Leukemia, Lymphoblastic, Acute, Philadelphia-Positive, Myeloid Leukemia, Chronic, Accelerated Phase
Conditions
Keywords
Accelerated Phase Chronic Myeloid Leukemia, Lymphoid Blast Phase Chronic Myeloid Leukemia, Myeloid Blast Phase Chronic Myeloid Leukemia, Philadelphia Positive Acute Lymphoblastic Leukemia
Brief summary
This is a phase III study of BMS-354825 in subjects with chronic myelogenous leukemia in accelerated phase, or in myeloid or lymphoid blast phase or with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia who are resistant or intolerant to imatinib mesylate (Gleevec).
Interventions
DRUGdasatinib
Tablets, Oral, 70 mg BID, indefinitely, survival study
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com. Inclusion Criteria: * Patients with Philadelphia-Positive (Ph+) (or BCR/ABL+) accelerated phase chronic myeloid leukemia, Ph+ (or BCR/ABL+) blast phase chronic myeloid leukemia, or Ph+ (or BCR/ABL+) acute lymphoblastic leukemia whose disease has primary or acquired hematologic resistance to imatinib mesylate or who are intolerant of imatinib mesylate * 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 at least 1 month before and at least 3 months after the study in such a manner that the risk of pregnancy is minimized * Eastern Cooperative Oncology Group (ECOG) performance status score 0 - 2
Exclusion criteria
* Women who are pregnant or breastfeeding * A serious uncontrolled medical disorder or active infection that would impair the ability of the subject 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 BMS-35425 * 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 |
|---|---|---|
| Percent of Participants With Major Hematologic Response (MaHR) With 6 Months of Follow-up From Date of Last Enrollment - Randomized Population | Randomization up to 6 months | MaHR defined by either complete hematologic response (CHR) or no evidence of leukemia (NEL). CHR defined as: white blood cells (WBC) ≤ upper limit of normal (ULN); absolute neutrophil count (ANC) ≥ 1,000/mm\^3; platelets ≥ 100,000/mm\^3; no blasts or promyelocytes in peripheral blood (PB); bone marrow (BM) blasts ≤ 5%; \<5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by same criteria as CHR except that platelets and ANC had to satisfy at least one of the following (note that both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \< 100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. After Year 2, Amendment 3 allowed participants to switch from the BID to the QD dosing schedule. Percentage: number of participants with MaHR/number of randomized participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Major Hematologic Response (MaHR) by Disease Group - Randomized Population | Randomization up to 2 years | MaHR was defined by either complete hematologic response (CHR) or no evidence of leukemia (NEL). CHR defined as: white blood cells (WBC) ≤ upper limit of normal (ULN); absolute neutrophil count (ANC) ≥ 1,000/mm\^3; platelets ≥ 100,000/mm\^3; no blasts or promyelocytes in peripheral blood (PB); bone marrow (BM) blasts ≤ 5%; \<5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by same criteria as CHR except that platelets and ANC had to satisfy at least one parameter of the following (note that both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \< 100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. After Year 2, Amendment 3 allowed participants to switch from the BID to the QD dosing schedule.. Percentage: participants with MaHR/randomized participants. |
| Median Time to Major Hematologic Response (MaHR) - Randomized Population | Day 1 up to 6 months (time of primary endpoint), 2 years | A participants' time to MaHR was defined as the time from the first dosing date until criteria are first met for CHR or NEL, whichever occurred first. Non-responders were censored at the maximum of the date of last hematologic or cytogenetic assessment. Median time was measured in months. |
| Median Duration of a Major Hematologic Response (MaHR) in Those Participants Who Achieved a MaHR During the Study | Day 1 up to 5 years | MaHR was defined by either CHR or no evidence of leukemia NEL. CHR was defined as: WBC ≤ ULN; ANC ≥ 1,000/mm\^3; - platelets ≥ 100,000/mm\^3; - no blasts or promyelocytes in PB; BM blasts ≤ 5%; \< 5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by the same criteria as CHR except that platelets and ANC had to satisfy at least one of the following (note that both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \< 100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. Median duration was measured in months. |
| Percent of Participants With Overall Hematologic Response - Randomized Population | Randomization up to 6 Months, 2 Years | Overall Hematologic Response (OHR) was defined as CHR, NEL or minor hematologic response (MiHR). CHR was defined as: WBC ≤ ULN; ANC ≥ 1,000/mm\^3; - platelets ≥ 100,000/mm\^3; - no blasts or promyelocytes in PB; BM blasts ≤ 5%; \< 5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by the same criteria as CHR except that platelets and ANC had to satisfy at least one of the following (note that both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \< 100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. MiHR defined as: \< 15% blasts in BM and in PB; \< 30% blasts + promyelocytes in BM and PB; \< 20% basophils in PB; No extra-medullary disease other than spleen and liver. Percentage: participants with OHR/ randomized participants. |
| Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | Randomization up to 6 months, 2 years | Type of hematologic response: CHR defined as: WBC ≤ ULN; ANC ≥ 1,000/mm\^3; - platelets ≥ 100,000/mm\^3; - no blasts or promyelocytes in PB; BM blasts ≤ 5%; \< 5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by the same criteria as CHR except that platelets and ANC had to satisfy at least one of the following (note that both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \<100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. Minor Hematologic Response (MiHR): \<15% blasts in BM and in PB; \< 30% blasts + promyelocytes in BM and PB; \< 20% basophils in PB; No extra-medullary disease other than spleen and liver. Major hematologic response (MaHR ) was CHR or NEL. Overall hematologic response was CHR or NEL or MiHR. |
| Percent of Participants With Major Cytogenetic Response (MCyR) - Randomized Population | Randomization up to 6 Months, 2 Years | Cytogenetic assessments were performed only for the first 2 years of study. CyR was based on the number of Ph+ metaphases among cells in metaphase on a BM sample. The criteria for CyR were as follows: Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM; Partial cytogenetic response (PCyR): 1% to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: 36% to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: 66% to 95% Ph+ cells in metaphase in BM; No cytogenetic response: 96% to 100% Ph+ cells in metaphase in BM; Major cytogenetic response (MCyR) was defined as CCyR or PCyR. Percentage: number of participants with MCyR and denominator is number of randomized participants. |
| Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Randomization up to 6 Months, 2 Years | Cytogenetic assessments were performed only for the first 2 years of study. CyR was based on the number of Ph+ metaphases among cells in metaphase on a BM sample. The criteria for CyR were as follows: Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM; Partial cytogenetic response (PCyR): 1% to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: 36% to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: 66% to 95% Ph+ cells in metaphase in BM; No cytogenetic response: 96% to 100% Ph+ cells in metaphase in BM. |
| Median Progression Free Survival (PFS) - Randomized Population | Randomization up to 5 Years | PFS was defined as: Time from randomization until any of the following: Progression of disease (per investigator), or death. For those with blast phase CML or Ph+ ALL, disease progression was: loss of OHR; no decrease from on-study baseline percent blasts in PB or BM on all assessments over a 4-week period after starting maximum dose; absolute increase of at least 50% in PB blast count over a 2-week period after starting maximum dose. For those with accelerated phase CML: the list above also included: Development of blast phase CML at any time after initiation of therapy and development of extra-medullary sites other than spleen or liver. Participants who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. Median duration was measured in months. |
| Percent of Participants With Major Hematological Response (MaHR) With 2 Years of Follow-up From Date of Last Enrollment - Randomized Population | Randomization up to 2 years | A MaHR was defined as a participant having either CHR or NEL. CHR was defined as: WBC ≤ ULN; ANC ≥ 1,000/mm\^3; - platelets ≥ 100,000/mm\^3; - no blasts or promyelocytes in PB; BM blasts ≤ 5%; \< 5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by the same criteria as CHR except that platelets and ANC had to satisfy at least one of the following (both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \< 100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. After Year 2, Amendment 3 allowed participants to switch from the BID to the QD dosing schedule. Percent: number of participants with MaHR /number of participants randomized. |
| Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | 24 months, 36 months, 48 months, 60 months | PFS was defined as time from randomization until any of the following: Progression of disease (per investigator), or death. For those with blast phase CML or Ph+ ALL, disease progression was: loss of OHR; no decrease from on-study baseline percent blasts in PB or BM on all assessments over a 4-week period after starting maximum dose; absolute increase of at least 50% in PB blast count over a 2-week period after starting maximum dose. For those with accelerated phase CML: the list above also included: Development of blast phase CML at any time after initiation of therapy and development of extra-medullary sites other than spleen or liver. Participants who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. OS was defined as time from randomization until date of death. Participants who had not died or were lost to follow-up were censored on the last date they were known to be alive. Median duration was measured in months. |
| Number of Participants With Changes From Baseline in QT Interval Corrected With Fridericia Formula (QTcF) up to Year 2 in Treated Participants | Baseline to Year 2 | A12-lead electrocardiogram (ECG) was obtained at baseline (baseline=within 2 weeks prior to randomization) and once between Days 8 and 29. Additional ECGs were done at the Investigator's discretion. ECGs were read centrally. The QT interval corrected with Fridericia formula is presented with categories of changes from baseline (BL) in milliseconds (msec). |
| Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation and Drug-related Fluid Retention AEs, up to Year 7 in Treated Participants | Day 1 to Year 7 | With protocol Amendment 6, the duration of the study was extended for 2 additional years (7 years total) for participants who continued to have clinical benefit and no feasible alternate access to dasatinib. However, after Year 5 the requirement to follow participants for survival and to collect other efficacy data was removed from the protocol for the remainder of the study. Only AEs and SAEs were collected up to Year 7. On-study AEs and SAEs were graded by severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. The investigator AE terms were coded and grouped by preferred term and system organ class using the Medical Dictionary for Regulatory Activities (MedDRA), version 16.0. |
| Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | Baseline to Year 2 | Laboratory abnormalities were graded according to the National Cancer Institute Common Terminology Criteria (NCI CTC) version 3.0. CTC Grade 3 and 4 criteria are defined as follows: White blood cells (WBC): Grade (Gr) 3:\<2.0 to 1.0\*10\^9/L, Gr 4:\<1.0\*10\^9/L. Absolute neutrophil count (ANC): Gr 3:\<1.0 to 0.5\*10\^9/L, Gr 4:\<0.5\*10\^9/L. Platelet count Gr 3:\<50.0 to 25.0\*10\^9/L, Gr 4:\<25.0 to 10\^9/L. Hemoglobin Gr 3:\<8.0 to 6.5 g/dL, Gr 4:\<6.5 g/dL. Baseline was laboratory value obtained within 2 weeks prior to randomization. |
| Number of Participants With Grade 4 Myelosuppression Determined From Hematology Evaluations | Day 1 up to Year 7 | Laboratory abnormalities were graded according to the National Cancer Institute Common Terminology Criteria (NCI CTC) Version 3.0. Grade 4 hematology evaluations used to determine myelosuppression included: WBC: \<1.0\*10\^9/L. ANC: \<0.5\*10\^9/L. Platelet count \<25.0 to 10\^9/L. |
| Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Baseline to Year 2 | Laboratory abnormalities were graded according to the NCI CTC version 3.0. Grade 3 and 4 criteria were defined as follows: Upper limit of normal (ULN). Alanine transaminase (ALT) Grade (Gr) 3: \>5.0 to 20.0\*ULN; Gr 4: \>20.0\*ULN. Aspartate aminotransferase (AST) Gr 3: \>5.0 to 20.0\*ULN; Gr 4: \>20.0\*ULN. Total bilirubin Gr 3: \>3.0 to 10..0\*ULN; Gr 4: \>10.0.0\*ULN. Serum creatinine (H) Gr 3: \>3.0 to 6.0\*ULN; Gr 4: \>6.0\*ULN. Calcium (L) Gr3: 6.0-7.0; Gr 4: \<6.0 mg/dL; Phosphorus (L): Gr 3: \<2.0 - 1.0 mg/dL , Gr 4: \<1.0 mg/dL. Non-hematologic laboratory results were not collected beyond Year 2. Baseline values were obtained within 2 weeks prior to randomization. |
| Number of Participants With Maximal QTcF Intervals up to Year 2 in Treated Participants | Baseline up to Year 2 | A12-lead ECG was obtained at baseline (baseline=within 2 weeks prior to randomization) and once between Day 8 and 29. Additional ECGs were done at the Investigator's discretion. ECGs were read centrally. QT Interval corrected with Fridericia formula was measured in msec. |
| Median Overall Survival (OS) - Randomized Population | Randomization up to 5 Years | OS was defined as time from randomization until date of death. Participants who had not died or who were lost to follow-up were censored on the last date on which the participant was known to be alive. Median duration was measured in months. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Czechia, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Netherlands, Norway, Peru, Philippines, Poland, Russia, Singapore, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, United Kingdom, United States
Participant flow
Recruitment details
Study started June 2005; recruitment completed March 2006; study ended June 2013 (Year 7) when the study closed and all participants were off study treatment. Those participants who were resistant or intolerant to prior imatinib were enrolled.
Pre-assignment details
638 participants were enrolled; 27 were not randomized due to: adverse event (1), death (5), other (5), poor/noncompliance (1), no longer met criteria (13), withdrew consent (2). A total of 611 were randomized to treatment; 609 were treated: 2 randomized but not treated due to death (1) and serious adverse event (1).
Participants by arm
| Arm | Count |
|---|---|
| Dasatinib 140 mg QD Dasatinib was administered orally at a dose of 140 mg once a day (QD) until disease progression, drug toxicity, withdrawal of consent, investigator or sponsor decision, pregnancy, or decision to do stem cell transplant. | 306 |
| Dasatinib 70 mg BID Dasatinib was administered orally at a dose of 70 mg twice a day (BID) until disease progression, drug toxicity, withdrawal of consent, investigator or sponsor decision, pregnancy, or decision to do stem cell transplant. | 305 |
| Total | 611 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Randomized | Death prior to starting treatment | 0 | 1 |
| Randomized | SAE prior to starting treatment | 1 | 0 |
| Treated With Study Drug | Adverse Event | 23 | 22 |
| Treated With Study Drug | Disease Progression | 141 | 122 |
| Treated With Study Drug | Other | 59 | 58 |
| Treated With Study Drug | Physician Decision | 8 | 9 |
| Treated With Study Drug | Study Drug Toxicity | 62 | 80 |
| Treated With Study Drug | Unknown (case report form lost) | 0 | 1 |
| Treated With Study Drug | Withdrawal by Subject | 11 | 13 |
Baseline characteristics
| Characteristic | Dasatinib 140 mg QD | Dasatinib 70 mg BID | Total |
|---|---|---|---|
| Age, Customized 21 - 45 years | 101 participants | 83 participants | 184 participants |
| Age, Customized 46 - 65 years | 143 participants | 143 participants | 286 participants |
| Age, Customized 66 - 75 years | 49 participants | 65 participants | 114 participants |
| Age, Customized Greater than (>) 75 years | 8 participants | 9 participants | 17 participants |
| Age, Customized Less than (<) 21 years | 5 participants | 4 participants | 9 participants |
| Age, Customized Not Reported | 0 participants | 1 participants | 1 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 0 | 138 participants | 134 participants | 272 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 1 | 121 participants | 109 participants | 230 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 2 | 40 participants | 58 participants | 98 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 3 | 7 participants | 2 participants | 9 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Not Reported | 0 participants | 2 participants | 2 participants |
| Imatinib Status Acquired Resistance | 192 participants | 190 participants | 382 participants |
| Imatinib Status Intolerance | 67 participants | 65 participants | 132 participants |
| Imatinib Status Missing | 4 participants | 1 participants | 5 participants |
| Imatinib Status Primary Resistance | 43 participants | 49 participants | 92 participants |
| Participants by Disease Phase Accelerated Phase CML | 158 participants | 159 participants | 317 participants |
| Participants by Disease Phase Blast Phase CML - Lymphoid | 33 participants | 28 participants | 61 participants |
| Participants by Disease Phase Blast Phase CML - Myeloid | 75 participants | 74 participants | 149 participants |
| Participants by Disease Phase Ph+ ALL | 40 participants | 44 participants | 84 participants |
| Race/Ethnicity, Customized Asian | 38 participants | 38 participants | 76 participants |
| Race/Ethnicity, Customized Black or African American | 17 participants | 18 participants | 35 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Other | 13 participants | 9 participants | 22 participants |
| Race/Ethnicity, Customized Unknown or Not reported | 3 participants | 3 participants | 6 participants |
| Race/Ethnicity, Customized White | 235 participants | 236 participants | 471 participants |
| Sex: Female, Male Female | 133 Participants | 134 Participants | 267 Participants |
| Sex: Female, Male Male | 173 Participants | 171 Participants | 344 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 289 / 304 | 290 / 305 |
| serious Total, serious adverse events | 228 / 304 | 236 / 305 |
Outcome results
Primary
Percent of Participants With Major Hematologic Response (MaHR) With 6 Months of Follow-up From Date of Last Enrollment - Randomized Population
MaHR defined by either complete hematologic response (CHR) or no evidence of leukemia (NEL). CHR defined as: white blood cells (WBC) ≤ upper limit of normal (ULN); absolute neutrophil count (ANC) ≥ 1,000/mm\^3; platelets ≥ 100,000/mm\^3; no blasts or promyelocytes in peripheral blood (PB); bone marrow (BM) blasts ≤ 5%; \<5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by same criteria as CHR except that platelets and ANC had to satisfy at least one of the following (note that both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \< 100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. After Year 2, Amendment 3 allowed participants to switch from the BID to the QD dosing schedule. Percentage: number of participants with MaHR/number of randomized participants.
Time frame: Randomization up to 6 months
Population: Participants were analyzed based on the treatment they were randomized to receive (not what they actually received). 95% exact confidence interval (CI) presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib 140 mg QD | Percent of Participants With Major Hematologic Response (MaHR) With 6 Months of Follow-up From Date of Last Enrollment - Randomized Population | 48.0 percentage of participants |
| Dasatinib 70 mg BID | Percent of Participants With Major Hematologic Response (MaHR) With 6 Months of Follow-up From Date of Last Enrollment - Randomized Population | 47.9 percentage of participants |
Comparison: Primary endpoint was to be assessed at 6-Months: Assuming a 45% MaHR rate in the 70 mg BID participants, the primary efficacy analysis required a total of 540 participants, approximately 270 in each dosing schedule, giving at least 80% power to deduce non-inferiority of the QD schedule relative to the BID schedule if the lower bound of the 95% CI for the difference in MaHR rates (MaHRRQD - MaHRRBID) is greater than -12%.95% CI: [-7.8, 8.1]
Secondary
Median Duration of a Major Hematologic Response (MaHR) in Those Participants Who Achieved a MaHR During the Study
MaHR was defined by either CHR or no evidence of leukemia NEL. CHR was defined as: WBC ≤ ULN; ANC ≥ 1,000/mm\^3; - platelets ≥ 100,000/mm\^3; - no blasts or promyelocytes in PB; BM blasts ≤ 5%; \< 5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by the same criteria as CHR except that platelets and ANC had to satisfy at least one of the following (note that both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \< 100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. Median duration was measured in months.
Time frame: Day 1 up to 5 years
Population: Participants who achieved a MaHR during the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib 140 mg QD | Median Duration of a Major Hematologic Response (MaHR) in Those Participants Who Achieved a MaHR During the Study | 21.1 Months |
| Dasatinib 70 mg BID | Median Duration of a Major Hematologic Response (MaHR) in Those Participants Who Achieved a MaHR During the Study | 24.7 Months |
Secondary
Median Overall Survival (OS) - Randomized Population
OS was defined as time from randomization until date of death. Participants who had not died or who were lost to follow-up were censored on the last date on which the participant was known to be alive. Median duration was measured in months.
Time frame: Randomization up to 5 Years
Population: Participants were analyzed based on the treatment they were randomized to receive.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib 140 mg QD | Median Overall Survival (OS) - Randomized Population | 17.7 Months |
| Dasatinib 70 mg BID | Median Overall Survival (OS) - Randomized Population | 22.4 Months |
Secondary
Median Progression Free Survival (PFS) - Randomized Population
PFS was defined as: Time from randomization until any of the following: Progression of disease (per investigator), or death. For those with blast phase CML or Ph+ ALL, disease progression was: loss of OHR; no decrease from on-study baseline percent blasts in PB or BM on all assessments over a 4-week period after starting maximum dose; absolute increase of at least 50% in PB blast count over a 2-week period after starting maximum dose. For those with accelerated phase CML: the list above also included: Development of blast phase CML at any time after initiation of therapy and development of extra-medullary sites other than spleen or liver. Participants who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. Median duration was measured in months.
Time frame: Randomization up to 5 Years
Population: Participants were analyzed based on the treatment they were randomized to receive.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib 140 mg QD | Median Progression Free Survival (PFS) - Randomized Population | 7.8 Months |
| Dasatinib 70 mg BID | Median Progression Free Survival (PFS) - Randomized Population | 10.4 Months |
Secondary
Median Time to Major Hematologic Response (MaHR) - Randomized Population
A participants' time to MaHR was defined as the time from the first dosing date until criteria are first met for CHR or NEL, whichever occurred first. Non-responders were censored at the maximum of the date of last hematologic or cytogenetic assessment. Median time was measured in months.
Time frame: Day 1 up to 6 months (time of primary endpoint), 2 years
Population: Participants were analyzed based on the treatment they were randomized to receive.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dasatinib 140 mg QD | Median Time to Major Hematologic Response (MaHR) - Randomized Population | 2 Years | 1.9 Months |
| Dasatinib 140 mg QD | Median Time to Major Hematologic Response (MaHR) - Randomized Population | 6 Months | 1.9 Months |
| Dasatinib 70 mg BID | Median Time to Major Hematologic Response (MaHR) - Randomized Population | 6 Months | 1.9 Months |
| Dasatinib 70 mg BID | Median Time to Major Hematologic Response (MaHR) - Randomized Population | 2 Years | 1.9 Months |
Secondary
Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population
Type of hematologic response: CHR defined as: WBC ≤ ULN; ANC ≥ 1,000/mm\^3; - platelets ≥ 100,000/mm\^3; - no blasts or promyelocytes in PB; BM blasts ≤ 5%; \< 5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by the same criteria as CHR except that platelets and ANC had to satisfy at least one of the following (note that both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \<100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. Minor Hematologic Response (MiHR): \<15% blasts in BM and in PB; \< 30% blasts + promyelocytes in BM and PB; \< 20% basophils in PB; No extra-medullary disease other than spleen and liver. Major hematologic response (MaHR ) was CHR or NEL. Overall hematologic response was CHR or NEL or MiHR.
Time frame: Randomization up to 6 months, 2 years
Population: Participants were analyzed based on the treatment they were randomized to receive.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 140 mg QD | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | Complete Response, 2 years | 108 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | Minor Response, 2 years | 29 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | No Evidence of Leukemia, 6 months | 53 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | No Response, 6 months | 125 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | MaHR, 6 months | 147 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | No Evidence of Leukemia, 2 years | 47 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | MaHR, 2 years | 155 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | No Response, 2 years | 122 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | Overall Response, 6 months | 181 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | Minor Response, 6 months | 34 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | Overall Response, 2 years | 184 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | Complete Response, 6 months | 94 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | Overall Response, 2 years | 180 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | Complete Response, 2 years | 110 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | No Response, 6 months | 130 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | Complete Response, 6 months | 96 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | No Evidence of Leukemia, 6 months | 50 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | No Evidence of Leukemia, 2 years | 42 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | Minor Response, 6 months | 29 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | Minor Response, 2 years | 28 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | No Response, 2 years | 125 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | MaHR, 6 months | 146 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | MaHR, 2 years | 152 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population | Overall Response, 6 months | 175 participants |
Secondary
Number of Participants With Best Cytogenic Response (CyR) - Randomized Population
Cytogenetic assessments were performed only for the first 2 years of study. CyR was based on the number of Ph+ metaphases among cells in metaphase on a BM sample. The criteria for CyR were as follows: Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM; Partial cytogenetic response (PCyR): 1% to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: 36% to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: 66% to 95% Ph+ cells in metaphase in BM; No cytogenetic response: 96% to 100% Ph+ cells in metaphase in BM.
Time frame: Randomization up to 6 Months, 2 Years
Population: Participants were analyzed based on the treatment they were randomized to receive.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 140 mg QD | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Partial CyR, 6 months | 24 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Complete CyR, 6 months | 89 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Complete CyR, 2 years | 97 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Partial CyR, 2 years | 30 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Minor CyR, 6 months | 19 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Minor CyR, 2 years | 13 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Minimal CyR, 6 months | 47 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Minimal CyR, 2 years | 43 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | No response, 6 months | 63 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | No response, 2 years | 60 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Unable to determine, 6 months | 64 participants |
| Dasatinib 140 mg QD | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Unable to determine, 2 years | 63 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Unable to determine, 6 months | 66 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Minimal CyR, 6 months | 45 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Complete CyR, 6 months | 84 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | No response, 2 years | 51 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Complete CyR, 2 years | 98 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Partial CyR, 6 months | 36 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Minimal CyR, 2 years | 40 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Partial CyR, 2 years | 28 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Unable to determine, 2 years | 72 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Minor CyR, 6 months | 18 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | No response, 6 months | 56 participants |
| Dasatinib 70 mg BID | Number of Participants With Best Cytogenic Response (CyR) - Randomized Population | Minor CyR, 2 years | 16 participants |
Secondary
Number of Participants With Changes From Baseline in QT Interval Corrected With Fridericia Formula (QTcF) up to Year 2 in Treated Participants
A12-lead electrocardiogram (ECG) was obtained at baseline (baseline=within 2 weeks prior to randomization) and once between Days 8 and 29. Additional ECGs were done at the Investigator's discretion. ECGs were read centrally. The QT interval corrected with Fridericia formula is presented with categories of changes from baseline (BL) in milliseconds (msec).
Time frame: Baseline to Year 2
Population: All participants who received at least one dose of study drug and had appropriate baseline and on-study ECG data available were analyzed. Participants were analyzed based on the treatment they actually received, not what they were randomized to receive.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 140 mg QD | Number of Participants With Changes From Baseline in QT Interval Corrected With Fridericia Formula (QTcF) up to Year 2 in Treated Participants | QTcF <-60 msec change from BL | 4 participants |
| Dasatinib 140 mg QD | Number of Participants With Changes From Baseline in QT Interval Corrected With Fridericia Formula (QTcF) up to Year 2 in Treated Participants | -60 - < -30 msec change from BL | 13 participants |
| Dasatinib 140 mg QD | Number of Participants With Changes From Baseline in QT Interval Corrected With Fridericia Formula (QTcF) up to Year 2 in Treated Participants | -30 - < 0 msec change from BL | 88 participants |
| Dasatinib 140 mg QD | Number of Participants With Changes From Baseline in QT Interval Corrected With Fridericia Formula (QTcF) up to Year 2 in Treated Participants | 0 - 30 msec change from BL | 114 participants |
| Dasatinib 140 mg QD | Number of Participants With Changes From Baseline in QT Interval Corrected With Fridericia Formula (QTcF) up to Year 2 in Treated Participants | > 30 - 60 msec change from BL | 31 participants |
| Dasatinib 140 mg QD | Number of Participants With Changes From Baseline in QT Interval Corrected With Fridericia Formula (QTcF) up to Year 2 in Treated Participants | > 60 msec change from BL | 19 participants |
| Dasatinib 70 mg BID | Number of Participants With Changes From Baseline in QT Interval Corrected With Fridericia Formula (QTcF) up to Year 2 in Treated Participants | > 30 - 60 msec change from BL | 24 participants |
| Dasatinib 70 mg BID | Number of Participants With Changes From Baseline in QT Interval Corrected With Fridericia Formula (QTcF) up to Year 2 in Treated Participants | QTcF <-60 msec change from BL | 7 participants |
| Dasatinib 70 mg BID | Number of Participants With Changes From Baseline in QT Interval Corrected With Fridericia Formula (QTcF) up to Year 2 in Treated Participants | 0 - 30 msec change from BL | 125 participants |
| Dasatinib 70 mg BID | Number of Participants With Changes From Baseline in QT Interval Corrected With Fridericia Formula (QTcF) up to Year 2 in Treated Participants | -60 - < -30 msec change from BL | 15 participants |
| Dasatinib 70 mg BID | Number of Participants With Changes From Baseline in QT Interval Corrected With Fridericia Formula (QTcF) up to Year 2 in Treated Participants | > 60 msec change from BL | 21 participants |
| Dasatinib 70 mg BID | Number of Participants With Changes From Baseline in QT Interval Corrected With Fridericia Formula (QTcF) up to Year 2 in Treated Participants | -30 - < 0 msec change from BL | 65 participants |
Secondary
Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation and Drug-related Fluid Retention AEs, up to Year 7 in Treated Participants
With protocol Amendment 6, the duration of the study was extended for 2 additional years (7 years total) for participants who continued to have clinical benefit and no feasible alternate access to dasatinib. However, after Year 5 the requirement to follow participants for survival and to collect other efficacy data was removed from the protocol for the remainder of the study. Only AEs and SAEs were collected up to Year 7. On-study AEs and SAEs were graded by severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. The investigator AE terms were coded and grouped by preferred term and system organ class using the Medical Dictionary for Regulatory Activities (MedDRA), version 16.0.
Time frame: Day 1 to Year 7
Population: All participants who received at least one dose of study drug were analyzed. Participants were analyzed based on the treatment they actually received, not what they were randomized to receive.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 140 mg QD | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation and Drug-related Fluid Retention AEs, up to Year 7 in Treated Participants | SAEs | 228 participants |
| Dasatinib 140 mg QD | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation and Drug-related Fluid Retention AEs, up to Year 7 in Treated Participants | AEs Leading to Discontinuation | 118 participants |
| Dasatinib 140 mg QD | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation and Drug-related Fluid Retention AEs, up to Year 7 in Treated Participants | Death within 30 Days | 66 participants |
| Dasatinib 140 mg QD | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation and Drug-related Fluid Retention AEs, up to Year 7 in Treated Participants | Drug-related Fluid Retention | 109 participants |
| Dasatinib 140 mg QD | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation and Drug-related Fluid Retention AEs, up to Year 7 in Treated Participants | Deaths | 203 participants |
| Dasatinib 70 mg BID | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation and Drug-related Fluid Retention AEs, up to Year 7 in Treated Participants | Drug-related Fluid Retention | 137 participants |
| Dasatinib 70 mg BID | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation and Drug-related Fluid Retention AEs, up to Year 7 in Treated Participants | Deaths | 186 participants |
| Dasatinib 70 mg BID | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation and Drug-related Fluid Retention AEs, up to Year 7 in Treated Participants | Death within 30 Days | 63 participants |
| Dasatinib 70 mg BID | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation and Drug-related Fluid Retention AEs, up to Year 7 in Treated Participants | AEs Leading to Discontinuation | 114 participants |
| Dasatinib 70 mg BID | Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation and Drug-related Fluid Retention AEs, up to Year 7 in Treated Participants | SAEs | 236 participants |
Secondary
Number of Participants With Grade 4 Myelosuppression Determined From Hematology Evaluations
Laboratory abnormalities were graded according to the National Cancer Institute Common Terminology Criteria (NCI CTC) Version 3.0. Grade 4 hematology evaluations used to determine myelosuppression included: WBC: \<1.0\*10\^9/L. ANC: \<0.5\*10\^9/L. Platelet count \<25.0 to 10\^9/L.
Time frame: Day 1 up to Year 7
Population: All participants who received at least one dose of study drug and had laboratory evaluations available were analyzed. Participants were analyzed based on the treatment they actually received, not what they were randomized to receive.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 140 mg QD | Number of Participants With Grade 4 Myelosuppression Determined From Hematology Evaluations | WBC (n=299, 303) | 64 participants |
| Dasatinib 140 mg QD | Number of Participants With Grade 4 Myelosuppression Determined From Hematology Evaluations | Platelets(n=299, 303) | 167 participants |
| Dasatinib 140 mg QD | Number of Participants With Grade 4 Myelosuppression Determined From Hematology Evaluations | ANC (n=299, 303) | 132 participants |
| Dasatinib 70 mg BID | Number of Participants With Grade 4 Myelosuppression Determined From Hematology Evaluations | WBC (n=299, 303) | 72 participants |
| Dasatinib 70 mg BID | Number of Participants With Grade 4 Myelosuppression Determined From Hematology Evaluations | Platelets(n=299, 303) | 164 participants |
| Dasatinib 70 mg BID | Number of Participants With Grade 4 Myelosuppression Determined From Hematology Evaluations | ANC (n=299, 303) | 142 participants |
Secondary
Number of Participants With Maximal QTcF Intervals up to Year 2 in Treated Participants
A12-lead ECG was obtained at baseline (baseline=within 2 weeks prior to randomization) and once between Day 8 and 29. Additional ECGs were done at the Investigator's discretion. ECGs were read centrally. QT Interval corrected with Fridericia formula was measured in msec.
Time frame: Baseline up to Year 2
Population: All participants who received at least one dose of study drug and had appropriate ECG data available were analyzed. Participants were analyzed based on the treatment they actually received, not what they were randomized to receive.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 140 mg QD | Number of Participants With Maximal QTcF Intervals up to Year 2 in Treated Participants | Maximum QTcF Interval < 450 msec | 252 participants |
| Dasatinib 140 mg QD | Number of Participants With Maximal QTcF Intervals up to Year 2 in Treated Participants | Maximum QTcF Interval 450 - 500 msec | 21 participants |
| Dasatinib 140 mg QD | Number of Participants With Maximal QTcF Intervals up to Year 2 in Treated Participants | Maximum QTcF Interval > 500 msec | 7 participants |
| Dasatinib 70 mg BID | Number of Participants With Maximal QTcF Intervals up to Year 2 in Treated Participants | Maximum QTcF Interval < 450 msec | 239 participants |
| Dasatinib 70 mg BID | Number of Participants With Maximal QTcF Intervals up to Year 2 in Treated Participants | Maximum QTcF Interval 450 - 500 msec | 26 participants |
| Dasatinib 70 mg BID | Number of Participants With Maximal QTcF Intervals up to Year 2 in Treated Participants | Maximum QTcF Interval > 500 msec | 5 participants |
Secondary
Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants
Laboratory abnormalities were graded according to the NCI CTC version 3.0. Grade 3 and 4 criteria were defined as follows: Upper limit of normal (ULN). Alanine transaminase (ALT) Grade (Gr) 3: \>5.0 to 20.0\*ULN; Gr 4: \>20.0\*ULN. Aspartate aminotransferase (AST) Gr 3: \>5.0 to 20.0\*ULN; Gr 4: \>20.0\*ULN. Total bilirubin Gr 3: \>3.0 to 10..0\*ULN; Gr 4: \>10.0.0\*ULN. Serum creatinine (H) Gr 3: \>3.0 to 6.0\*ULN; Gr 4: \>6.0\*ULN. Calcium (L) Gr3: 6.0-7.0; Gr 4: \<6.0 mg/dL; Phosphorus (L): Gr 3: \<2.0 - 1.0 mg/dL , Gr 4: \<1.0 mg/dL. Non-hematologic laboratory results were not collected beyond Year 2. Baseline values were obtained within 2 weeks prior to randomization.
Time frame: Baseline to Year 2
Population: All participants who received at least one dose of study drug were analyzed. Participants were analyzed based on the treatment they actually received, not what they were randomized to receive. Participants who did not have a parameter reported at baseline are indicated.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | ALT not reported at baseline | 4 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Hypocalcemia | 14 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Elevated AST | 3 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Bilirubin not reported at baseline | 2 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | AST not reported at baseline | 3 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Calcium not reported at baseline | 5 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Elevated Bilirubin | 4 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Phosphorus not reported at baseline | 14 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Elevated Serum Creatinine | 4 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Elevated ALT | 8 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Serum Creatinine not reported at baseline | 1 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Hypophosphatemia | 28 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Serum Creatinine not reported at baseline | 3 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Hypophosphatemia | 26 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Phosphorus not reported at baseline | 20 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Hypocalcemia | 9 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Calcium not reported at baseline | 13 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Elevated ALT | 4 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | ALT not reported at baseline | 4 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Elevated AST | 2 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | AST not reported at baseline | 6 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Bilirubin not reported at baseline | 7 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Elevated Serum Creatinine | 2 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants | Elevated Bilirubin | 3 participants |
Secondary
Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants
Laboratory abnormalities were graded according to the National Cancer Institute Common Terminology Criteria (NCI CTC) version 3.0. CTC Grade 3 and 4 criteria are defined as follows: White blood cells (WBC): Grade (Gr) 3:\<2.0 to 1.0\*10\^9/L, Gr 4:\<1.0\*10\^9/L. Absolute neutrophil count (ANC): Gr 3:\<1.0 to 0.5\*10\^9/L, Gr 4:\<0.5\*10\^9/L. Platelet count Gr 3:\<50.0 to 25.0\*10\^9/L, Gr 4:\<25.0 to 10\^9/L. Hemoglobin Gr 3:\<8.0 to 6.5 g/dL, Gr 4:\<6.5 g/dL. Baseline was laboratory value obtained within 2 weeks prior to randomization.
Time frame: Baseline to Year 2
Population: All participants who received at least one dose of study drug were analyzed. Participants were analyzed based on the treatment they actually received, not what they were randomized to receive. Those participants who did not have a parameter reported at baseline are indicated.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | WBC | 129 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | WBC not reported at baseline | 2 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | Platelets | 64 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | Platelets not reported at baseline | 2 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | Hemoglobin | 12 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | Hemoglobin not reported at baseline | 2 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | ANC | 127 participants |
| Dasatinib 140 mg QD | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | ANC not reported at baseline | 9 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | ANC not reported at baseline | 8 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | WBC | 114 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | Hemoglobin | 13 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | WBC not reported at baseline | 2 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | ANC | 143 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | Platelets | 79 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | Hemoglobin not reported at baseline | 2 participants |
| Dasatinib 70 mg BID | Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants | Platelets not reported at baseline | 2 participants |
Secondary
Percent of Participants With Major Cytogenetic Response (MCyR) - Randomized Population
Cytogenetic assessments were performed only for the first 2 years of study. CyR was based on the number of Ph+ metaphases among cells in metaphase on a BM sample. The criteria for CyR were as follows: Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM; Partial cytogenetic response (PCyR): 1% to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: 36% to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: 66% to 95% Ph+ cells in metaphase in BM; No cytogenetic response: 96% to 100% Ph+ cells in metaphase in BM; Major cytogenetic response (MCyR) was defined as CCyR or PCyR. Percentage: number of participants with MCyR and denominator is number of randomized participants.
Time frame: Randomization up to 6 Months, 2 Years
Population: Participants were analyzed based on the treatment they were randomized to receive.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 140 mg QD | Percent of Participants With Major Cytogenetic Response (MCyR) - Randomized Population | 6 Months | 36.9 percentage of participants |
| Dasatinib 140 mg QD | Percent of Participants With Major Cytogenetic Response (MCyR) - Randomized Population | 2 Years | 41.5 percentage of participants |
| Dasatinib 70 mg BID | Percent of Participants With Major Cytogenetic Response (MCyR) - Randomized Population | 6 Months | 39.3 percentage of participants |
| Dasatinib 70 mg BID | Percent of Participants With Major Cytogenetic Response (MCyR) - Randomized Population | 2 Years | 41.3 percentage of participants |
Secondary
Percent of Participants With Major Hematological Response (MaHR) With 2 Years of Follow-up From Date of Last Enrollment - Randomized Population
A MaHR was defined as a participant having either CHR or NEL. CHR was defined as: WBC ≤ ULN; ANC ≥ 1,000/mm\^3; - platelets ≥ 100,000/mm\^3; - no blasts or promyelocytes in PB; BM blasts ≤ 5%; \< 5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by the same criteria as CHR except that platelets and ANC had to satisfy at least one of the following (both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \< 100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. After Year 2, Amendment 3 allowed participants to switch from the BID to the QD dosing schedule. Percent: number of participants with MaHR /number of participants randomized.
Time frame: Randomization up to 2 years
Population: Participants were analyzed based on the treatment they were randomized to receive.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib 140 mg QD | Percent of Participants With Major Hematological Response (MaHR) With 2 Years of Follow-up From Date of Last Enrollment - Randomized Population | 50.7 percentage of participants |
| Dasatinib 70 mg BID | Percent of Participants With Major Hematological Response (MaHR) With 2 Years of Follow-up From Date of Last Enrollment - Randomized Population | 49.8 percentage of participants |
Secondary
Percent of Participants With Major Hematologic Response (MaHR) by Disease Group - Randomized Population
MaHR was defined by either complete hematologic response (CHR) or no evidence of leukemia (NEL). CHR defined as: white blood cells (WBC) ≤ upper limit of normal (ULN); absolute neutrophil count (ANC) ≥ 1,000/mm\^3; platelets ≥ 100,000/mm\^3; no blasts or promyelocytes in peripheral blood (PB); bone marrow (BM) blasts ≤ 5%; \<5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by same criteria as CHR except that platelets and ANC had to satisfy at least one parameter of the following (note that both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \< 100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. After Year 2, Amendment 3 allowed participants to switch from the BID to the QD dosing schedule.. Percentage: participants with MaHR/randomized participants.
Time frame: Randomization up to 2 years
Population: Participants were analyzed based on the treatment they were randomized to receive. n=number of participants in disease group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 140 mg QD | Percent of Participants With Major Hematologic Response (MaHR) by Disease Group - Randomized Population | Lymphoid Blast Phase (n=33,28) | 42.4 percentage of participants |
| Dasatinib 140 mg QD | Percent of Participants With Major Hematologic Response (MaHR) by Disease Group - Randomized Population | Accelerated Phase (n=158, 159) | 66.5 percentage of participants |
| Dasatinib 140 mg QD | Percent of Participants With Major Hematologic Response (MaHR) by Disease Group - Randomized Population | Ph+ Acute Lymphoblastic Leukemia (n=40,44) | 37.5 percentage of participants |
| Dasatinib 140 mg QD | Percent of Participants With Major Hematologic Response (MaHR) by Disease Group - Randomized Population | Myeloid Blast Phase (n=75,74) | 28.0 percentage of participants |
| Dasatinib 70 mg BID | Percent of Participants With Major Hematologic Response (MaHR) by Disease Group - Randomized Population | Ph+ Acute Lymphoblastic Leukemia (n=40,44) | 31.8 percentage of participants |
| Dasatinib 70 mg BID | Percent of Participants With Major Hematologic Response (MaHR) by Disease Group - Randomized Population | Myeloid Blast Phase (n=75,74) | 28.4 percentage of participants |
| Dasatinib 70 mg BID | Percent of Participants With Major Hematologic Response (MaHR) by Disease Group - Randomized Population | Lymphoid Blast Phase (n=33,28) | 32.1 percentage of participants |
| Dasatinib 70 mg BID | Percent of Participants With Major Hematologic Response (MaHR) by Disease Group - Randomized Population | Accelerated Phase (n=158, 159) | 67.9 percentage of participants |
Secondary
Percent of Participants With Overall Hematologic Response - Randomized Population
Overall Hematologic Response (OHR) was defined as CHR, NEL or minor hematologic response (MiHR). CHR was defined as: WBC ≤ ULN; ANC ≥ 1,000/mm\^3; - platelets ≥ 100,000/mm\^3; - no blasts or promyelocytes in PB; BM blasts ≤ 5%; \< 5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by the same criteria as CHR except that platelets and ANC had to satisfy at least one of the following (note that both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \< 100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. MiHR defined as: \< 15% blasts in BM and in PB; \< 30% blasts + promyelocytes in BM and PB; \< 20% basophils in PB; No extra-medullary disease other than spleen and liver. Percentage: participants with OHR/ randomized participants.
Time frame: Randomization up to 6 Months, 2 Years
Population: Participants were analyzed based on the treatment they were randomized to receive.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 140 mg QD | Percent of Participants With Overall Hematologic Response - Randomized Population | 6 Months | 59.2 percentage of participants |
| Dasatinib 140 mg QD | Percent of Participants With Overall Hematologic Response - Randomized Population | 2 Years | 60.1 percentage of participants |
| Dasatinib 70 mg BID | Percent of Participants With Overall Hematologic Response - Randomized Population | 6 Months | 57.4 percentage of participants |
| Dasatinib 70 mg BID | Percent of Participants With Overall Hematologic Response - Randomized Population | 2 Years | 59.0 percentage of participants |
Secondary
Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population
PFS was defined as time from randomization until any of the following: Progression of disease (per investigator), or death. For those with blast phase CML or Ph+ ALL, disease progression was: loss of OHR; no decrease from on-study baseline percent blasts in PB or BM on all assessments over a 4-week period after starting maximum dose; absolute increase of at least 50% in PB blast count over a 2-week period after starting maximum dose. For those with accelerated phase CML: the list above also included: Development of blast phase CML at any time after initiation of therapy and development of extra-medullary sites other than spleen or liver. Participants who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. OS was defined as time from randomization until date of death. Participants who had not died or were lost to follow-up were censored on the last date they were known to be alive. Median duration was measured in months.
Time frame: 24 months, 36 months, 48 months, 60 months
Population: Participants were analyzed based on the treatment they were randomized to receive. Kaplan-Meir estimates of PFS or OS (95% Confidence Interval) are provided below.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib 140 mg QD | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | PFS at 24 Months | 29.5 percentage of participants |
| Dasatinib 140 mg QD | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | OS at 24 Months | 43.3 percentage of participants |
| Dasatinib 140 mg QD | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | PFS at 48 Months | 19.8 percentage of participants |
| Dasatinib 140 mg QD | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | OS at 36 Months | 37.1 percentage of participants |
| Dasatinib 140 mg QD | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | PFS at 36 Months | 24.1 percentage of participants |
| Dasatinib 140 mg QD | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | OS at 48 Months | 32.7 percentage of participants |
| Dasatinib 140 mg QD | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | PFS at 60 Months | 16.9 percentage of participants |
| Dasatinib 140 mg QD | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | OS at 60 Months | 28.8 percentage of participants |
| Dasatinib 70 mg BID | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | PFS at 60 Months | 15.9 percentage of participants |
| Dasatinib 70 mg BID | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | PFS at 24 Months | 33.1 percentage of participants |
| Dasatinib 70 mg BID | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | PFS at 36 Months | 26.6 percentage of participants |
| Dasatinib 70 mg BID | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | PFS at 48 Months | 20.5 percentage of participants |
| Dasatinib 70 mg BID | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | OS at 60 Months | 36.1 percentage of participants |
| Dasatinib 70 mg BID | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | OS at 24 Months | 48.7 percentage of participants |
| Dasatinib 70 mg BID | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | OS at 36 Months | 42.5 percentage of participants |
| Dasatinib 70 mg BID | Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population | OS at 48 Months | 38.2 percentage of participants |