Myeloid Leukemia, Chronic
Conditions
Keywords
Imatinib resistant or intolerant chronic phase CML
Brief summary
The objective is to evaluate the cytogenetic response to Dasatinib (BMS-354825) administered for 24 weeks in subjects with Imatinib resistant or intolerant chronic phase chronic myeloid leukemia (CML) once daily (QD) or twice daily. (BID)
Interventions
DRUGDasatinib
tablets, Oral, 100 mg, once daily
DRUGdasatinib
tablets, Oral, 50 mg, twice daily
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Philadelphia chromosome positive or bcr-abl gene positive Chronic phase Chronic Myelogenous Leukemia (CML) subjects must have primary or acquired resistance to Imatinib mesylate or have intolerance of imatinib mesylate * Performance status (general conditions) specified by the Eastern Cooperative Oncology Group: 0-2 * Men and women, ages 20 to 75 * Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 3 months after the study in such a manner that the risk of pregnancy is minimized
Exclusion criteria
* Subjects who are eligible and willing to undergo transplantation at pre-study * Women who are pregnant or breastfeeding * Uncontrolled or significant cardiovascular disease * History of significant bleeding disorder unrelated to CML * Adequate hepatic function * Adequate renal function * Medication that increases bleeding risk * Medication that changes heart rhythms * Subjects who are compulsory detained for legal reasons or 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 |
|---|---|---|
| Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | Week 24 | Cytogenetic responses (CyR) are based on the percentage of Philadelphia-positive (Ph+) metaphases among at least 20 metaphase cells in each bone marrow (BM) sample. The criteria for cytogenetic responses are as follows. Best CyR is defined as the best response obtained at any time during the study. Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR; 0 Ph+ Cells in Metaphase in BM), and Partial Cytogenetic Response (PCyR; 1 - 35 Ph+ Cells in Metaphase in BM). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to CHR | time from first dose of Dasatinib (BMS-354825) until the first day CHR criteria are met | Time to CHR = time from first dose of Dasatinib until the first day CHR criteria are met (provided subjects achieved a cCHR). CHR=all of the following criteria: white blood cell count ≤ upper limit of normal; platelets \<450,000/mm³; no blasts or promyelocytes in peripheral blood; \<5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils \<20%; no extramedullary involvement. A confirmed CHR (cCHR) is obtained when all above criteria are maintained for at least 28 days after they are first met. All hematologic responses can begin only 14 days after the dosing start date. |
| Mutational Spectrum of BCR-ABL | Baseline and at the end of long term extension period (The enrollment period was followed by an extension period until the launch of dasatinib in Japan, January 2009.) | Number of participants with a particular BCR-ABL mutation at Baseline and End-of-Study. |
| Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at End of Study | Baseline and at the end of long term extension period (The enrollment period was followed by an extension period until the launch of dasatinib in Japan, January 2009.) | Cytogenetic response (CyR) as reflected in the major cytogenetic response was determined by bone marrow (BM) aspirates and are based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each BM sample. Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR; 0 Ph+ Cells in Metaphase in BM), or Partial Cytogenetic Response (PCyR; 1 - 35 Ph+ Cells in Metaphase in BM). |
| Hematologic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at End of Study | Baseline and at the end of long term extension period (The enrollment period was followed by an extension period until the launch of dasatinib in Japan, January 2009.) | CHR=all of the following criteria: white blood cell count ≤ institutional upper limit of normal; platelets \< 450,000/mm³; no blasts or promyelocytes in peripheral blood; \< 5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils \< 20%; no extramedullary involvement. A confirmed CHR (cCHR) is obtained when all above criteria are maintained for at least 28 days after they are first met. All hematologic responses can begin only 14 days after the dosing start date. |
| Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations, and Deaths During Treatment | Throughout study period to last observation. Dosing period=6 months; if beneficial, medication may continue in the extension period (ending in January 2009). Last observation=30 days past last dosing day or the discontinuation day. | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. Related AE=relationship of certain, probable, possible, or missing. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in the development of drug dependency or drug abuse, is an important medical event. |
| Complete Hematologic Response (CHR) in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | Week 24 | CHR=all of the following criteria: white blood cell count ≤ institutional upper limit of normal; platelets \< 450,000/mm³; no blasts or promyelocytes in peripheral blood; \< 5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils \< 20%; no extramedullary involvement. A confirmed CHR (cCHR) is obtained when all above criteria are maintained for at least 28 days after they are first met. All hematologic responses can begin only 14 days after the dosing start date. |
| Time to Major Cytogenetic Response (MCyR) | time from first dose of Dasatinib (BMS-354825) until the first day criteria for CCyR or PCyR, whichever occurs first, are first met | Time to MCyR is defined as the time from first dose of Dasatinib (BMS-354825) until the first day criteria for CCyR or PCyR, whichever occurs first, are first met. MCyR = a complete and a partial cytogenetic response (CyR), based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow sample. Percentage of Ph+ Cells in Metaphase in bone marrow: Complete Cytogenetic Response (CCyR) = 0; Partial Cytogenetic Response (PCyR) 1 - 35 |
| Pharmacokinetics of Dasatinib (BMS-354825) as Characterized by Population Pharmacokinetics | Six or more peripheral blood samples were collected at any visit after Day 7, pre-dose and 5 - 8 hours after dose administration. | Blood sample collection for pharmacokinetic (PK) analysis that will contribute to PK modeling. |
| Duration of MCyR | from the first day all criteria are met for CCyR or PCyR until the date of progressed disease (PD) or death | The duration of MCyR will be measured from the first day all criteria are met for CCyR or PCyR until the date of progressed disease (PD) or death. Subjects who neither progress nor die will be censored on the date of their last cytogenetic assessment.MCyR = a complete and a partial cytogenetic response (CyR), based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow sample. Percentage of Philadelphia-positive (Ph+) Cells in Metaphase in bone marrow: Complete Cytogenetic Response (CCyR) = 0; Partial Cytogenetic Response (PCyR) 1 - 35 |
| Duration of CHR | measured from the first day all criteria were first met for CHR (provided subjects achieved a cCHR), until the date PD is first reported or until death | The duration of CHR were measured from the first day all criteria were first met for CHR (provided subjects achieved a cCHR), until the date PD is first reported or until death. Subjects who neither progress nor die were censored on the date of their last hematologic assessment. |
| Progression-Free Survival (PFS) | time from first dose of Dasatinib (BMS-354825) until the first day criteria for CCyR or PCyR, whichever occurs first, are first met | Progressed disease=achieving a CHR & subsequently no longer meeting criteria consistently over a consecutive 2-week period after starting maximum dose; no CHR after receiving maximum dose & increase in white blood cell count (doubling of count from lowest value to \>20,000/mm3 or an increase by \>50,000/mm3 on 2 assessments done ≥2 weeks apart); meeting the criteria of accelerated or blastic phase chronic myeloid leukemia at any time; having an MCyR & subsequently no longer meeting the criteria for MCyR after starting maximum dose; or having a \>=30% absolute increase in number of Ph+ metaphases. |
| Expression of BCR-ABL Gene Mutations of RNA (mRNA) | Baseline and at the end of long term extension period (The enrollment period was followed by an extension period until the launch of dasatinib in Japan, January 2009.) | Number of participants with positive (\>= 2.0 log copies/mg) and negative (\<2.0 log copies/mg) expression of mRNA at Baseline and at end of study. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table) | Months 0, 4, 8, 12, 16, 20, 24 | Progressed disease=achieving a CHR and subsequently no longer meeting criteria consistently over a consecutive 2-week period after starting maximum dose; no CHR after receiving maximum dose and an increase in white blood cell count (doubling of the count from lowest value to \>20,000/mm3 or an increase by \>50,000/mm3 on 2 assessments done at least 2 weeks apart); meeting the criteria of accelerated or blastic phase CML at any time; having an MCyR and subsequently no longer meeting the criteria for MCyR after starting maximum dose; or having a \>=30% absolute increase in number of Ph+ metaphases. |
| Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table) | Months 0, 4, 8, 12, 16, 20, 24 | CHR=all of the following criteria: white blood cell count ≤ institutional upper limit of normal; platelets \< 450,000/mm³; no blasts or promyelocytes in peripheral blood; \< 5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils \< 20%; no extramedullary involvement. A confirmed CHR (cCHR) is obtained when all above criteria are maintained for at least 28 days after they are first met. All hematologic responses can begin only 14 days after the dosing start date. |
| Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table) | Months 0, 4, 8, 12, 16, 20, 24 | MCyR = a complete and a partial cytogenetic response (CyR), based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow sample. Percentage of Ph+ Cells in Metaphase in BM: Complete Cytogenetic Response (CCyR) = 0; Partial Cytogenetic Response (PCyR) 1 - 35 |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dasatinib 100 mg Once-daily (QD) Starting Dose Starting dose of 100 mg QD oral continuous daily dosing of Dasatinib (BMS-354825) for 24 weeks. One dose escalation allowed for nonresponding participants; dose reduction mandated according to the observed toxicity. | 11 |
| Dasatinib 50 mg Twice-daily (BID) Starting Dose Starting dose of 50 mg BID oral continuous daily dosing of Dasatinib (BMS-354825) for 24 weeks. One dose escalation allowed for nonresponding participants; dose reduction mandated according to the observed toxicity. | 12 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Poor compliance | 1 | 0 |
Baseline characteristics
| Characteristic | Dasatinib 100 mg Once-daily (QD) Starting Dose | Dasatinib 50 mg Twice-daily (BID) Starting Dose | Total |
|---|---|---|---|
| Age Continuous | 48.5 years STANDARD_DEVIATION 14.2 | 49.9 years STANDARD_DEVIATION 16 | 49.3 years STANDARD_DEVIATION 14.8 |
| Age, Customized <65 years | 9 participants | 10 participants | 19 participants |
| Age, Customized >=65 years | 2 participants | 2 participants | 4 participants |
| Eastern Cooperative Oncology Group Performace Status (ECOG-PS) Status=0 | 11 participants | 12 participants | 23 participants |
| Eastern Cooperative Oncology Group Performace Status (ECOG-PS) Status=1 | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group Performace Status (ECOG-PS) Status=2 | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group Performace Status (ECOG-PS) Status=3 | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group Performace Status (ECOG-PS) Status=4 | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group Performace Status (ECOG-PS) Status=5 | 0 participants | 0 participants | 0 participants |
| Imatinib Status Imatinib-intolerant | 4 participants | 5 participants | 9 participants |
| Imatinib Status Imatinib-resistant | 7 participants | 7 participants | 14 participants |
| Region of Enrollment Japan | 11 participants | 12 participants | 23 participants |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 11 | 12 / 12 | 23 / 23 |
| serious Total, serious adverse events | 4 / 11 | 6 / 12 | 10 / 23 |
Outcome results
Primary
Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24
Cytogenetic responses (CyR) are based on the percentage of Philadelphia-positive (Ph+) metaphases among at least 20 metaphase cells in each bone marrow (BM) sample. The criteria for cytogenetic responses are as follows. Best CyR is defined as the best response obtained at any time during the study. Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR; 0 Ph+ Cells in Metaphase in BM), and Partial Cytogenetic Response (PCyR; 1 - 35 Ph+ Cells in Metaphase in BM).
Time frame: Week 24
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 100 mg QD Starting Dose Cohort | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | MCyR | 45 percentage of participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | CCyR | 27 percentage of participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | MCyR | 29 percentage of participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | CCyR | 14 percentage of participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-intolerant | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | MCyR | 75 percentage of participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-intolerant | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | CCyR | 50 percentage of participants |
| Dasatinib 50 mg BID Starting Dose Cohort | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | MCyR | 92 percentage of participants |
| Dasatinib 50 mg BID Starting Dose Cohort | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | CCyR | 58 percentage of participants |
| Dasatinib 50 mg BID Starting Dose - Imatinib-resistant | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | MCyR | 86 percentage of participants |
| Dasatinib 50 mg BID Starting Dose - Imatinib-resistant | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | CCyR | 43 percentage of participants |
| Dasatinib 50 mg BID Starting Dose - Imatinib-intolerant | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | MCyR | 100 percentage of participants |
| Dasatinib 50 mg BID Starting Dose - Imatinib-intolerant | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | CCyR | 80 percentage of participants |
Secondary
Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations, and Deaths During Treatment
AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. Related AE=relationship of certain, probable, possible, or missing. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in the development of drug dependency or drug abuse, is an important medical event.
Time frame: Throughout study period to last observation. Dosing period=6 months; if beneficial, medication may continue in the extension period (ending in January 2009). Last observation=30 days past last dosing day or the discontinuation day.
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 100 mg QD Starting Dose Cohort | Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations, and Deaths During Treatment | AEs (symptoms/signs and laboratory abnormalities) | 11 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations, and Deaths During Treatment | SAEs (symptoms/signs and laboratory abnormalities) | 4 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations, and Deaths During Treatment | Deaths | 0 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations, and Deaths During Treatment | AEs that led to discontinuation | 0 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations, and Deaths During Treatment | AEs that led to discontinuation | 0 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations, and Deaths During Treatment | AEs (symptoms/signs and laboratory abnormalities) | 12 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations, and Deaths During Treatment | Deaths | 0 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations, and Deaths During Treatment | SAEs (symptoms/signs and laboratory abnormalities) | 6 participants |
Secondary
Complete Hematologic Response (CHR) in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24
CHR=all of the following criteria: white blood cell count ≤ institutional upper limit of normal; platelets \< 450,000/mm³; no blasts or promyelocytes in peripheral blood; \< 5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils \< 20%; no extramedullary involvement. A confirmed CHR (cCHR) is obtained when all above criteria are maintained for at least 28 days after they are first met. All hematologic responses can begin only 14 days after the dosing start date.
Time frame: Week 24
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib 100 mg QD Starting Dose Cohort | Complete Hematologic Response (CHR) in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | 91 percentage of participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Complete Hematologic Response (CHR) in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | 86 percentage of participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-intolerant | Complete Hematologic Response (CHR) in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | 100 percentage of participants |
| Dasatinib 50 mg BID Starting Dose Cohort | Complete Hematologic Response (CHR) in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | 83 percentage of participants |
| Dasatinib 50 mg BID Starting Dose - Imatinib-resistant | Complete Hematologic Response (CHR) in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | 86 percentage of participants |
| Dasatinib 50 mg BID Starting Dose - Imatinib-intolerant | Complete Hematologic Response (CHR) in Imatinib-Intolerant and Imatinib-Resistant Participants at Week 24 | 80 percentage of participants |
Secondary
Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at End of Study
Cytogenetic response (CyR) as reflected in the major cytogenetic response was determined by bone marrow (BM) aspirates and are based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each BM sample. Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR; 0 Ph+ Cells in Metaphase in BM), or Partial Cytogenetic Response (PCyR; 1 - 35 Ph+ Cells in Metaphase in BM).
Time frame: Baseline and at the end of long term extension period (The enrollment period was followed by an extension period until the launch of dasatinib in Japan, January 2009.)
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 100 mg QD Starting Dose Cohort | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at End of Study | MCyR | 55 percentage of participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at End of Study | CCyR | 36 percentage of participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at End of Study | MCyR | 92 percentage of participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Cytogenetic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at End of Study | CCyR | 67 percentage of participants |
Secondary
Duration of CHR
The duration of CHR were measured from the first day all criteria were first met for CHR (provided subjects achieved a cCHR), until the date PD is first reported or until death. Subjects who neither progress nor die were censored on the date of their last hematologic assessment.
Time frame: measured from the first day all criteria were first met for CHR (provided subjects achieved a cCHR), until the date PD is first reported or until death
Population: Median duration of CHR was not reach at the time of this report. See corresponding life table presented in Outcome Measure 15.
Secondary
Duration of MCyR
The duration of MCyR will be measured from the first day all criteria are met for CCyR or PCyR until the date of progressed disease (PD) or death. Subjects who neither progress nor die will be censored on the date of their last cytogenetic assessment.MCyR = a complete and a partial cytogenetic response (CyR), based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow sample. Percentage of Philadelphia-positive (Ph+) Cells in Metaphase in bone marrow: Complete Cytogenetic Response (CCyR) = 0; Partial Cytogenetic Response (PCyR) 1 - 35
Time frame: from the first day all criteria are met for CCyR or PCyR until the date of progressed disease (PD) or death
Population: Median duration was not reached at the time of this report; see Outcome Measure 14 for corresponding life table.
Secondary
Expression of BCR-ABL Gene Mutations of RNA (mRNA)
Number of participants with positive (\>= 2.0 log copies/mg) and negative (\<2.0 log copies/mg) expression of mRNA at Baseline and at end of study.
Time frame: Baseline and at the end of long term extension period (The enrollment period was followed by an extension period until the launch of dasatinib in Japan, January 2009.)
Population: Treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 100 mg QD Starting Dose Cohort | Expression of BCR-ABL Gene Mutations of RNA (mRNA) | Positive at Baseline | 11 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Expression of BCR-ABL Gene Mutations of RNA (mRNA) | Negative at Baseline | 0 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Expression of BCR-ABL Gene Mutations of RNA (mRNA) | Positive at End-of-Study | 8 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Expression of BCR-ABL Gene Mutations of RNA (mRNA) | Negative at End-of-Study | 3 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Expression of BCR-ABL Gene Mutations of RNA (mRNA) | Negative at End-of-Study | 9 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Expression of BCR-ABL Gene Mutations of RNA (mRNA) | Positive at Baseline | 11 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Expression of BCR-ABL Gene Mutations of RNA (mRNA) | Positive at End-of-Study | 3 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Expression of BCR-ABL Gene Mutations of RNA (mRNA) | Negative at Baseline | 1 participants |
Secondary
Hematologic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at End of Study
CHR=all of the following criteria: white blood cell count ≤ institutional upper limit of normal; platelets \< 450,000/mm³; no blasts or promyelocytes in peripheral blood; \< 5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils \< 20%; no extramedullary involvement. A confirmed CHR (cCHR) is obtained when all above criteria are maintained for at least 28 days after they are first met. All hematologic responses can begin only 14 days after the dosing start date.
Time frame: Baseline and at the end of long term extension period (The enrollment period was followed by an extension period until the launch of dasatinib in Japan, January 2009.)
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib 100 mg QD Starting Dose Cohort | Hematologic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at End of Study | 91 percentage of participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Hematologic Response in Imatinib-Intolerant and Imatinib-Resistant Participants at End of Study | 83 percentage of participants |
Secondary
Mutational Spectrum of BCR-ABL
Number of participants with a particular BCR-ABL mutation at Baseline and End-of-Study.
Time frame: Baseline and at the end of long term extension period (The enrollment period was followed by an extension period until the launch of dasatinib in Japan, January 2009.)
Population: Treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 100 mg QD Starting Dose Cohort | Mutational Spectrum of BCR-ABL | T315I mutation at End-of-Study | 0 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Mutational Spectrum of BCR-ABL | F317L mutation at Baseline | 0 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Mutational Spectrum of BCR-ABL | F317L mutation at End-of-Study | 1 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Mutational Spectrum of BCR-ABL | G250E mutation at Baseline | 1 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Mutational Spectrum of BCR-ABL | T315I mutation at Baseline | 0 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Mutational Spectrum of BCR-ABL | G250E mutation at End-of-Study | 1 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Mutational Spectrum of BCR-ABL | T315I mutation at Baseline | 1 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Mutational Spectrum of BCR-ABL | G250E mutation at End-of-Study | 0 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Mutational Spectrum of BCR-ABL | G250E mutation at Baseline | 3 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Mutational Spectrum of BCR-ABL | F317L mutation at Baseline | 0 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Mutational Spectrum of BCR-ABL | F317L mutation at End-of-Study | 0 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Mutational Spectrum of BCR-ABL | T315I mutation at End-of-Study | 1 participants |
Secondary
Pharmacokinetics of Dasatinib (BMS-354825) as Characterized by Population Pharmacokinetics
Blood sample collection for pharmacokinetic (PK) analysis that will contribute to PK modeling.
Time frame: Six or more peripheral blood samples were collected at any visit after Day 7, pre-dose and 5 - 8 hours after dose administration.
Population: Blood samples were collected for PK to be included in separate population PK analyses. No study specific PK analyses were planned for this report.
Secondary
Progression-Free Survival (PFS)
Progressed disease=achieving a CHR & subsequently no longer meeting criteria consistently over a consecutive 2-week period after starting maximum dose; no CHR after receiving maximum dose & increase in white blood cell count (doubling of count from lowest value to \>20,000/mm3 or an increase by \>50,000/mm3 on 2 assessments done ≥2 weeks apart); meeting the criteria of accelerated or blastic phase chronic myeloid leukemia at any time; having an MCyR & subsequently no longer meeting the criteria for MCyR after starting maximum dose; or having a \>=30% absolute increase in number of Ph+ metaphases.
Time frame: time from first dose of Dasatinib (BMS-354825) until the first day criteria for CCyR or PCyR, whichever occurs first, are first met
Population: Median months of progression-free survival was not reached at the time of this report. See corresponding life table in Outcome Measure 16.
Secondary
Time to CHR
Time to CHR = time from first dose of Dasatinib until the first day CHR criteria are met (provided subjects achieved a cCHR). CHR=all of the following criteria: white blood cell count ≤ upper limit of normal; platelets \<450,000/mm³; no blasts or promyelocytes in peripheral blood; \<5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils \<20%; no extramedullary involvement. A confirmed CHR (cCHR) is obtained when all above criteria are maintained for at least 28 days after they are first met. All hematologic responses can begin only 14 days after the dosing start date.
Time frame: time from first dose of Dasatinib (BMS-354825) until the first day CHR criteria are met
Population: Treated participants - responders
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib 100 mg QD Starting Dose Cohort | Time to CHR | 1.0 months |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Time to CHR | 0.6 months |
Secondary
Time to Major Cytogenetic Response (MCyR)
Time to MCyR is defined as the time from first dose of Dasatinib (BMS-354825) until the first day criteria for CCyR or PCyR, whichever occurs first, are first met. MCyR = a complete and a partial cytogenetic response (CyR), based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow sample. Percentage of Ph+ Cells in Metaphase in bone marrow: Complete Cytogenetic Response (CCyR) = 0; Partial Cytogenetic Response (PCyR) 1 - 35
Time frame: time from first dose of Dasatinib (BMS-354825) until the first day criteria for CCyR or PCyR, whichever occurs first, are first met
Population: Treated participants - responders
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib 100 mg QD Starting Dose Cohort | Time to Major Cytogenetic Response (MCyR) | 5.5 months |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Time to Major Cytogenetic Response (MCyR) | 4.2 months |
Other Pre-specified
Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table)
CHR=all of the following criteria: white blood cell count ≤ institutional upper limit of normal; platelets \< 450,000/mm³; no blasts or promyelocytes in peripheral blood; \< 5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils \< 20%; no extramedullary involvement. A confirmed CHR (cCHR) is obtained when all above criteria are maintained for at least 28 days after they are first met. All hematologic responses can begin only 14 days after the dosing start date.
Time frame: Months 0, 4, 8, 12, 16, 20, 24
Population: Treated participants. Median duration was not reached at the time of this report (see Outcome Measure 7)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table) | Month 12 | 9 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table) | Month 16 | 8 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table) | Month 20 | 4 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table) | Month 24 | 0 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table) | Month 0 | 10 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table) | Month 4 | 9 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table) | Month 8 | 9 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table) | Month 24 | 0 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table) | Month 12 | 8 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table) | Month 0 | 10 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table) | Month 16 | 7 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table) | Month 8 | 8 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table) | Month 20 | 4 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With CHR at Months 0 - 24 (Duration of MCyR Life Table) | Month 4 | 10 participants |
Other Pre-specified
Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table)
MCyR = a complete and a partial cytogenetic response (CyR), based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow sample. Percentage of Ph+ Cells in Metaphase in BM: Complete Cytogenetic Response (CCyR) = 0; Partial Cytogenetic Response (PCyR) 1 - 35
Time frame: Months 0, 4, 8, 12, 16, 20, 24
Population: Treated participants. Median duration was not reached at the time of this report (see Outcome Measure 6)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table) | Month 24 | 0 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table) | Month 0 | 6 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table) | Month 4 | 6 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table) | Month 8 | 6 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table) | Month 12 | 4 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table) | Month 16 | 3 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table) | Month 20 | 0 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table) | Month 24 | 0 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table) | Month 12 | 8 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table) | Month 0 | 11 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table) | Month 20 | 1 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table) | Month 4 | 9 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table) | Month 16 | 3 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With Major Cytogenetic Response at Months 0 - 24 (Duration of MCyR Life Table) | Month 8 | 9 participants |
Other Pre-specified
Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table)
Progressed disease=achieving a CHR and subsequently no longer meeting criteria consistently over a consecutive 2-week period after starting maximum dose; no CHR after receiving maximum dose and an increase in white blood cell count (doubling of the count from lowest value to \>20,000/mm3 or an increase by \>50,000/mm3 on 2 assessments done at least 2 weeks apart); meeting the criteria of accelerated or blastic phase CML at any time; having an MCyR and subsequently no longer meeting the criteria for MCyR after starting maximum dose; or having a \>=30% absolute increase in number of Ph+ metaphases.
Time frame: Months 0, 4, 8, 12, 16, 20, 24
Population: Treated participants. Median duration was not reached at the time of this report (see Outcome Measure 7)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table) | Month 4 | 11 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table) | Month 12 | 9 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table) | Month 8 | 9 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table) | Month 0 | 11 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table) | Month 20 | 7 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table) | Month 24 | 0 participants |
| Dasatinib 100 mg QD Starting Dose Cohort | Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table) | Month 16 | 9 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table) | Month 24 | 0 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table) | Month 12 | 10 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table) | Month 20 | 7 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table) | Month 0 | 12 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table) | Month 4 | 12 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table) | Month 16 | 10 participants |
| Dasatinib 100 mg QD Starting Dose - Imatinib-resistant | Number of Participants With Progression-Free Survival (PFS) at Months 0 - 24 (PFS Life Table) | Month 8 | 10 participants |