecutive records of non-response (ie, a single record of non-response between 2 assessments of response was not considered a loss of response). | Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment | 
| Time to MaHR and OHR | Median time from first dosing to date of OHR and/or MaHR in subjects who achieved OHR and MaHR. MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). OHR=best confirmed response of MaHR or minor hematologic response (MiHR). Criteria for MaHR are specified in Outcome Measure 2. Criteria for MiHR are specified in Outcome Measure 1. | Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment | 
| Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Best confirmed cytogenetic response. Determination of cytogenetic response is based on the prevalence (percentage) of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase in a bone marrow sample (aspirates/biopsies). | Baseline (within 4 weeks of therapy start); Every month for Cycles 1-3; Every 12 weeks for Cycles 4+; end of treatment | 
| Number of Participants With CHR or NEL, MiHR, or no Hematologic Response | Best confirmed hematologic response. Confirmed hematologic response=response that is confirmed after at least 4 weeks with no concomitant use of anagrelide or hydroxyurea use during this interval. Criteria for complete hematologic response (CHR) or No Evidence of Leukemia (NEL) are specified in Outcome Measure 2. Criteria for minor hematologic response (MiHR) are specified in Outcome Measure 1. | Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycles 1 and 2; After every 2nd cycle for Cycles 3+; at end of treatment | 
| Number of Participants Achieving Major Molecular Response (MMR) | Number of participants who achieved an MMR at any time during the treatment period. MMR was calulated by measuring BCR-ABL transcripts in blood during treatment using quantitative reverse transcription-polymerase chain reaction (RT-PCR). BCR-ABL=the fused gene found in subjects with this type of Chronic Myeloid Leukemia (CML). | Baseline, every 12 weeks, and at time of Complete Cytogenetic Response (CCyR) for quantitative Polyermase Chain Reaction (qPCR) analysis | 
| MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | MaHR and MCyR in subjects with mutations at baseline, including imatinib-resistant mutations (IRM) and specific BCR-ABL mutations (SBAM). Criteria for MaHR are specified in Outcome Measure 2. MCyR=rate of complete cytogenetic responses + the rate of partial cytogenetic responses, as defined in Outcome Measure 5. BCR-ABL=the fused gene found in subjects with this type of CML. This table contains those mutations observed in at least 3 participants. The categories 1 IRM w/2-4-fold increase in resistance and ≥1 IRM w/≥5-fold increase in resistance refer to increase in resistance to imatinib. | baseline, at time of disease progression | 
| Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Number of subjects with minimally significant changes from baseline in the health-related quality of life questionnaire FACT-G. FACT-G=27 questions in 4 domains: physical, social/family, emotional, & functional well-being (PWB, SWB, EWB, FWB). Score range: 0-108; 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, & SWB score change of 2 or more=minimal clinical important change. | Baseline, Every 2 weeks for the first 3 cycles, following every 4-week cycle, and once at follow-up | 
| Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | 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 throughout study, from pre-treatment visit through end of study (due to death, unacceptable toxicity, treatment failure, etc) and follow-up period | 
| Pharmacokinetics (PK) of Dasatinib - Maximum Observed Plasma Concentration (Cmax) | The Cmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared. | Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours. | 
| Pharmacokinetics (PK) of Dasatinib - Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point Within the Dosing Interval of 12 h or 24 h(AUC[0-T]) | The AUC(0-T) was calculated using the mixed log-linear trapezoidal algorithm in Kinetica™. In the calculation of AUC(0-T), predose concentrations that were < lower limit of qualtitation were assigned a value of zero. | Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours. | 
| Pharmacokinetics (PK) of Dasatinib - Time to Maximum Observed Plasma Concentration (Tmax) | The Tmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared. | Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours. | 
| Pharmacokinetics (PK) of Dasatinib - Plasma Half-life (T-HALF) | The T-HALF was calculated as Ln2/Lz,where Lz was the absolute value of the slope of the terminal log-linear phase. | Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours. | 
| Pharmacokinetics (PK) of Dasatinib's Metabolite BMS-582691 - Maximum Observed Plasma Concentration (Cmax) | The Cmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared. | Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours. | 
| Pharmacokinetics (PK) of Dasatinib's Metabolite BMS-582691 - Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point Within the Dosing Interval of 12 h (AUC[0-T]) | The AUC(0-T) was calculated using the mixed log-linear trapezoidal algorithm in Kinetica™. In the calculation of AUC(0-T), predose concentrations that were less than the lower limit of quantitation (LLQ) were assigned a value of zero. | Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours. | 
| Pharmacokinetics (PK) of Dasatinib's Metabolite BMS-582691 - Time to Maximum Observed Plasma Concentration (Tmax) | The Tmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared. | Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours. | 
| Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Plasma Half-life (T-HALF) | The T-HALF was calculated as Ln2/Lz,where Lz was the absolute value of the slope of the terminal log-linear phase. | Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours. | 
| Population PK of Dasatinib | Population pharmacokinetic analysis was not done because it is not meaningful for this single study | Day 8 immediately prior to the first daily dose and between 30 minutes to 3 hours following this dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myeloid blast phase Chronic Myeloid Leukemia (CML)