Blast Crisis, Chronic Myeloid Leukemia
Conditions
Keywords
Myeloid blast phase Chronic Myeloid Leukemia (CML)
Brief summary
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.
Interventions
DRUGDasatinib
Tablets, Oral, 70 mg, twice daily, Until disease progression or intolerable toxicity, switch to the roll-over study or study closure.
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major and Overall Hematologic Response (MaHR and OHR) | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Duration of Overall Hematologic Response (OHR) | 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 | 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). |
| Time to MaHR and OHR | 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 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. |
| Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Baseline (within 4 weeks of therapy start); Every month for Cycles 1-3; Every 12 weeks for Cycles 4+; end of treatment | 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). |
| Number of Participants With CHR or NEL, MiHR, or no Hematologic Response | 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 | 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. |
| Number of Participants Achieving Major Molecular Response (MMR) | Baseline, every 12 weeks, and at time of Complete Cytogenetic Response (CCyR) for quantitative Polyermase Chain Reaction (qPCR) analysis | 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). |
| MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | baseline, at time of disease progression | 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. |
| Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Baseline, Every 2 weeks for the first 3 cycles, following every 4-week cycle, and once at follow-up | 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. |
| Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | Continuously throughout study, from pre-treatment visit through end of study (due to death, unacceptable toxicity, treatment failure, etc) and follow-up period | 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) |
| Median Duration of Major Hematologic Response (MaHR) | 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 | 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. |
| 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]) | 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. | 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. |
| Pharmacokinetics (PK) of Dasatinib - Time to Maximum Observed Plasma Concentration (Tmax) | 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. | 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. |
| Pharmacokinetics (PK) of Dasatinib - Plasma Half-life (T-HALF) | 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. | The T-HALF was calculated as Ln2/Lz,where Lz was the absolute value of the slope of the terminal log-linear phase. |
| Pharmacokinetics (PK) of Dasatinib's Metabolite BMS-582691 - Maximum Observed Plasma Concentration (Cmax) | 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. | 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. |
| 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]) | 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. | 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. |
| Pharmacokinetics (PK) of Dasatinib's Metabolite BMS-582691 - Time to Maximum Observed Plasma Concentration (Tmax) | 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. | 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. |
| Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Plasma Half-life (T-HALF) | 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. | The T-HALF was calculated as Ln2/Lz,where Lz was the absolute value of the slope of the terminal log-linear phase. |
| Population PK of Dasatinib | Day 8 immediately prior to the first daily dose and between 30 minutes to 3 hours following this dose. | Population pharmacokinetic analysis was not done because it is not meaningful for this single study |
| Pharmacokinetics (PK) of Dasatinib - Maximum Observed Plasma Concentration (Cmax) | 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. | 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. |
Countries
Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Israel, Italy, Netherlands, Norway, Philippines, Singapore, South Korea, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 124 participants were enrolled in this study; 15 were never treated (11 participants did not meet inclusion criteria; 3 participants died; 1 participant failed screening).
Participants by arm
| Arm | Count |
|---|---|
| Imatinib-intolerant Defined as: i) Toxicity that was considered at least possibly related to imatinib ≤400 mg/day that led to a discontinuation of imatinib therapy ii) Ability to tolerate only \<400 mg/day imatinib. A subject who tolerated 400 mg/day imatinib, but was intolerant of higher doses was not considered imatinib-intolerant. Receiving oral dasatinib at a starting dose of 70 mg twice daily (BID), with dose modifications as necessary for the management of disease progression or toxicity. | 10 |
| Imatinib-resistant Defined as any of the following: i) Subjects initially diagnosed with chronic phase chronic myeloid leukemia (CML) who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥400 mg/day. ii) Subjects initially diagnosed with accelerated phase CML who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥600 mg/day (or 400 to \<600 mg/day if subject is intolerant of ≥600 mg/day). iii) Subjects initially diagnosed with myeloid blast phase CML who meet the criteria for myeloid phase blast crisis after at least 4 weeks of treatment prescribed at a dose of ≥600 mg/day (or 400 to \<600 mg/day if subject is intolerant of ≥600 mg/day). Each of these definitions includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance). Oral dasatinib 70 mg BID, with dose modifications as necessary to manage disease progression or toxicity. | 99 |
| Total | 109 |
Baseline characteristics
| Characteristic | Total | Imatinib-resistant | Imatinib-intolerant |
|---|---|---|---|
| Age Continuous | 51.4 years STANDARD_DEVIATION 14 | 50.4 years STANDARD_DEVIATION 14 | 60.5 years STANDARD_DEVIATION 10.9 |
| Age, Customized >75 years | 1 participants | 0 participants | 1 participants |
| Age, Customized Between 21 and 45 years | 36 participants | 35 participants | 1 participants |
| Age, Customized Between 46 and 65 years | 53 participants | 46 participants | 7 participants |
| Age, Customized Between 66 and 75 years | 19 participants | 18 participants | 1 participants |
| Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) Not Reported | 5 Participants | 4 Participants | 1 Participants |
| Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) Score=0 | 22 Participants | 21 Participants | 1 Participants |
| Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) Score=1 | 45 Participants | 39 Participants | 6 Participants |
| Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) Score=2 | 35 Participants | 33 Participants | 2 Participants |
| Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) Score=3 | 2 Participants | 2 Participants | 0 Participants |
| Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) Score=4 | 0 Participants | 0 Participants | 0 Participants |
| Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) Score=5 | 0 Participants | 0 Participants | 0 Participants |
| Functional Assessment of Cancer Therapy-General (FACT-G) Emotional Well-Being | 16.7 units on a scale STANDARD_DEVIATION 5.2 | 16.8 units on a scale STANDARD_DEVIATION 5.3 | 15.3 units on a scale STANDARD_DEVIATION 2.1 |
| Functional Assessment of Cancer Therapy-General (FACT-G) Functional Well-Being | 13.8 units on a scale STANDARD_DEVIATION 5.7 | 13.9 units on a scale STANDARD_DEVIATION 5.9 | 13.0 units on a scale STANDARD_DEVIATION 4.5 |
| Functional Assessment of Cancer Therapy-General (FACT-G) Physical Well Being | 16.5 units on a scale STANDARD_DEVIATION 6.1 | 16.4 units on a scale STANDARD_DEVIATION 6.3 | 17.2 units on a scale STANDARD_DEVIATION 3.8 |
| Functional Assessment of Cancer Therapy-General (FACT-G) Social/Family Well-Being | 21.9 units on a scale STANDARD_DEVIATION 4.7 | 22.1 units on a scale STANDARD_DEVIATION 4.7 | 20.1 units on a scale STANDARD_DEVIATION 23.6 |
| Functional Assessment of Cancer Therapy-General (FACT-G) Total FACT-G | 68.9 units on a scale STANDARD_DEVIATION 15.4 | 69.2 units on a scale STANDARD_DEVIATION 16 | 65.6 units on a scale STANDARD_DEVIATION 7.1 |
| Race/Ethnicity, Customized Asian | 18 Participants | 18 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 13 Participants | 13 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 77 Participants | 67 Participants | 10 Participants |
| Sex: Female, Male Female | 63 Participants | 60 Participants | 3 Participants |
| Sex: Female, Male Male | 46 Participants | 39 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 10 | 97 / 99 |
| serious Total, serious adverse events | 7 / 10 | 80 / 99 |
Outcome results
Primary
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.
Time frame: 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
Population: All treated subjects
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib-intolerant | Major and Overall Hematologic Response (MaHR and OHR) | OHR | 4 Participants |
| Imatinib-intolerant | Major and Overall Hematologic Response (MaHR and OHR) | MaHR | 2 Participants |
| Imatinib-resistant | Major and Overall Hematologic Response (MaHR and OHR) | MaHR | 34 Participants |
| Imatinib-resistant | Major and Overall Hematologic Response (MaHR and OHR) | OHR | 50 Participants |
| Total | Major and Overall Hematologic Response (MaHR and OHR) | MaHR | 36 Participants |
| Total | Major and Overall Hematologic Response (MaHR and OHR) | OHR | 54 Participants |
Secondary
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)
Time frame: Continuously throughout study, from pre-treatment visit through end of study (due to death, unacceptable toxicity, treatment failure, etc) and follow-up period
Population: All treated subjects
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib-intolerant | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | AEs Leading to Discontinuation | 3 Participants |
| Imatinib-intolerant | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | Death | 6 Participants |
| Imatinib-intolerant | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | Drug-Related AEs | 9 Participants |
| Imatinib-intolerant | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | SAEs | 7 Participants |
| Imatinib-intolerant | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | AEs | 10 Participants |
| Imatinib-intolerant | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | Death Within 30 Days | 6 Participants |
| Imatinib-resistant | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | Death Within 30 Days | 38 Participants |
| Imatinib-resistant | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | AEs Leading to Discontinuation | 39 Participants |
| Imatinib-resistant | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | AEs | 99 Participants |
| Imatinib-resistant | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | SAEs | 80 Participants |
| Imatinib-resistant | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | Drug-Related AEs | 91 Participants |
| Imatinib-resistant | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | Death | 49 Participants |
| Total | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | Drug-Related AEs | 100 Participants |
| Total | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | Death Within 30 Days | 44 Participants |
| Total | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | Death | 55 Participants |
| Total | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | AEs | 109 Participants |
| Total | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | AEs Leading to Discontinuation | 42 Participants |
| Total | Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs | SAEs | 87 Participants |
Secondary
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.
Time frame: baseline, at time of disease progression
Population: All subjects with baseline mutation data; n=the number of participants with the specified mutation. Baseline mutation data were reported for 103 of the 109 subjects (10/10 imatinib-intolerant and 93/99 imatinib-resistant). At baseline, 39 (42%) imatinib-resistant subjects and 3 imatinib-intolerant subject had imatinib-resistant mutations
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib-intolerant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [F359I/V] at baseline (n=3) | 0 Percentage of Participants |
| Imatinib-intolerant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | ≥1 IRM in activation loop (n=8) | 38 Percentage of Participants |
| Imatinib-intolerant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [E255K/V] at baseline (n=5) | 0 Percentage of Participants |
| Imatinib-intolerant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [F486S] at baseline (n=4) | 0 Percentage of Participants |
| Imatinib-intolerant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [H396R] at baseline (n=4) | 25 Percentage of Participants |
| Imatinib-intolerant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | Participants with IRM (n=42) | 31 Percentage of Participants |
| Imatinib-intolerant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | ≥1 IRM in P-loop (n=19) | 26 Percentage of Participants |
| Imatinib-intolerant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | ≥1 IRM in other location (n=17) | 29 Percentage of Participants |
| Imatinib-intolerant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | ≥1 IRM w/2-4-fold increase in resistance (n=4) | 75 Percentage of Participants |
| Imatinib-intolerant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | ≥1 IRM w/≥5-fold increase in resistance (n=28) | 25 Percentage of Participants |
| Imatinib-intolerant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [M244V] at baseline (n=3) | 33 Percentage of Participants |
| Imatinib-intolerant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [G250E] at baseline (n=7) | 29 Percentage of Participants |
| Imatinib-intolerant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [Y253H] at baseline (n=6) | 50 Percentage of Participants |
| Imatinib-intolerant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [T315I] at baseline (n=5) | 0 Percentage of Participants |
| Imatinib-intolerant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [M351T/V] at baseline (n=3) | 67 Percentage of Participants |
| Imatinib-resistant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [Y253H] at baseline (n=6) | 50 Percentage of Participants |
| Imatinib-resistant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | ≥1 IRM w/2-4-fold increase in resistance (n=4) | 50 Percentage of Participants |
| Imatinib-resistant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | ≥1 IRM in activation loop (n=8) | 13 Percentage of Participants |
| Imatinib-resistant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [E255K/V] at baseline (n=5) | 20 Percentage of Participants |
| Imatinib-resistant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | ≥1 IRM w/≥5-fold increase in resistance (n=28) | 25 Percentage of Participants |
| Imatinib-resistant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [F486S] at baseline (n=4) | 0 Percentage of Participants |
| Imatinib-resistant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [F359I/V] at baseline (n=3) | 0 Percentage of Participants |
| Imatinib-resistant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [M351T/V] at baseline (n=3) | 67 Percentage of Participants |
| Imatinib-resistant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [H396R] at baseline (n=4) | 0 Percentage of Participants |
| Imatinib-resistant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [T315I] at baseline (n=5) | 20 Percentage of Participants |
| Imatinib-resistant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | Participants with IRM (n=42) | 29 Percentage of Participants |
| Imatinib-resistant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [G250E] at baseline (n=7) | 14 Percentage of Participants |
| Imatinib-resistant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | SBAM [M244V] at baseline (n=3) | 33 Percentage of Participants |
| Imatinib-resistant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | ≥1 IRM in P-loop (n=19) | 26 Percentage of Participants |
| Imatinib-resistant | MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations | ≥1 IRM in other location (n=17) | 35 Percentage of Participants |
Secondary
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.
Time frame: 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
Population: Participants who achieved MaHR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib-intolerant | Median Duration of Major Hematologic Response (MaHR) | 22.4 months |
Secondary
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).
Time frame: 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
Population: Participants who achieved OHR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib-intolerant | Median Duration of Overall Hematologic Response (OHR) | 14.7 months |
Secondary
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.
Time frame: Baseline, Every 2 weeks for the first 3 cycles, following every 4-week cycle, and once at follow-up
Population: Number of participants with FACT-G assessments at baseline and at least one assessment during treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib-intolerant | Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Emotional Well-Being | 4 Participants |
| Imatinib-intolerant | Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Social/Family Well-Being | 4 Participants |
| Imatinib-intolerant | Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Total Fact-G | 5 Participants |
| Imatinib-intolerant | Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Physical Well-Being | 5 Participants |
| Imatinib-intolerant | Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Functional Well-Being | 3 Participants |
| Imatinib-resistant | Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Social/Family Well-Being | 35 Participants |
| Imatinib-resistant | Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Total Fact-G | 46 Participants |
| Imatinib-resistant | Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Physical Well-Being | 54 Participants |
| Imatinib-resistant | Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Emotional Well-Being | 37 Participants |
| Imatinib-resistant | Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Functional Well-Being | 42 Participants |
| Total | Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Functional Well-Being | 45 Participants |
| Total | Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Emotional Well-Being | 41 Participants |
| Total | Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Total Fact-G | 51 Participants |
| Total | Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Social/Family Well-Being | 39 Participants |
| Total | Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Physical Well-Being | 59 Participants |
Secondary
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).
Time frame: Baseline, every 12 weeks, and at time of Complete Cytogenetic Response (CCyR) for quantitative Polyermase Chain Reaction (qPCR) analysis
Population: treated participants with or without CCyR who were assessed for major molecular response
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib-intolerant | Number of Participants Achieving Major Molecular Response (MMR) | MMR in Assessed Subjects with CCyR (n=2; n=17) | 2 participants |
| Imatinib-intolerant | Number of Participants Achieving Major Molecular Response (MMR) | MMR in Assessed Subjects without CCyR (n=1; n=28) | 0 participants |
| Imatinib-resistant | Number of Participants Achieving Major Molecular Response (MMR) | MMR in Assessed Subjects with CCyR (n=2; n=17) | 11 participants |
| Imatinib-resistant | Number of Participants Achieving Major Molecular Response (MMR) | MMR in Assessed Subjects without CCyR (n=1; n=28) | 1 participants |
| Total | Number of Participants Achieving Major Molecular Response (MMR) | MMR in Assessed Subjects with CCyR (n=2; n=17) | 13 participants |
| Total | Number of Participants Achieving Major Molecular Response (MMR) | MMR in Assessed Subjects without CCyR (n=1; n=28) | 1 participants |
Secondary
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.
Time frame: 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
Population: All treated subjects
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib-intolerant | Number of Participants With CHR or NEL, MiHR, or no Hematologic Response | Minor | 2 Participants |
| Imatinib-intolerant | Number of Participants With CHR or NEL, MiHR, or no Hematologic Response | No evidence of leukemia | 0 Participants |
| Imatinib-intolerant | Number of Participants With CHR or NEL, MiHR, or no Hematologic Response | Complete | 2 Participants |
| Imatinib-intolerant | Number of Participants With CHR or NEL, MiHR, or no Hematologic Response | No response | 6 Participants |
| Imatinib-resistant | Number of Participants With CHR or NEL, MiHR, or no Hematologic Response | Minor | 16 Participants |
| Imatinib-resistant | Number of Participants With CHR or NEL, MiHR, or no Hematologic Response | Complete | 26 Participants |
| Imatinib-resistant | Number of Participants With CHR or NEL, MiHR, or no Hematologic Response | No response | 49 Participants |
| Imatinib-resistant | Number of Participants With CHR or NEL, MiHR, or no Hematologic Response | No evidence of leukemia | 8 Participants |
| Total | Number of Participants With CHR or NEL, MiHR, or no Hematologic Response | No response | 55 Participants |
| Total | Number of Participants With CHR or NEL, MiHR, or no Hematologic Response | Complete | 28 Participants |
| Total | Number of Participants With CHR or NEL, MiHR, or no Hematologic Response | No evidence of leukemia | 8 Participants |
| Total | Number of Participants With CHR or NEL, MiHR, or no Hematologic Response | Minor | 18 Participants |
Secondary
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).
Time frame: Baseline (within 4 weeks of therapy start); Every month for Cycles 1-3; Every 12 weeks for Cycles 4+; end of treatment
Population: All treated subjects
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib-intolerant | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Minimal (>65% to 95% Ph+ metaphases) | 0 Participants |
| Imatinib-intolerant | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | No Response (>95% to 100% Ph+ metaphases) | 4 Participants |
| Imatinib-intolerant | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Complete (0% Ph+ metaphases) | 2 Participants |
| Imatinib-intolerant | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Minor (>35% to 65% Ph+ metaphases) | 0 Participants |
| Imatinib-intolerant | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Unable to Determine | 4 Participants |
| Imatinib-intolerant | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Partial (>0% to 35% Ph+ metaphases) | 0 Participants |
| Imatinib-resistant | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Complete (0% Ph+ metaphases) | 27 Participants |
| Imatinib-resistant | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Minor (>35% to 65% Ph+ metaphases) | 3 Participants |
| Imatinib-resistant | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Unable to Determine | 22 Participants |
| Imatinib-resistant | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Minimal (>65% to 95% Ph+ metaphases) | 11 Participants |
| Imatinib-resistant | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Partial (>0% to 35% Ph+ metaphases) | 8 Participants |
| Imatinib-resistant | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | No Response (>95% to 100% Ph+ metaphases) | 28 Participants |
| Total | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Minimal (>65% to 95% Ph+ metaphases) | 11 Participants |
| Total | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Partial (>0% to 35% Ph+ metaphases) | 8 Participants |
| Total | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Unable to Determine | 26 Participants |
| Total | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | No Response (>95% to 100% Ph+ metaphases) | 32 Participants |
| Total | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Complete (0% Ph+ metaphases) | 29 Participants |
| Total | Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response | Minor (>35% to 65% Ph+ metaphases) | 3 Participants |
Secondary
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.
Time frame: 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: 26 participants had dense PK sampling on Day 1 \& Day 8; parameters for 1 participant on Day 1 \& 1 on Day 8 were excluded due to unreliable data. Participants w/all concentration-time values \<than limit of quantitation were treated as missing for PK analysis. n=participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imatinib-intolerant | Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Plasma Half-life (T-HALF) | 4.95 hours | Standard Deviation 3.93 |
| Imatinib-resistant | Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Plasma Half-life (T-HALF) | 4.38 hours | Standard Deviation 3.97 |
Secondary
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.
Time frame: 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: 26 participants had dense PK sampling on Day 1 and Day 8; parameters for 1 participant on Day 8 was excluded due to unreliable data. Participants with all concentration-time values \< than the limit of quantitation were treated as missing for PK analysis. n= participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imatinib-intolerant | 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]) | 161.17 ng∙h/mL | Standard Deviation 150.29 |
| Imatinib-resistant | 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]) | 295.92 ng∙h/mL | Standard Deviation 169.2 |
Secondary
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.
Time frame: 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: 26 participants had dense PK sampling on Day 1 and Day 8; parameters for 1 participant on Day 8 was excluded due to unreliable data. Participants with all concentration-time values \< than the limit of quantitation were treated as missing for PK analysis. n= participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imatinib-intolerant | Pharmacokinetics (PK) of Dasatinib - Maximum Observed Plasma Concentration (Cmax) | 60.34 ng/mL | Standard Deviation 55.86 |
| Imatinib-resistant | Pharmacokinetics (PK) of Dasatinib - Maximum Observed Plasma Concentration (Cmax) | 110.42 ng/mL | Standard Deviation 44.31 |
Secondary
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.
Time frame: 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: 26 participants had dense PK sampling on Day 1 and Day 8; parameters for 1 participant on Day 8 was excluded due to unreliable data. Participants with all concentration-time values \< than the limit of quantitation were treated as missing for PK analysis. n= participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imatinib-intolerant | Pharmacokinetics (PK) of Dasatinib - Plasma Half-life (T-HALF) | 3.71 hours | Standard Deviation 1.78 |
| Imatinib-resistant | Pharmacokinetics (PK) of Dasatinib - Plasma Half-life (T-HALF) | 4.26 hours | Standard Deviation 2.15 |
Secondary
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.
Time frame: 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: 26 participants had dense PK sampling on Day 1 \& Day 8; parameters for 1 participant on Day 1 \& 1 on Day 8 were excluded due to unreliable data. Participants w/all concentration-time values \<than limit of quantitation were treated as missing for PK analysis. n=participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imatinib-intolerant | 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]) | 7.08 ng∙h/mL | Standard Deviation 7.8 |
| Imatinib-resistant | 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]) | 13.81 ng∙h/mL | Standard Deviation 11.96 |
Secondary
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.
Time frame: 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: 26 participants had dense PK sampling on Day 1 \& Day 8; parameters for 1 participant on Day 1 \& 1 on Day 8 were excluded due to unreliable data. Participants w/all concentration-time values \<than limit of quantitation were treated as missing for PK analysis. n=participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imatinib-intolerant | Pharmacokinetics (PK) of Dasatinib's Metabolite BMS-582691 - Maximum Observed Plasma Concentration (Cmax) | 2.44 ng/mL | Standard Deviation 1.32 |
| Imatinib-resistant | Pharmacokinetics (PK) of Dasatinib's Metabolite BMS-582691 - Maximum Observed Plasma Concentration (Cmax) | 3.87 ng/mL | Standard Deviation 1.67 |
Secondary
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.
Time frame: 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: 26 participants had dense PK sampling on Day 1 \& Day 8; parameters for 1 participant on Day 1 \& 1 on Day 8 were excluded due to unreliable data. Participants w/all concentration-time values \<than limit of quantitation were treated as missing for PK analysis. n=participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imatinib-intolerant | Pharmacokinetics (PK) of Dasatinib's Metabolite BMS-582691 - Time to Maximum Observed Plasma Concentration (Tmax) | 1.71 hours | Standard Deviation 1 |
| Imatinib-resistant | Pharmacokinetics (PK) of Dasatinib's Metabolite BMS-582691 - Time to Maximum Observed Plasma Concentration (Tmax) | 1.90 hours | Standard Deviation 1.49 |
Secondary
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.
Time frame: 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: 26 participants had dense PK sampling on Day 1 and Day 8; parameters for 1 participant on Day 8 was excluded due to unreliable data. Participants with all concentration-time values \< than the limit of quantitation were treated as missing for PK analysis. n= participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imatinib-intolerant | Pharmacokinetics (PK) of Dasatinib - Time to Maximum Observed Plasma Concentration (Tmax) | 1.79 hours | Standard Deviation 1.45 |
| Imatinib-resistant | Pharmacokinetics (PK) of Dasatinib - Time to Maximum Observed Plasma Concentration (Tmax) | 1.22 hours | Standard Deviation 0.97 |
Secondary
Population PK of Dasatinib
Population pharmacokinetic analysis was not done because it is not meaningful for this single study
Time frame: Day 8 immediately prior to the first daily dose and between 30 minutes to 3 hours following this dose.
Secondary
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.
Time frame: 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
Population: Participants who achieved OHR and MaHR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib-intolerant | Time to MaHR and OHR | 63.5 days |
| Imatinib-resistant | Time to MaHR and OHR | 30.0 days |