Chronic Myelogenous Leukemia
Conditions
Keywords
Chronic myelogenous leukemia (CML): Accelerated phase
Brief summary
The purpose of this clinical research study is to learn if BMS-354825 will have activity, defined by hematologic response, in subjects who have accelerated phase chronic myeloid leukemia (CML) who are resistant to or intolerant to imatinib mesylate. The safety of this treatment will also be studied.
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 Philadelphia chromosome positive (PH+) or the fused gene BCR/ABL positive (BCR/ABL+) accelerated phase chronic myeloid leukemia (CML) whose disease has primary or acquired hematologic resistance to imatinib mesylate or who are intolerant of imatinib mesylate. * Subjects must have had prior exposure to imatinib. However, imatinib mesylate does not need to be their most recent CML treatment prior to coming on this study. * Men and women, 18 years of age or older. * Adequate hepatic function. * Adequate renal function. * Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for a period of least 1 month before and at least 3 months after the study in such a manner that the risk of pregnancy is minimized.
Exclusion criteria
* Women who are pregnant or breastfeeding. * Subjects who are eligible and willing to undergo transplantation during the screening period. * A serious uncontrolled medical disorder or active infection that would impair the ability of the subjects to receive protocol therapy. * Uncontrolled or significant cardiovascular disease. * Medications that increase bleeding risk. * Medications that change heart rhythms. * Dementia or altered mental status that would prohibit the understanding or rendering of informed consent. * History of significant bleeding disorder unrelated to CML. * Concurrent incurable malignancy other than CML. * Evidence of organ dysfunction or digestive dysfunction that would prevent administration of study therapy. * Prior therapy with dasatinib (BMS-354825). * Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.
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 treatment; at end of treatment | 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). Confirmed hematologic response=response confirmed ≥4 weeks after first documented event with no concomitant use of anagrelide or hydroxyurea. Maintaining a response=no 2 consecutive records of nonresponse at assessment. Criteria for CHR and NEL specified in Outcome Measure 2 and criteria for MiHR in Outcome Measure 4. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved MaHR and Did Not Progress at 24 Months in the Imatinib-Resistant Group (Based on the Kaplan-Meier Estimate of the Duration of Response) | 24 months | Percentage of participants in the Imatinib-Resistant Group who achieved MaHR and did not progress at Month 24, based on the Kaplan-Meier estimate of the duration of response. MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). Criteria for MaHR and NEL are specified in Outcome Measure 2. |
| Percentage of Participants Who Achieved OHR and Did Not Progress at 12 Months and 24 Months | 12 months, 24 months | Percentage of participants who achieved OHR and did not progress at specified timepoints, based on the Kaplan-Meier estimate of the duration of response. OHR=best confirmed response of MaHR or MiHR. MaHR criteria in Outcome Measure 2. 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= confirmed ≥4 weeks after 1st documented event with no concomitant use of anagrelide or hydroxyurea. |
| Median Time in Days From First Dosing Date to Date of MaHR | Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during treatment; at end of treatment | MaHR=best 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: ANC ≥500/mm3 & \<1000/mm3; platelets ≥20,000/mm3 & \<100,000/mm3. |
| Time to OHR | Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during treatment; at end of treatment | Median time (in months) from first dosing date to date of OHR. OHR=best confirmed response of MaHR or MiHR. Criteria for MaHR specified in Outcome Measure 2. 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 1st documented event with no concomitant use of anagrelide or hydroxyurea. |
| Best Cytogenetic Response | 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 complete, partial, minor, minimal, or no cytogenetic response. Determination of cytogenetic response based on the prevalence (percentage) of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase in a bone marrow sample (aspirates/biopsies). |
| Best Confirmed Hematologic Response | Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during treatment; at end of treatment | Number of participants with confirmed complete hematologic response (CHR) or No Evidence of Leukemia (NEL), minor hematologic response (MiHR), or no 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 CHR and NEL are specified in Outcome Measure 2; criteria for MiHR are specified in Outcome Measure 4. |
| Number of Participants Who Achieved a Major Molecular Response (MMR) During Treatment Period | Baseline, every 12 weeks throughout study (treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria). | Number of participants who achieved an MMR at any time during the treatment period. MMR was calculated 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). |
| Percentage of Participants Who Achieved MaHR and Did Not Progress at 12 Months (Based on the Kaplan-Meier Estimate of the Duration of Response) | 12 months | MaHR=best 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: ANC ≥500/mm3 & \<1000/mm3; platelets ≥20,000/mm3 & \<100,000/mm3. |
| Minimal Clinically Significant Change 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.(treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria). | 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, and functional well-being (PWB, SWB, EWB, FWB). Total score=0 to 108; higher score=better health-related quality of life. Total Score change of 7 or more=minimal clinical important change; PWB, EWB, and FWB score change of 3 or more, and SWB score change of 2 or more=minimal clinically important change. |
| Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Continuous from pretreatment through each 4-week cycle and at follow-up. (treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria). | 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) |
| Pharmacokinetics (PK) of Dasatinib and Its 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 and Its 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 Hours (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 and Its 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 |
| MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | Baseline, at time of disease progression. (treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria). | Major hematologic and cytogenetic responses (MaHR and MCyR) to dasatinib in subjects with mutations at baseline, including imatinib-resistant mutations (IRM) and specific BCR-ABL mutations (SBAM). BCR-ABL=the fused gene found in subjects with this type of CML. Criteria for MaHR are specified in Outcome Measure 2. MCyR=combined complete cytogenetic and partial cytogenetic response rate. Complete Cytogenetic Response= 0% Ph+ Cells in Metaphase in Bone Marrow, Partial Cytogenetic Response \> 0% to 35% Ph+ Cells in Metaphase in Bone Marrow. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Denmark, Finland, France, Germany, Israel, Italy, Netherlands, Norway, Peru, Philippines, Singapore, South Korea, Sweden, Switzerland, Taiwan, Thailand, United Kingdom, United States
Participant flow
Pre-assignment details
197 participants were enrolled into the study; 23 participants were not treated (3 participants died, 13 participants no longer met study criteria, 3 participants switched into other studies, 2 participants had adverse events, 1 participant excluded for administrative reasons, and 1 participant withdrew consent).
Participants by arm
| Arm | Count |
|---|---|
| Imatinib-intolerant Defined as either: 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-tolerant. | 13 |
| Imatinib-resistant Defined as any of the following: i) initial diagnosis of chronic phase of chronic myeloid leukemia (CML) that progressed to accelerated phase while on treatment with imatinib ≥ 400 mg/day (primary or acquired resistance); ii) initial diagnosis of accelerated phase CML and failure to achieve a hematologic response after ≥ 4 weeks (or ≥ 2 weeks for subjects showing rapid disease progression) of imatinib ≥ 600 mg/day; the required prior imatinib dose was 400 to \< 600 mg/day if the subject was intolerant to ≥ 600 mg/day (primary resistance); iii) initial diagnosis of accelerated or blast phase CML that progressed to accelerated phase CML following an initial hematologic response to imatinib ≥ 600 mg/day (acquired resistance). The required prior imatinib dose was 400 to \< 600 mg/day if the subject was intolerant of ≥ 600 mg/day. | 161 |
| Total | 174 |
Baseline characteristics
| Characteristic | Imatinib-intolerant | Imatinib-resistant | Total |
|---|---|---|---|
| Age Continuous | 58.4 years STANDARD_DEVIATION 14.2 | 54.5 years STANDARD_DEVIATION 13.7 | 54.8 years STANDARD_DEVIATION 13.7 |
| Age, Customized 21 to 45 years | 2 participants | 41 participants | 43 participants |
| Age, Customized 46 to 65 years | 6 participants | 87 participants | 93 participants |
| Age, Customized 66 to 75 years | 4 participants | 25 participants | 29 participants |
| Age, Customized >75 years | 1 participants | 8 participants | 9 participants |
| Functional Assessment of Cancer Therapy-General (FACT-G) Emotional Well-Being | 17.7 units on a scale STANDARD_DEVIATION 4.8 | 16.7 units on a scale STANDARD_DEVIATION 4.9 | 16.8 units on a scale STANDARD_DEVIATION 4.9 |
| Functional Assessment of Cancer Therapy-General (FACT-G) Functional Well-Being | 19.2 units on a scale STANDARD_DEVIATION 6.9 | 16.9 units on a scale STANDARD_DEVIATION 6.7 | 17.1 units on a scale STANDARD_DEVIATION 6.8 |
| Functional Assessment of Cancer Therapy-General (FACT-G) Physical Well Being | 22.3 units on a scale STANDARD_DEVIATION 5.2 | 19.0 units on a scale STANDARD_DEVIATION 7.1 | 19.2 units on a scale STANDARD_DEVIATION 7 |
| Functional Assessment of Cancer Therapy-General (FACT-G) Social/Family Well-Being | 22.8 units on a scale STANDARD_DEVIATION 5.1 | 22.7 units on a scale STANDARD_DEVIATION 4.8 | 22.7 units on a scale STANDARD_DEVIATION 4.8 |
| Functional Assessment of Cancer Therapy-General (FACT-G) Total FACT-G | 81.9 units on a scale STANDARD_DEVIATION 14.4 | 75.3 units on a scale STANDARD_DEVIATION 18 | 75.8 units on a scale STANDARD_DEVIATION 17.8 |
| Performance Status - Eastern Cooperative Oncology Group Scale (ECOG) score=0 fully active | 6 units on a scale | 73 units on a scale | 79 units on a scale |
| Performance Status - Eastern Cooperative Oncology Group Scale (ECOG) score=1 physically strenuous activity restricted | 4 units on a scale | 67 units on a scale | 71 units on a scale |
| Performance Status - Eastern Cooperative Oncology Group Scale (ECOG) score=2 capable of all selfcare, unable to work | 3 units on a scale | 21 units on a scale | 24 units on a scale |
| Performance Status - Eastern Cooperative Oncology Group Scale (ECOG) score=3 limited selfcare, bed/chair confined >50% | 0 units on a scale | 0 units on a scale | 0 units on a scale |
| Performance Status - Eastern Cooperative Oncology Group Scale (ECOG) score=4 completely disabled, bed/chair confined | 0 units on a scale | 0 units on a scale | 0 units on a scale |
| Performance Status - Eastern Cooperative Oncology Group Scale (ECOG) score=5 dead | 0 units on a scale | 0 units on a scale | 0 units on a scale |
| Race/Ethnicity, Customized Asian | 1 participants | 23 participants | 24 participants |
| Race/Ethnicity, Customized Black or African American | 1 participants | 8 participants | 9 participants |
| Race/Ethnicity, Customized Other | 0 participants | 3 participants | 3 participants |
| Race/Ethnicity, Customized White | 11 participants | 127 participants | 138 participants |
| Sex: Female, Male Female | 9 Participants | 69 Participants | 78 Participants |
| Sex: Female, Male Male | 4 Participants | 92 Participants | 96 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 13 | 158 / 161 |
| serious Total, serious adverse events | 12 / 13 | 113 / 161 |
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). OHR=best confirmed response of MaHR or minor hematologic response (MiHR). Confirmed hematologic response=response confirmed ≥4 weeks after first documented event with no concomitant use of anagrelide or hydroxyurea. Maintaining a response=no 2 consecutive records of nonresponse at assessment. Criteria for CHR and NEL specified in Outcome Measure 2 and criteria for MiHR in Outcome Measure 4.
Time frame: Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during treatment; at end of treatment
Population: All treated subjects
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib-intolerant | Major and Overall Hematologic Response (MaHR and OHR) | MaHR | 9 participants |
| Imatinib-intolerant | Major and Overall Hematologic Response (MaHR and OHR) | OHR | 12 participants |
| Imatinib-resistant | Major and Overall Hematologic Response (MaHR and OHR) | MaHR | 103 participants |
| Imatinib-resistant | Major and Overall Hematologic Response (MaHR and OHR) | OHR | 127 participants |
| Total | Major and Overall Hematologic Response (MaHR and OHR) | MaHR | 112 participants |
| Total | Major and Overall Hematologic Response (MaHR and OHR) | OHR | 139 participants |
Secondary
Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation
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: Continuous from pretreatment through each 4-week cycle and at follow-up. (treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib-intolerant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Discontinuations due to Study Drug Toxicity | 2 Participants |
| Imatinib-intolerant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Any AE | 13 Participants |
| Imatinib-intolerant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Grade 3/4 AEs | 12 Participants |
| Imatinib-intolerant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Drug-Related AEs | 13 Participants |
| Imatinib-intolerant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Drug-Related Grade 3-4 AEs | 11 Participants |
| Imatinib-intolerant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Death within 30 days of last dose | 2 Participants |
| Imatinib-intolerant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | SAEs | 12 Participants |
| Imatinib-intolerant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Fluid-Retention AEs -Overall | 10 Participants |
| Imatinib-intolerant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Fluid-Retention AEs - Superficial Edema | 8 Participants |
| Imatinib-intolerant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Fluid-Retention AEs -Pleural Effusion | 4 Participants |
| Imatinib-intolerant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Fluid-Retention AEs - Other | 4 Participants |
| Imatinib-intolerant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Grade 3/4 Hematologic Toxicity - Anemia | 11 Participants |
| Imatinib-intolerant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Grade 3/4 Hematologic Toxicity - Thrombocytopenia | 10 Participants |
| Imatinib-intolerant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Grade 3/4 Hematologic Toxicity - Neutropenia | 13 Participants |
| Imatinib-intolerant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Grade 3/4 Hematologic Toxicity - Leukopenia | 11 Participants |
| Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Discontinuations due to Study Drug Toxicity | 19 Participants |
| Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Fluid-Retention AEs - Superficial Edema | 73 Participants |
| Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Any AE | 160 Participants |
| Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Grade 3/4 Hematologic Toxicity - Thrombocytopenia | 132 Participants |
| Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Grade 3/4 AEs | 116 Participants |
| Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Fluid-Retention AEs -Pleural Effusion | 60 Participants |
| Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Drug-Related AEs | 155 Participants |
| Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Grade 3/4 Hematologic Toxicity - Leukopenia | 91 Participants |
| Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Drug-Related Grade 3-4 AEs | 95 Participants |
| Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Fluid-Retention AEs - Other | 43 Participants |
| Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Death within 30 days of last dose | 15 Participants |
| Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Grade 3/4 Hematologic Toxicity - Neutropenia | 120 Participants |
| Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | SAEs | 113 Participants |
| Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Grade 3/4 Hematologic Toxicity - Anemia | 111 Participants |
| Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, Hematologic Toxicities, and Toxicities Leading to Discontinuation | Fluid-Retention AEs -Overall | 104 Participants |
Secondary
Best Confirmed Hematologic Response
Number of participants with confirmed complete hematologic response (CHR) or No Evidence of Leukemia (NEL), minor hematologic response (MiHR), or no 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 CHR and NEL are specified in Outcome Measure 2; criteria for MiHR are specified in Outcome Measure 4.
Time frame: Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during treatment; at end of treatment
Population: All treated subjects
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib-intolerant | Best Confirmed Hematologic Response | Complete HR (CHR) | 7 Participants |
| Imatinib-intolerant | Best Confirmed Hematologic Response | No Evidence of Leukemia (NEL) | 2 Participants |
| Imatinib-intolerant | Best Confirmed Hematologic Response | Minor HR (MiHR) | 3 Participants |
| Imatinib-intolerant | Best Confirmed Hematologic Response | No Response | 1 Participants |
| Imatinib-resistant | Best Confirmed Hematologic Response | No Response | 34 Participants |
| Imatinib-resistant | Best Confirmed Hematologic Response | Complete HR (CHR) | 80 Participants |
| Imatinib-resistant | Best Confirmed Hematologic Response | Minor HR (MiHR) | 24 Participants |
| Imatinib-resistant | Best Confirmed Hematologic Response | No Evidence of Leukemia (NEL) | 23 Participants |
| Total | Best Confirmed Hematologic Response | No Response | 35 Participants |
| Total | Best Confirmed Hematologic Response | No Evidence of Leukemia (NEL) | 25 Participants |
| Total | Best Confirmed Hematologic Response | Minor HR (MiHR) | 27 Participants |
| Total | Best Confirmed Hematologic Response | Complete HR (CHR) | 87 Participants |
Secondary
Best Cytogenetic Response
Number of participants with complete, partial, minor, minimal, or no cytogenetic response. Determination of cytogenetic response 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 | Best Cytogenetic Response | Complete (0% Ph+ metaphases) | 5 Participants |
| Imatinib-intolerant | Best Cytogenetic Response | Partial (>0% to 35% Ph+ metaphases) | 0 Participants |
| Imatinib-intolerant | Best Cytogenetic Response | Minor (>35% to 65% Ph+ metaphases) | 0 Participants |
| Imatinib-intolerant | Best Cytogenetic Response | Minimal (>65% to 95% Ph+ metaphases) | 3 Participants |
| Imatinib-intolerant | Best Cytogenetic Response | No Response (>95% to 100% Ph+ metaphases) | 4 Participants |
| Imatinib-intolerant | Best Cytogenetic Response | Unable to determine | 1 Participants |
| Imatinib-resistant | Best Cytogenetic Response | Unable to determine | 14 Participants |
| Imatinib-resistant | Best Cytogenetic Response | Complete (0% Ph+ metaphases) | 53 Participants |
| Imatinib-resistant | Best Cytogenetic Response | Minimal (>65% to 95% Ph+ metaphases) | 37 Participants |
| Imatinib-resistant | Best Cytogenetic Response | No Response (>95% to 100% Ph+ metaphases) | 37 Participants |
| Imatinib-resistant | Best Cytogenetic Response | Partial (>0% to 35% Ph+ metaphases) | 12 Participants |
| Imatinib-resistant | Best Cytogenetic Response | Minor (>35% to 65% Ph+ metaphases) | 8 Participants |
| Total | Best Cytogenetic Response | Partial (>0% to 35% Ph+ metaphases) | 12 Participants |
| Total | Best Cytogenetic Response | Minor (>35% to 65% Ph+ metaphases) | 8 Participants |
| Total | Best Cytogenetic Response | Unable to determine | 15 Participants |
| Total | Best Cytogenetic Response | Minimal (>65% to 95% Ph+ metaphases) | 40 Participants |
| Total | Best Cytogenetic Response | Complete (0% Ph+ metaphases) | 58 Participants |
| Total | Best Cytogenetic Response | No Response (>95% to 100% Ph+ metaphases) | 41 Participants |
Secondary
MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations
Major hematologic and cytogenetic responses (MaHR and MCyR) to dasatinib in subjects with mutations at baseline, including imatinib-resistant mutations (IRM) and specific BCR-ABL mutations (SBAM). BCR-ABL=the fused gene found in subjects with this type of CML. Criteria for MaHR are specified in Outcome Measure 2. MCyR=combined complete cytogenetic and partial cytogenetic response rate. Complete Cytogenetic Response= 0% Ph+ Cells in Metaphase in Bone Marrow, Partial Cytogenetic Response \> 0% to 35% Ph+ Cells in Metaphase in Bone Marrow.
Time frame: Baseline, at time of disease progression. (treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria).
Population: All subjects with baseline mutation data; n=the number of participants with the specified mutation. Baseline mutation data were reported for 162 of the 174 subjects (12/13 imatinib-intolerant and 150/161 imatinib-resistant). At baseline, 89 (59%) imatinib-resistant subjects and 1 imatinib-intolerant subject expressed imatinib resistant mutations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | Participants with IRM (n=90) | 73 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | with ≥1 IRM in P-loop (n=35) | 69 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | with ≥1 IRM in activation loop (n=15) | 73 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | with ≥1 IRM in P-loop & activation loop (n=3) | 33 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | with ≥1 IRM in other location only (n=43) | 74 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | w/ ≥1 IRM w/2-4-fold increase in IR (n=15) | 87 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | w/ ≥1 IMR w/≥5-fold increase in IR (n=60) | 67 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [M244V] at baseline (n=7) | 86 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [L248V] at baseline (n=3) | 100 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [G250E] at baseline (n=10) | 60 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [Y253F/H] at baseline (n=11) | 82 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [E255K/V] at baseline (n=11) | 64 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [T315I] at baseline (n=9) | 0 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [F317L] at baseline (n=4) | 100 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [M351T/V] at baseline (n=13) | 85 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [E355G] at baseline (n=4) | 50 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [F359C/I/V] at baseline (n=12) | 83 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [V379I] at baseline (n=6) | 67 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [H396R] at baseline (n=6) | 67 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [S417Y] at baseline (n=3) | 33 Percentage of participants |
| Imatinib-intolerant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [E459K] at baseline (n=3) | 33 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [Y253F/H] at baseline (n=11) | 45 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | Participants with IRM (n=90) | 40 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [H396R] at baseline (n=6) | 33 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | with ≥1 IRM in P-loop (n=35) | 31 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [E255K/V] at baseline (n=11) | 18 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | with ≥1 IRM in activation loop (n=15) | 53 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [F359C/I/V] at baseline (n=12) | 42 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | with ≥1 IRM in P-loop & activation loop (n=3) | 67 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [T315I] at baseline (n=9) | 0 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | with ≥1 IRM in other location only (n=43) | 44 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [E459K] at baseline (n=3) | 100 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | w/ ≥1 IRM w/2-4-fold increase in IR (n=15) | 33 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [F317L] at baseline (n=4) | 0 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | w/ ≥1 IMR w/≥5-fold increase in IR (n=60) | 35 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [V379I] at baseline (n=6) | 67 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [M244V] at baseline (n=7) | 71 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [M351T/V] at baseline (n=13) | 38 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [L248V] at baseline (n=3) | 67 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [S417Y] at baseline (n=3) | 0 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [G250E] at baseline (n=10) | 20 Percentage of participants |
| Imatinib-resistant | MaHR and MCyR Among Participants With Baseline BCR-ABL Point Mutations | SBAM [E355G] at baseline (n=4) | 50 Percentage of participants |
Secondary
Median Time in Days From First Dosing Date to Date of MaHR
MaHR=best 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: 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 treatment; at end of treatment
Population: Population is comprised of responders only
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib-intolerant | Median Time in Days From First Dosing Date to Date of MaHR | 84 Days |
| Imatinib-resistant | Median Time in Days From First Dosing Date to Date of MaHR | 63 Days |
| Total | Median Time in Days From First Dosing Date to Date of MaHR | 65 Days |
Secondary
Minimal Clinically Significant Change 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, and functional well-being (PWB, SWB, EWB, FWB). Total score=0 to 108; higher score=better health-related quality of life. Total Score change of 7 or more=minimal clinical important change; PWB, EWB, and FWB score change of 3 or more, and SWB score change of 2 or more=minimal clinically important change.
Time frame: Baseline, every 2 weeks for the first 3 cycles, following every 4-week cycle, and once at follow-up.(treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria).
Population: Number of participants with FACT-G assessments at baseline and at least one assessment during treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib-intolerant | Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Emotional Well-Being | 7 Participants |
| Imatinib-intolerant | Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Social/Family Well-Being | 6 Participants |
| Imatinib-intolerant | Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Total FACT-G | 5 Participants |
| Imatinib-intolerant | Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Physical Well-Being | 4 Participants |
| Imatinib-intolerant | Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Functional Well-Being | 4 Participants |
| Imatinib-resistant | Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Social/Family Well-Being | 50 Participants |
| Imatinib-resistant | Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Total FACT-G | 76 Participants |
| Imatinib-resistant | Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Physical Well-Being | 85 Participants |
| Imatinib-resistant | Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Emotional Well-Being | 77 Participants |
| Imatinib-resistant | Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Functional Well-Being | 63 Participants |
| Total | Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Functional Well-Being | 67 Participants |
| Total | Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Emotional Well-Being | 84 Participants |
| Total | Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Total FACT-G | 81 Participants |
| Total | Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Social/Family Well-Being | 56 Participants |
| Total | Minimal Clinically Significant Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) | Physical Well-Being | 89 Participants |
Secondary
Number of Participants Who Achieved a Major Molecular Response (MMR) During Treatment Period
Number of participants who achieved an MMR at any time during the treatment period. MMR was calculated 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 throughout study (treatment continued until discontinuation due to toxicity, disease progression, or other protocol-specified criteria).
Population: Number of Participants Analyzed=all treated subjects who were assessed for major molecular response; n=participants with or without CCyR in cohort.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib-intolerant | Number of Participants Who Achieved a Major Molecular Response (MMR) During Treatment Period | MMR in Assessed Participants w/CCyR(n=2;n=39;n=41) | 2 participants |
| Imatinib-intolerant | Number of Participants Who Achieved a Major Molecular Response (MMR) During Treatment Period | MMR in Assessed Subjects w/o CCyR(n=2;n=51;n=53) | 0 participants |
| Imatinib-resistant | Number of Participants Who Achieved a Major Molecular Response (MMR) During Treatment Period | MMR in Assessed Participants w/CCyR(n=2;n=39;n=41) | 17 participants |
| Imatinib-resistant | Number of Participants Who Achieved a Major Molecular Response (MMR) During Treatment Period | MMR in Assessed Subjects w/o CCyR(n=2;n=51;n=53) | 11 participants |
| Total | Number of Participants Who Achieved a Major Molecular Response (MMR) During Treatment Period | MMR in Assessed Participants w/CCyR(n=2;n=39;n=41) | 19 participants |
| Total | Number of Participants Who Achieved a Major Molecular Response (MMR) During Treatment Period | MMR in Assessed Subjects w/o CCyR(n=2;n=51;n=53) | 1 participants |
Secondary
Percentage of Participants Who Achieved MaHR and Did Not Progress at 12 Months (Based on the Kaplan-Meier Estimate of the Duration of Response)
MaHR=best 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: ANC ≥500/mm3 & \<1000/mm3; platelets ≥20,000/mm3 & \<100,000/mm3.
Time frame: 12 months
Population: Population comprised of responders only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib-intolerant | Percentage of Participants Who Achieved MaHR and Did Not Progress at 12 Months (Based on the Kaplan-Meier Estimate of the Duration of Response) | 85.7 percentage of responders |
| Imatinib-resistant | Percentage of Participants Who Achieved MaHR and Did Not Progress at 12 Months (Based on the Kaplan-Meier Estimate of the Duration of Response) | 78.3 percentage of responders |
| Total | Percentage of Participants Who Achieved MaHR and Did Not Progress at 12 Months (Based on the Kaplan-Meier Estimate of the Duration of Response) | 79.0 percentage of responders |
Secondary
Percentage of Participants Who Achieved MaHR and Did Not Progress at 24 Months in the Imatinib-Resistant Group (Based on the Kaplan-Meier Estimate of the Duration of Response)
Percentage of participants in the Imatinib-Resistant Group who achieved MaHR and did not progress at Month 24, based on the Kaplan-Meier estimate of the duration of response. MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). Criteria for MaHR and NEL are specified in Outcome Measure 2.
Time frame: 24 months
Population: Population comprised of responders only. NOTE: Projected duration of MaHR at 24 months in the Imatinib-Intolerant group was beyond the maximum observed time for this cohort, and therefore only the Imatinib-Resistant group is presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib-intolerant | Percentage of Participants Who Achieved MaHR and Did Not Progress at 24 Months in the Imatinib-Resistant Group (Based on the Kaplan-Meier Estimate of the Duration of Response) | 60.9 percentage of responders |
| Imatinib-resistant | Percentage of Participants Who Achieved MaHR and Did Not Progress at 24 Months in the Imatinib-Resistant Group (Based on the Kaplan-Meier Estimate of the Duration of Response) | 59.6 percentage of responders |
Secondary
Percentage of Participants Who Achieved OHR and Did Not Progress at 12 Months and 24 Months
Percentage of participants who achieved OHR and did not progress at specified timepoints, based on the Kaplan-Meier estimate of the duration of response. OHR=best confirmed response of MaHR or MiHR. MaHR criteria in Outcome Measure 2. 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= confirmed ≥4 weeks after 1st documented event with no concomitant use of anagrelide or hydroxyurea.
Time frame: 12 months, 24 months
Population: Population is comprised of responders only
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib-intolerant | Percentage of Participants Who Achieved OHR and Did Not Progress at 12 Months and 24 Months | OHR at 12 months | 69.8 Percentage of responders |
| Imatinib-intolerant | Percentage of Participants Who Achieved OHR and Did Not Progress at 12 Months and 24 Months | OHR at 24 months | 34.9 Percentage of responders |
| Imatinib-resistant | Percentage of Participants Who Achieved OHR and Did Not Progress at 12 Months and 24 Months | OHR at 12 months | 69.7 Percentage of responders |
| Imatinib-resistant | Percentage of Participants Who Achieved OHR and Did Not Progress at 12 Months and 24 Months | OHR at 24 months | 51.2 Percentage of responders |
| Total | Percentage of Participants Who Achieved OHR and Did Not Progress at 12 Months and 24 Months | OHR at 12 months | 69.8 Percentage of responders |
| Total | Percentage of Participants Who Achieved OHR and Did Not Progress at 12 Months and 24 Months | OHR at 24 months | 50.0 Percentage of responders |
Secondary
Pharmacokinetics (PK) of Dasatinib and Its 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 Hours (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: 29 participants had dense PK sampling on Day 1 and Day 8; parameters for 2 participants on Day 8 were 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 | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Imatinib-intolerant | Pharmacokinetics (PK) of Dasatinib and Its 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 Hours (AUC[0-T]) | Dasatinib (n=29; n=27) | 207.76 ng∙h/mL | Standard Deviation 126.05 |
| Imatinib-intolerant | Pharmacokinetics (PK) of Dasatinib and Its 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 Hours (AUC[0-T]) | BMS-582691 (n=24; n=24) | 9.51 ng∙h/mL | Standard Deviation 8.11 |
| Imatinib-resistant | Pharmacokinetics (PK) of Dasatinib and Its 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 Hours (AUC[0-T]) | Dasatinib (n=29; n=27) | 265.02 ng∙h/mL | Standard Deviation 184.73 |
| Imatinib-resistant | Pharmacokinetics (PK) of Dasatinib and Its 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 Hours (AUC[0-T]) | BMS-582691 (n=24; n=24) | 18.67 ng∙h/mL | Standard Deviation 15.58 |
Secondary
Pharmacokinetics (PK) of Dasatinib and Its 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: 29 participants had dense PK sampling on Day 1 and Day 8; parameters for 2 participants on Day 8 were 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 | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Imatinib-intolerant | Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Maximum Observed Plasma Concentration (Cmax) | Dasatinib (n=29; n=27) | 69.31 ng/mL | Standard Deviation 43.08 |
| Imatinib-intolerant | Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Maximum Observed Plasma Concentration (Cmax) | BMS-582691 (n=24; n=24) | 2.81 ng/mL | Standard Deviation 1.53 |
| Imatinib-resistant | Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Maximum Observed Plasma Concentration (Cmax) | Dasatinib (n=29; n=27) | 89.18 ng/mL | Standard Deviation 68.38 |
| Imatinib-resistant | Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Maximum Observed Plasma Concentration (Cmax) | BMS-582691 (n=24; n=24) | 4.52 ng/mL | Standard Deviation 3.04 |
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: 29 participants had dense PK sampling on Day 1 and Day 8; parameters for 2 participants on Day 8 were 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 | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Imatinib-intolerant | Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Plasma Half-life (T-HALF) | Dasatinib (n=28; n=26) | 3.15 hours | Standard Deviation 0.86 |
| Imatinib-intolerant | Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Plasma Half-life (T-HALF) | BMS-582691 (n=22; n=20) | 3.30 hours | Standard Deviation 1.94 |
| Imatinib-resistant | Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Plasma Half-life (T-HALF) | Dasatinib (n=28; n=26) | 5.18 hours | Standard Deviation 2.12 |
| Imatinib-resistant | Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Plasma Half-life (T-HALF) | BMS-582691 (n=22; n=20) | 5.70 hours | Standard Deviation 4.89 |
Secondary
Pharmacokinetics (PK) of Dasatinib and Its 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: A total of 29 participants had dense PK sampling on both Day 1 and Day 8; parameters for 2 participants on Day 8 were excluded due to unreliable concentration-time profiles. n=the number of participants on Day 1 and Day 8 who were included in the statistical analyses of PK parameters.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Imatinib-intolerant | Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Time to Maximum Observed Plasma Concentration (Tmax) | Dasatinib (n=29; n=27) | 1.26 hours | Standard Deviation 0.98 |
| Imatinib-intolerant | Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Time to Maximum Observed Plasma Concentration (Tmax) | BMS-582691 (n=24; n=24) | 1.86 hours | Standard Deviation 0.88 |
| Imatinib-resistant | Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Time to Maximum Observed Plasma Concentration (Tmax) | Dasatinib (n=29; n=27) | 1.13 hours | Standard Deviation 0.93 |
| Imatinib-resistant | Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Time to Maximum Observed Plasma Concentration (Tmax) | BMS-582691 (n=24; n=24) | 1.75 hours | Standard Deviation 1.12 |
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 OHR
Median time (in months) from first dosing date to date of OHR. OHR=best confirmed response of MaHR or MiHR. Criteria for MaHR specified in Outcome Measure 2. 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 1st 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 treatment; at end of treatment
Population: Population comprised of responders only
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib-intolerant | Time to OHR | 34 days |
| Imatinib-resistant | Time to OHR | 30 days |
| Total | Time to OHR | 30 days |