Leukemia
Conditions
Brief summary
To determine the long term safety and tolerability of dasatinib exposure in subjects previously treated in CA180-002.
Interventions
DRUGDasatinib
Tablets, Oral, The dosing ranges from 50mg to a total of 240mg daily with the following 3 schedules: * 5 days on, 2 days off * 6 days on, 1 day off * Continuous daily dosing Once Daily (QD) or Twice Daily (BID) dosing, Subjects will be treated until progression of disease despite escalation/reductions of dose to the level deemed safe by available data, until intolerable/unacceptable toxicity or until subject withdrawal from the study or discontinuation of the study
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
This study enrolled participants with Philadelphia chromosome positive (Ph+)chronic myelogenous leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) who had demonstrated hematologic resistance or intolerance to imatinib mesylate (Gleevec) and had experienced clinical benefit (in Investigator's opinion) on protocol CA180002. Inclusion Criteria: * Signed written informed consent * Previous treatment with dasatinib on protocol CA180-002 and receiving clinical benefit in the opinion of the investigator * Completed a minimum of 3 months on protocol CA180-002 * Eastern Cooperative Oncology Group (ECOG)performance status 0, 1, or 2 (See Appendix 1) * Prior history of Ph+ chronic, accelerated, or blast phase CML or Ph+ ALL
Exclusion criteria
* Women of childbearing potential(WOCBP)who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 12 weeks after the study * WOCBP using a prohibited contraceptive method * Women who are pregnant or breastfeeding * Met the criteria as defined in protocol CA180-002 for discontinuation of therapy which includes: * Withdrawal of informed consent (subject's decision to withdraw for any reason) * Any clinical adverse event, laboratory abnormality or intercurrent illness which, in the opinion of the investigator, indicates that continued treatment with dasatinib is not in the best interest of the subject * Imprisonment or the compulsory detention for treatment of either a psychiatric or physical (e.g., infectious disease) illness Medical History and Concurrent Diseases * A serious uncontrolled medical disorder or active infection which would impair the ability of the patient to receive protocol therapy; * Uncontrolled angina within 3 months * Diagnosed or suspected congenital long QT syndrome * Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) * Prolonged corrected QT(QTc) interval on pre-entry electrocardiogram (\> 450 msec) * Uncontrolled hypertension * Dementia or altered mental status that would prohibit the understanding or rendering of informed consent; * History of significant bleeding disorder unrelated to CML, including: 1. Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease) 2. Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) Physical and Laboratory Test Findings * Total bilirubin ≥ 1.5 mg/dl * alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≥ 2 times the institutional upper limits of normal * Serum creatinine ≥ 1.5 times the institutional upper limits of normal Prohibited Therapies and/or Medications * Patients currently taking drugs that are generally accepted to have a risk of causing Torsades de Pointes including: * quinidine, procainamide, disopyramide * amiodarone, sotalol, ibutilide, dofetilide * erythromycins, clarithromycin * chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide * cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine. * Medications that inhibit platelet function and any non-steroidal anti-inflammatory drug) or anticoagulants are prohibited unless a previous exception on CA180-002 was granted by the medical monitor. Subjects taking anagrelide for thrombocytosis due to CML are eligible for this protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | From start of study until up to 30 days after end of study participation. Median duration of exposure (on-study time) was 23.4 months. | AEs: any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued the study due to AEs were recorded. These data differ from that in the Participant Flow section. This is because the data were collected on 2 different pages of the Case Report Form and were not reconciled. |
| Number of Participants Who Experienced Drug-related AEs and Drug-related SAEs. | From start of study until up to 30 days after end of study participation. Median duration of exposure (on-study time) was 23.4 months. | Drug-related AEs are those events with a relationship to the study therapy of certain; probable; or possible or missing. Drug-related SAEs are those events with any relationship to the study therapy. |
| Number of Participants With Grade 3-4 Hematology Abnormalities | From start of study until up to 30 days after end of study participation. Median duration of exposure (on-study time) was 23.4 months. | Abnormalities were graded per the National Cancer Institute(NCI)Common Toxicity Criteria (CTC), v3.0(Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening). Grade 3 and 4 criteria are as follows: Hemoglobin: Grade 3:6.5 - \<8.0g/dL, Grade 4: \<6.5g/dL. Platelets: Grade 3: 25.0 - \<50.0\*10\^9/L, Grade 4: \<25.0\*10. Absolute Neutrophil Count (ANC): Grade 3: 0.5 - \<1.0\*10\^9/L, Grade 4: \<0.5\*10\^9/L.White Blood Cells (WBC) : Grade 3: 1.0 - \<2.0\*10\^9/L, Grade 4: \<1.0\*10\^9/L. |
| Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | From start of study until up to 30 days after end of study participation. Median duration of exposure (on-study time) was 23.4 months. | Abnormalities were graded per the NCI (CTC), v3.0 (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening). Grade 3 and 4 criteria are as follows: Alanine aminotransferase (ALT): Grade 3: 5.0-20.0 \* ULN (upper limit of normal), Grade 4: \>20.0 \* ULN; Calcium: Grade 3: 6.0-\<7.0 or \>12.5-13.5 mg/dL, Grade 4: \<0.6-\>13.5 mg/dL; Bilirubin: Grade 3: \>3-10 \* ULN, Grade 4: \>10 \* ULN; Creatinine: Grade 3: \>3.0-6.0 \* ULN, Grade 4: \>6.0 \* ULN; Albumin: Grade 3: \<2g/dL (Grade 4 not defined in NCI CTC); Magnesium: Grade 3: 0.6-\<0.8 or \>2.46-6.6mEq/L, Grade 4: \<0.6 or \>6.6mEq/L. |
| Number of Participants With Dose Interruptions and Dose Reductions | From start of study to final assessment (up to 32.2 months). | Dose interruptions and reductions were allowed, in order to optimize individual participant's hematologic, cytogenetic, and molecular response while maintaining and evaluating safety and tolerability of long-term exposure to dasatinib. A dose reduction is defined as the administration of a dose at a lower level compared to previous dose and such that reduced dose, or a lower dose, is given at least 4 consecutive times. In determining the reductions, dose level would be compared to the previous non-null dose. Dose interruption is defined as a complete omission of dosing for 4 consecutive times. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Number of Months of Progression-free Survival (PFS) (Kaplan Meier Method) | Baseline to study discontinuation. Median duration of exposure (on-study time) was 23.4 months. | Interval between randomization date & earliest date of disease progression/death due to any cause, assessed by the Independent Radiology Review Committee (IRRC) using modified World Health Organization (WHO) criteria to define progressive disease (PD): \>=25% increase in sum of products of diameters (SOPD) of lesions compared with smallest SOPD recorded for study period or progression of any non-index lesion/appearance of new lesion. If no progression/death, date of last tumor assessment used. For participants who had no on-study tumor assessments & were still alive, date of randomization used. |
| Number of Participants With Complete Hematologic Response (CHR) | Pre-treatment to study discontinuation. Median duration of exposure (on-study time) was 23.4 months. | CHR should meet all of the following criteria: WBC \<= Institutional ULN; ANC \>= 1000/mm\^3 ; Platelets \< 450 000/mm\^3 , no blasts or promyelocytes in peripheral blood; \< 5% myelocytes plus metamyelocytes in peripheral blood; basophils in peripheral blood \< 20% and no extramedullary involvement (including no hepatomegaly or splenomegaly). CHR can begin only 14 days after the start of treatment. |
| Median Number of Months of Overall Survival (OS) (Kaplan Meier Method) | Baseline to study discontinuation. Median duration of exposure (on-study time) was 23.4 months. | Overall survival was defined as the median number of months from baseline to death from any cause. |
| Median Number of Months of CHR (Kaplan Meier Method) | Pre-treatment to study discontinuation. Median duration of exposure (on-study time) was 23.4 months. | CHR: WBC\<=ULN (range: 9.29-12.5\*10\^3 c\\uL); ANC \>=1000/mm\^3;Platelets \<450000/mm\^3,no blasts/promyelocytes in peripheral blood; \<5% myelocytes+metamyelocytes in peripheral blood; basophils in peripheral blood \<20% & no extramedullary involvement. Duration computed for chronic phase participants, measured in months from first day CHR criteria met, provided they are confirmed 4 weeks later, until progression of disease, treatment discontinuation due to progressive disease or death. Participants who neither discontinue due to progression, nor progress nor die censored on date of last assessment. |
| Number of Participants With Major Cytogenetic Response (MCyR) | Pre-treatment to study discontinuation. Median duration of exposure (on-study time) was 23.4 months. | Cytogenetic responses are based on the prevalence of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase on a bone marrow sample. MCyR is defined as number of participants with Complete Cytogenetic Response (CCyR): 0% Ph+ cells in metaphase in bone marrow or Partial Cytogenetic Response (PCyR): \>0% to 35% Ph+ cells in metaphase in bone marrow. |
| Median Number of Months of Major Cytogenetic Response (MCyR) | Pre-treatment to study discontinuation. Median duration of exposure (on-study time) was 23.4 months. | MCyR: 0% Ph+ cells in metaphase in bone marrow or Partial Cytogenetic Response (PCyR): \>0% to 35% Ph+ cells in metaphase in bone marrow.The duration of MCyR was computed for chronic phase participants whose best response is either CCyR or PCyR. It was measured in months from the time measurement criteria are first met for CCyR or PCyR (whichever status is recorded first) until the date of progression or death. Participants who neither progress nor die are censored on the date of their last cytogenetic assessment. |
| Number of Participants With Best Cytogenetic Response | Pre-treatment to study discontinuation. Median duration of exposure (on-study time) was 23.4 months. | Cytogenetic responses are based on the prevalence of Ph+ metaphases among cells in metaphase on a bone marrow sample. CCyR: 0% Ph+ cells in metaphase in bone marrow, PCyR: \>0% to 35% Ph+ cells in metaphase in bone marrow, Minor CyR: \>35% to 65% Ph+ cells in metaphase in bone marrow, Minimal CyR: \>65% to 95% Ph+ cells in metaphase in bone marrow and No CyR: \>95% to 100% Ph+ cells in metaphase in bone marrow. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry Participants with Chronic Myelogenous Leukemia (CML)were continued on the last dose and schedule of dasatinib that was received within the previous protocol CA180002 (NCT00064233). A total daily dose (TDD) of 50 mg, 75 mg, 105 mg, 140 mg or 180 mg dasatinib was taken once daily (QD). Participants were dosed on 1 of 3 schedules (5 days on, 2 days off; 6 days on, 1 day off or continuous daily dosing) and were permitted to escalate or reduce by 1 dose level at a time, switch from QD dosing to BID dosing and vice versa provided they did not exceed a change of 1 dose level from the TDD. The weekly schedule was also permitted to be increased or decreased 1 level at a time. | 22 |
| CML: BID Dosing at Study Entry Participants with CML were continued on the last dose and schedule of dasatinib that was received within the previous protocol CA180002 (NCT00064233). Treatment was received BID, with a TDD of 50 mg, 70 mg, 100 mg, 140 mg, 180 mg or 240 mg dasatinib. Participants were dosed on 1 of 3 schedules (5 days on, 2 days off; 6 days on, 1 day off or continuous daily dosing) and were permitted to escalate or reduce by 1 dose level at a time, switch from QD dosing to BID dosing and vice versa provided they did not exceed a change of 1 dose level from the TDD. The weekly schedule was also permitted to be increased or decreased 1 level at a time. | 15 |
| Accelerated Phase CML: BID Dosing at Study Entry Participants with accelerated phase CML were continued on the last dose and schedule of dasatinib that was received within the previous protocol CA180002 (NCT00064233). A TDD of 50 mg, 75 mg, 105 mg, 120 mg, 140 mg or 180 mg dasatinib was taken QD or split into 2 doses and taken BID (TDD of 50 mg, 70 mg, 100 mg, 140 mg, 180 mg or 240 mg). Participants were dosed on 1 of 3 schedules (5 days on, 2 days off; 6 days on, 1 day off or continuous daily dosing) and were permitted to escalate or reduce by 1 dose level at a time, switch from QD dosing to BID dosing and vice versa provided they did not exceed a change of 1 dose level from the TDD. The weekly schedule was also permitted to be increased or decreased 1 level at a time. | 5 |
| Myeloid Blast Phase CML: BID Dosing at Study Entry Participants with myeloid blast phase CML were continued on the last dose and schedule of dasatinib that was received within the previous protocol CA180002 (NCT00064233). A TDD of 50 mg, 75 mg, 105 mg, 120 mg, 140 mg or 180 mg dasatinib was taken QD or split into 2 doses and taken BID (TDD of 50 mg, 70 mg, 100 mg, 140 mg, 180 mg or 240 mg). Participants were dosed on 1 of 3 schedules: 5 days on, 2 days off; 6 days on, 1 day off; or continuous daily dosing and were permitted to escalate or reduce by 1 dose level at a time, switch from QD dosing to BID dosing and vice versa provided they did not exceed a change of 1 dose level from the TDD. The weekly schedule was also permitted to be increased or decreased 1 level at a time. | 4 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Administrative reason | 3 | 3 | 1 | 0 |
| Overall Study | Adverse Event | 5 | 2 | 0 | 0 |
| Overall Study | Death | 4 | 1 | 1 | 0 |
| Overall Study | Deterioration without progression | 0 | 1 | 0 | 0 |
| Overall Study | Disease progression/relapse | 5 | 4 | 2 | 2 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Overall Study | No response | 1 | 0 | 0 | 0 |
| Overall Study | Participant's request | 1 | 0 | 0 | 0 |
| Overall Study | Study closure | 3 | 4 | 1 | 1 |
Baseline characteristics
| Characteristic | Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | CML: BID Dosing at Study Entry | Accelerated Phase CML: BID Dosing at Study Entry | Myeloid Blast Phase CML: BID Dosing at Study Entry | Total |
|---|---|---|---|---|---|
| Age Continuous | 58 years | 68 years | 63 years | 51 years | 64 years |
| Age, Customized < 65 years | 12 participants | 5 participants | 3 participants | 4 participants | 24 participants |
| Age, Customized >= 65 years | 10 participants | 10 participants | 2 participants | 0 participants | 22 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 = fully active | 18 participants | 13 participants | 3 participants | 4 participants | 38 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 1 = restricted physically strenuous activity | 4 participants | 1 participants | 2 participants | 0 participants | 7 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 2 = ambulatory but unable to work | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 3 = capable of only limited self care | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 4 = completely disabled | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 5 = dead | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Not reported | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black/African American | 2 participants | 3 participants | 1 participants | 0 participants | 6 participants |
| Race/Ethnicity, Customized Caucasian | 18 participants | 11 participants | 3 participants | 3 participants | 35 participants |
| Race/Ethnicity, Customized Other races | 2 participants | 0 participants | 1 participants | 1 participants | 4 participants |
| Sex: Female, Male Female | 11 Participants | 7 Participants | 4 Participants | 1 Participants | 23 Participants |
| Sex: Female, Male Male | 11 Participants | 8 Participants | 1 Participants | 3 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 5 | 21 / 22 | 15 / 15 | 4 / 4 |
| serious Total, serious adverse events | 3 / 5 | 10 / 22 | 9 / 15 | 3 / 4 |
Outcome results
Primary
Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation.
AEs: any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued the study due to AEs were recorded. These data differ from that in the Participant Flow section. This is because the data were collected on 2 different pages of the Case Report Form and were not reconciled.
Time frame: From start of study until up to 30 days after end of study participation. Median duration of exposure (on-study time) was 23.4 months.
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | Deaths | 3 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | SAEs | 10 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | AEs | 22 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | Discontinuation due to AEs | 4 participants |
| CML: BID Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | SAEs | 9 participants |
| CML: BID Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | AEs | 15 participants |
| CML: BID Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | Discontinuation due to AEs | 3 participants |
| CML: BID Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | Deaths | 2 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | AEs | 5 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | SAEs | 3 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | Discontinuation due to AEs | 1 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | Deaths | 1 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | Discontinuation due to AEs | 0 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | SAEs | 3 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | Deaths | 1 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Adverse Events (AEs) and AEs Leading to Study Drug Discontinuation. | AEs | 4 participants |
Primary
Number of Participants Who Experienced Drug-related AEs and Drug-related SAEs.
Drug-related AEs are those events with a relationship to the study therapy of certain; probable; or possible or missing. Drug-related SAEs are those events with any relationship to the study therapy.
Time frame: From start of study until up to 30 days after end of study participation. Median duration of exposure (on-study time) was 23.4 months.
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants Who Experienced Drug-related AEs and Drug-related SAEs. | Drug-related SAEs | 4 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants Who Experienced Drug-related AEs and Drug-related SAEs. | Drug-related AEs | 14 participants |
| CML: BID Dosing at Study Entry | Number of Participants Who Experienced Drug-related AEs and Drug-related SAEs. | Drug-related AEs | 9 participants |
| CML: BID Dosing at Study Entry | Number of Participants Who Experienced Drug-related AEs and Drug-related SAEs. | Drug-related SAEs | 4 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants Who Experienced Drug-related AEs and Drug-related SAEs. | Drug-related AEs | 3 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants Who Experienced Drug-related AEs and Drug-related SAEs. | Drug-related SAEs | 1 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants Who Experienced Drug-related AEs and Drug-related SAEs. | Drug-related SAEs | 1 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants Who Experienced Drug-related AEs and Drug-related SAEs. | Drug-related AEs | 3 participants |
Primary
Number of Participants With Dose Interruptions and Dose Reductions
Dose interruptions and reductions were allowed, in order to optimize individual participant's hematologic, cytogenetic, and molecular response while maintaining and evaluating safety and tolerability of long-term exposure to dasatinib. A dose reduction is defined as the administration of a dose at a lower level compared to previous dose and such that reduced dose, or a lower dose, is given at least 4 consecutive times. In determining the reductions, dose level would be compared to the previous non-null dose. Dose interruption is defined as a complete omission of dosing for 4 consecutive times.
Time frame: From start of study to final assessment (up to 32.2 months).
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Dose Interruptions and Dose Reductions | Dose reductions | 8 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Dose Interruptions and Dose Reductions | Dose interruptions | 7 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Dose Interruptions and Dose Reductions | Dose interruptions | 9 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Dose Interruptions and Dose Reductions | Dose reductions | 4 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants With Dose Interruptions and Dose Reductions | Dose reductions | 2 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants With Dose Interruptions and Dose Reductions | Dose interruptions | 2 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants With Dose Interruptions and Dose Reductions | Dose reductions | 1 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants With Dose Interruptions and Dose Reductions | Dose interruptions | 2 participants |
Primary
Number of Participants With Grade 3-4 Hematology Abnormalities
Abnormalities were graded per the National Cancer Institute(NCI)Common Toxicity Criteria (CTC), v3.0(Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening). Grade 3 and 4 criteria are as follows: Hemoglobin: Grade 3:6.5 - \<8.0g/dL, Grade 4: \<6.5g/dL. Platelets: Grade 3: 25.0 - \<50.0\*10\^9/L, Grade 4: \<25.0\*10. Absolute Neutrophil Count (ANC): Grade 3: 0.5 - \<1.0\*10\^9/L, Grade 4: \<0.5\*10\^9/L.White Blood Cells (WBC) : Grade 3: 1.0 - \<2.0\*10\^9/L, Grade 4: \<1.0\*10\^9/L.
Time frame: From start of study until up to 30 days after end of study participation. Median duration of exposure (on-study time) was 23.4 months.
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | WBC | 2 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | ANC | 3 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | Platelet Count | 3 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | Hemoglobin | 0 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | ANC | 1 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | Platelet Count | 1 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | Hemoglobin | 1 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | WBC | 1 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | Platelet Count | 0 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | ANC | 0 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | Hemoglobin | 1 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | WBC | 0 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | Hemoglobin | 1 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | ANC | 2 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | WBC | 0 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Hematology Abnormalities | Platelet Count | 1 participants |
Primary
Number of Participants With Grade 3-4 Serum Chemistry Abnormalities
Abnormalities were graded per the NCI (CTC), v3.0 (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening). Grade 3 and 4 criteria are as follows: Alanine aminotransferase (ALT): Grade 3: 5.0-20.0 \* ULN (upper limit of normal), Grade 4: \>20.0 \* ULN; Calcium: Grade 3: 6.0-\<7.0 or \>12.5-13.5 mg/dL, Grade 4: \<0.6-\>13.5 mg/dL; Bilirubin: Grade 3: \>3-10 \* ULN, Grade 4: \>10 \* ULN; Creatinine: Grade 3: \>3.0-6.0 \* ULN, Grade 4: \>6.0 \* ULN; Albumin: Grade 3: \<2g/dL (Grade 4 not defined in NCI CTC); Magnesium: Grade 3: 0.6-\<0.8 or \>2.46-6.6mEq/L, Grade 4: \<0.6 or \>6.6mEq/L.
Time frame: From start of study until up to 30 days after end of study participation. Median duration of exposure (on-study time) was 23.4 months.
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low Albumin | 1 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | High ALT | 1 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | High Total Bilirubin | 0 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low Calcium | 0 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low Magnesium | 0 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | High Serum Creatinine | 0 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low Magnesium | 0 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low Albumin | 0 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | High ALT | 1 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | High Total Bilirubin | 0 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | High Serum Creatinine | 0 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low Calcium | 0 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | High Serum Creatinine | 0 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low Magnesium | 0 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low Calcium | 0 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low Albumin | 0 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | High Total Bilirubin | 0 participants |
| Accelerated Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | High ALT | 0 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low Magnesium | 0 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | High ALT | 0 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | High Serum Creatinine | 0 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | High Total Bilirubin | 0 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low Calcium | 0 participants |
| Myeloid Blast Phase CML: BID Dosing at Study Entry | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities | Low Albumin | 0 participants |
Secondary
Median Number of Months of CHR (Kaplan Meier Method)
CHR: WBC\<=ULN (range: 9.29-12.5\*10\^3 c\\uL); ANC \>=1000/mm\^3;Platelets \<450000/mm\^3,no blasts/promyelocytes in peripheral blood; \<5% myelocytes+metamyelocytes in peripheral blood; basophils in peripheral blood \<20% & no extramedullary involvement. Duration computed for chronic phase participants, measured in months from first day CHR criteria met, provided they are confirmed 4 weeks later, until progression of disease, treatment discontinuation due to progressive disease or death. Participants who neither discontinue due to progression, nor progress nor die censored on date of last assessment.
Time frame: Pre-treatment to study discontinuation. Median duration of exposure (on-study time) was 23.4 months.
Population: All treated participants with CML (whether QD or BID dosing), who had CHR. Data were not analyzed and reported for the other two groups (Accelerated Phase CML and Myeloid Blast Phase CML) due to small sample sizes.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Median Number of Months of CHR (Kaplan Meier Method) | 52.0 months |
Secondary
Median Number of Months of Major Cytogenetic Response (MCyR)
MCyR: 0% Ph+ cells in metaphase in bone marrow or Partial Cytogenetic Response (PCyR): \>0% to 35% Ph+ cells in metaphase in bone marrow.The duration of MCyR was computed for chronic phase participants whose best response is either CCyR or PCyR. It was measured in months from the time measurement criteria are first met for CCyR or PCyR (whichever status is recorded first) until the date of progression or death. Participants who neither progress nor die are censored on the date of their last cytogenetic assessment.
Time frame: Pre-treatment to study discontinuation. Median duration of exposure (on-study time) was 23.4 months.
Population: All treated participants with CML (whether QD or BID dosing), who had MCyR (13 participants had MCyR in QD group and 9 in BID group). Data were not analyzed and reported for the other two groups (Accelerated Phase CML and Myeloid Blast Phase CML) due to small sample sizes.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Median Number of Months of Major Cytogenetic Response (MCyR) | 50.1 months |
Secondary
Median Number of Months of Overall Survival (OS) (Kaplan Meier Method)
Overall survival was defined as the median number of months from baseline to death from any cause.
Time frame: Baseline to study discontinuation. Median duration of exposure (on-study time) was 23.4 months.
Population: All treated participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Median Number of Months of Overall Survival (OS) (Kaplan Meier Method) | NA months |
Secondary
Median Number of Months of Progression-free Survival (PFS) (Kaplan Meier Method)
Interval between randomization date & earliest date of disease progression/death due to any cause, assessed by the Independent Radiology Review Committee (IRRC) using modified World Health Organization (WHO) criteria to define progressive disease (PD): \>=25% increase in sum of products of diameters (SOPD) of lesions compared with smallest SOPD recorded for study period or progression of any non-index lesion/appearance of new lesion. If no progression/death, date of last tumor assessment used. For participants who had no on-study tumor assessments & were still alive, date of randomization used.
Time frame: Baseline to study discontinuation. Median duration of exposure (on-study time) was 23.4 months.
Population: All treated participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Median Number of Months of Progression-free Survival (PFS) (Kaplan Meier Method) | 32.0 months |
Secondary
Number of Participants With Best Cytogenetic Response
Cytogenetic responses are based on the prevalence of Ph+ metaphases among cells in metaphase on a bone marrow sample. CCyR: 0% Ph+ cells in metaphase in bone marrow, PCyR: \>0% to 35% Ph+ cells in metaphase in bone marrow, Minor CyR: \>35% to 65% Ph+ cells in metaphase in bone marrow, Minimal CyR: \>65% to 95% Ph+ cells in metaphase in bone marrow and No CyR: \>95% to 100% Ph+ cells in metaphase in bone marrow.
Time frame: Pre-treatment to study discontinuation. Median duration of exposure (on-study time) was 23.4 months.
Population: All treated participants with evaluable sample sizes. Data was not analyzed and reported for the Accelerated Phase CML and Myeloid Blast Phase CML groups due to small sample sizes, which would lead to response rate estimates that are not stable.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Best Cytogenetic Response | Minimal (66-95%) | 3 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Best Cytogenetic Response | Partial (1-35%) | 3 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Best Cytogenetic Response | No response | 4 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Best Cytogenetic Response | Complete (0%) | 10 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Best Cytogenetic Response | Unable to determine | 2 participants |
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Best Cytogenetic Response | Minor (36-65%) | 0 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Best Cytogenetic Response | Unable to determine | 1 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Best Cytogenetic Response | Complete (0%) | 7 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Best Cytogenetic Response | Partial (1-35%) | 2 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Best Cytogenetic Response | Minimal (66-95%) | 1 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Best Cytogenetic Response | No response | 3 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Best Cytogenetic Response | Minor (36-65%) | 1 participants |
Secondary
Number of Participants With Complete Hematologic Response (CHR)
CHR should meet all of the following criteria: WBC \<= Institutional ULN; ANC \>= 1000/mm\^3 ; Platelets \< 450 000/mm\^3 , no blasts or promyelocytes in peripheral blood; \< 5% myelocytes plus metamyelocytes in peripheral blood; basophils in peripheral blood \< 20% and no extramedullary involvement (including no hepatomegaly or splenomegaly). CHR can begin only 14 days after the start of treatment.
Time frame: Pre-treatment to study discontinuation. Median duration of exposure (on-study time) was 23.4 months.
Population: All treated participants. Data was not analyzed and reported for the other two groups (Accelerated Phase CML and Myeloid Blast Phase CML) due to small sample sizes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Complete Hematologic Response (CHR) | 16 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Complete Hematologic Response (CHR) | 13 participants |
Secondary
Number of Participants With Major Cytogenetic Response (MCyR)
Cytogenetic responses are based on the prevalence of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase on a bone marrow sample. MCyR is defined as number of participants with Complete Cytogenetic Response (CCyR): 0% Ph+ cells in metaphase in bone marrow or Partial Cytogenetic Response (PCyR): \>0% to 35% Ph+ cells in metaphase in bone marrow.
Time frame: Pre-treatment to study discontinuation. Median duration of exposure (on-study time) was 23.4 months.
Population: All treated participants with evaluable sample sizes. Data was not analyzed and reported for the Accelerated Phase CML and Myeloid Blast Phase CML groups due to small sample sizes, which would lead to response rate estimates that are not stable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chronic Myelogenous Leukemia (CML): QD Dosing at Study Entry | Number of Participants With Major Cytogenetic Response (MCyR) | 13 participants |
| CML: BID Dosing at Study Entry | Number of Participants With Major Cytogenetic Response (MCyR) | 9 participants |