Rollover Study of BMS-354825 in Patients With CML and Ph+ALL

AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. Related AE=relationship of certain, probable, possible, or missing. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event.

Time frame: baseline; every 4 weeks (if on study < 6 months, including CA180-031(NCT00337454); every 12 weeks (if on study >=6 months and <=2 years); every 24 weeks (if on study >2 years); at discontinuation

Population: All treated participants. Number of deaths represents all reported deaths, including after the study end. For AEs leading to discontinuation: 4 in CML-CP=1 insufficient effect (IE) +3 AEs in Participant Flow (PF); 7 in CML-AP/BP= 1 death + 5 AEs + 1 IE in PF; 4 in Ph+ALL=3 IE + 1AE in PF.

Blood samples for pharmacokinetic analysis of Dasatinib BID that will contribute to population pharmacokinetic modeling were collected.

Time frame: At any visit of later than Day 7, draw sample(s) at pretreatment trough (within 1 hour prior to dosing) or between 3 hours following treatment and prior to the next dose

Population: There was no individual PK analysis done for this study; analyses were integrated and evaluated as a part of population PK of this drug.

Duration of CHR was computed only for chronic phase CML subjects whose best response is CHR. It was measured from the first day complete hematologic response criteria are met provided they are confirmed 28 days later until the date treatment is discontinued due to PD or death. Subjects who neither progressed nor died were censored on the date of their last hematologic assessment.

Time frame: baseline; every 4 weeks < 6 months on study (including study CA180031/NCT00337454); every 12 weeks >=6 months and <=2 years; every 24 weeks >2 years; at discontinuation

Population: Participants achieving CHR. Duration of CHR in the CML AP/BP arm has not yet been reached.

Major Hematologic Response (MaHR)=Complete Hematologic Response (CHR) or No Evidence of Leukemia (NEL; see Outcome Measures 14 and 15 for full definitions). Subjects who neither progressed nor died were censored on the date of their last hematologic assessment.

Time frame: baseline; every 4 weeks < 6 months on study (including study CA180031/NCT00337454); every 12 weeks >=6 months and <=2 years; every 24 weeks >2 years; at discontinuation

Population: Duration of MaHR was computed only for advanced diseases subjects whose best response is a MaHR and was measured from the first day MaHR criteria are met, provided they were confirmed 28 days later until the date of PD or death. Median Duration of MaHR was not yet reached in the CML-AP/BP arm.

The overall hematologic response (OHR) rate is defined as the proportion of all treated subjects with a best response of major or minor hematologic response. Subjects who neither progressed nor died were censored on the date of last hematologic assessment.

Time frame: baseline; every 4 weeks < 6 months on study (including study CA180031/NCT00337454); every 12 weeks >=6 months and <=2 years; every 24 weeks >2 years; at discontinuation

Population: Duration of OHR was computed only for participants whose best response was CHR or a MaHR or MiHR \& was measured from the first day hematologic response criteria were met, provided they were confirmed 28 days later until the date of PD or death. Median duration of OHR in the CML-AP/BP arm was not yet reached.

Cytogenetic responses (CyR) are based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow (BM) sample. The criteria for cytogenetic responses are as follows. Best CyR is defined as the best response obtained at any time during the study. Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR; 0 Ph+ Cells in Metaphase in BM), plus Partial Cytogenetic Response (PCyR; 1 - 35 Philadelphia positive \[Ph+\] Cells in Metaphase in BM).

Time frame: At baseline, every 24 weeks thereafter (including study CA180031/NCT00337454)

Population: Treated CML-CP participants

Cytogenetic responses (CyR) are based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow (BM) sample. The criteria for cytogenetic responses are as follows. Best CyR is defined as the best response obtained at any time during the study. Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR; 0 Ph+ Cells in Metaphase in BM), plus Partial Cytogenetic Response (PCyR; 1 - 35 Ph+ Cells in Metaphase in BM).

Time frame: At baseline, every 12 weeks up to 2 years on study (including study CA180031/NCT00337454), every 24 weeks thereafter

Population: Treated CML-AP/BP participants

Cytogenetic responses (CyR) are based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow (BM) sample. Complete Cytogenetic Response (CCyR) = 0 Ph+ Cells in Metaphase in BM. Duration of CCyR was measured from the time measurement criteria are first met for CCyR until the first date of PD or death. Subjects who neither relapsed nor died will be censored on the date of their last assessment.

Time frame: At baseline, every 12 weeks up to 2 years on study (including study CA180031/NCT00337454), every 24 weeks thereafter

Population: Participants achieving CCyR. Median duration of CCyR was not yet reached in the CML-AP/BP group.

Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR; 0 Ph+ Cells in Metaphase in BM), plus Partial Cytogenetic Response (PCyR; 1 - 35 Ph+ Cells in Metaphase in BM). Duration of MCyR was measured from the time measurement criteria are first met for CCyR or PCyR (whichever status is recorded first) until the first date of progressive disease (PD) or death. Subjects who neither relapsed nor died were censored on the date of their last assessment.

Time frame: At baseline, every 12 weeks up to 2 years on study (including study CA180031/NCT00337454), every 24 weeks thereafter

Population: Duration of MCyR was computed for subjects whose best response was either CCyR or PCyR. Median duration of MCyR was not yet reached in the CML-AP/BP arm.

Cytogenetic responses (CyR) are based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow (BM) sample. Complete Cytogenetic Response (CCyR) = 0 Ph+ Cells in Metaphase in BM. Time to complete CCyR is defined as the time from first dose of dasatinib until measurement criteria are first met for CCyR, and is computed only for subjects whose best response is CCyR.

Time frame: At baseline, every 12 weeks up to 2 years on study (including study CA180031/NCT00337454), every 24 weeks thereafter

Population: Participants achieving CCyR

Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR; 0 Ph+ Cells in Metaphase in BM), plus Partial Cytogenetic Response (PCyR; 1 - 35 Ph+ Cells in Metaphase in BM). Time to MCyR was defined as the time from first dose of dasatinib until measurement criteria were first met for CCyR or PCyR (whichever status is recorded first).

Time frame: At baseline, every 12 weeks up to 2 years on study (including study CA180031/NCT00337454), every 24 weeks thereafter

Population: Time to MCyR was computed only for participants whose best response was CCyR or PCyR.

Major Hematologic Response=Complete Hematologic Response (CHR) or No Evidence of Leukemia (NEL). CHR=WBC \<ULN; absolute neutrophil count (ANC) \>1,000/mm3; platelets \>100,000/mm3; no blasts or promyelocytes in peripheral blood; BM blasts ≤5%; \<5% myelocytes + metamyelocytes in peripheral blood; \<20% basophils in peripheral blood; no extramedullary involvement. NEL=(see Outcome Measure 15, below). Overall hematologic response (OHR)=best response of CHR, NEL or return to chronic phase (RTC).

Time frame: baseline; every 4 weeks < 6 months on study (including study CA180031/NCT00337454); every 12 weeks >=6 months and <=2 years; every 24 weeks >2 years; at discontinuation

Population: Treated CML-AP/BP participants

Cytogenetic responses (CyR) are based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow (BM) sample. Complete Cytogenetic Response (CCyR) = 0 Ph+ Cells in Metaphase in BM. Duration of CCyR was measured from the time measurement criteria are first met for CCyR until the first date of progressed disease (PD) or death. Subjects who neither relapsed nor died will be censored on the date of their last assessment.

Time frame: At baseline, every 24 weeks thereafter (including study CA180031/NCT00337454)

Population: Participants achieving CCyR. Median duration of CCyR was not yet reached in the CML-CP group.

Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR; 0 Ph+ Cells in Metaphase in BM), plus Partial Cytogenetic Response (PCyR; 1 - 35 Ph+ Cells in Metaphase in BM). Duration of MCyR was measured from the time measurement criteria are first met for CCyR or PCyR (whichever status is recorded first) until the first date of progressive disease (PD) or death. Subjects who neither relapsed nor died were censored on the date of their last assessment.

Time frame: At baseline, every 24 weeks thereafter (including study CA180031/NCT00337454)

Population: Duration of MCyR was computed for subjects whose best response was either CCyR or PCyR. Median duration of MCyR was not yet reached in the CML-CP arm.

CHR=all of the following criteria: white blood cell count (WBC) ≤institutional upper limit of normal(ULN); platelets \<450,000/mm³; no blasts or promyelocytes in peripheral blood; \<5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils \<20%; no extramedullary involvement.

Time frame: baseline; every 4 weeks < 6 months on study (including study CA180031/NCT00337454), every 12 weeks >=6 months and <=2 years; every 24 weeks >2 years; at discontinuation

Population: Treated CML-CP participants

Cytogenetic responses (CyR) are based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow (BM) sample. Complete Cytogenetic Response (CCyR) = 0 Ph+ Cells in Metaphase in BM. Time to complete CCyR is defined as the time from first dose of dasatinib until measurement criteria are first met for CCyR, and is computed only for subjects whose best response is CCyR.

Time frame: At baseline, every 24 weeks thereafter (including study CA180031/NCT00337454),

Population: Participants achieving CCyR

Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR; 0 Ph+ Cells in Metaphase in BM), plus Partial Cytogenetic Response (PCyR; 1 - 35 Ph+ Cells in Metaphase in BM). Time to MCyR was defined as the time from first dose of dasatinib until measurement criteria were first met for CCyR or PCyR (whichever status is recorded first).

Time frame: At baseline, every 24 weeks thereafter (including study CA180031/NCT00337454)

Population: Time to MCyR was computed only for participants whose best response was CCyR or PCyR.

Detectable BCR-ABL transcripts (b3a2, b2a2 or minor) \>=2.0 log copy/micrograms RNA, as measured by real-time quantitative PCR (RQ-PCR) at baseline and best achievement post-dose.

Time frame: At baseline, every 12 weeks up to 2 years on study (including study CA180031/NCT00337454), every 24 weeks thereafter, and at discontinuation

Population: Treated participants

Cytogenetic responses (CyR) are based on the percentage of Ph+ metaphases among at least 20 metaphase cells in each bone marrow (BM) sample. The criteria for cytogenetic responses are as follows. Best CyR is defined as the best response obtained at any time during the study. Major Cytogenetic Response (MCyR) = Complete Cytogenetic Response (CCyR; 0 Ph+ Cells in Metaphase in BM), plus Partial Cytogenetic Response (PCyR; 1 - 35 Ph+ Cells in Metaphase in BM).

Time frame: At baseline, every 12 weeks up to 2 years on study (including study CA180031/NCT00337454), every 24 weeks thereafter

Population: Treated Ph+ ALL participants

Major Hematologic Response=Complete Hematologic Response (CHR) or No Evidence of Leukemia (NEL). CHR=(see Outcome Measure 14, above). NEL=WBC ≤ULN; BM blasts ≤5%; no blasts or promyelocytes in peripheral blood; \<5% myelocytes plus metamyelocytes in peripheral blood; \<20% peripheral blood basophils; no extramedullary involvement; and at least 1 of the following: ANC ≥500/mm3 and \<2000/mm3 or platelets ≥20,000/mm3 and \<100,000/mm3. Overall hematologic response (OHR)=best response of CHR, NEL or return to chronic phase (RTC).

Time frame: baseline; every 4 weeks < 6 months on study (including study CA180031/NCT00337454); every 12 weeks >=6 months and <=2 years; every 24 weeks >2 years; at discontinuation

Population: Treated Ph+ ALL participants

Point mutations of BCR-ABL detected or undetected in the Quantitative real-time PCR polymerase chain reaction (RQ-PCR) products

Time frame: At baseline and discontinuation--the study period was extended until the launch of dasatinib in Japan, January 2009.

Population: Treated participants

CHR=all of the following criteria: WBC ≤institutional upper limit of normal(ULN); platelets \<450,000/mm³; no blasts or promyelocytes in peripheral blood; \<5% myelocytes plus metamyelocytes in peripheral blood; peripheral blood basophils \<20%; no extramedullary involvement. Time to CHR=time from first dose of dasatinib until the first day criteria for CHR are met provided they are confirmed 28 days later and was computed only for chronic phase CML subjects whose best response is CHR. Subjects who neither progressed nor died were censored at date of last hematologic assessment.

Time frame: baseline; every 4 weeks < 6 months on study (including study CA180031/NCT00337454); every 12 weeks >=6 months and <=2 years; every 24 weeks >2 years; at discontinuation

Population: Participants achieving CHR

Major Hematologic Response=Complete Hematologic Response (CHR) or No Evidence of Leukemia (NEL; see Outcome Measures 14 and 15 for full definitions). Time to major hematologic response (MaHR)=time from first dose of dasatinib until the first day the measurement criteria for MaHR and is computed only for advanced diseases subjects whose best response is a major hematologic response. Subjects who neither progressed nor died were censored on the date of their last hematologic assessment.

Time frame: baseline; every 4 weeks < 6 months on study (including study CA180031/NCT00337454); every 12 weeks >=6 months and <=2 years; every 24 weeks >2 years; at discontinuation

Population: Participants achieving MaHR

The overall hematologic response (OHR) rate is defined as the proportion of all treated subjects with a best response of major or minor hematologic response. Time to OHR = time from first dose of dasatinib until the first day measurement criteria are first met for hematologic response provided they were confirmed 28 days later. Subjects who neither progressed nor died were censored on the date of last hematologic assessment.

Time frame: baseline; every 4 weeks < 6 months on study (including study CA180031/NCT00337454); every 12 weeks >=6 months and <=2 years; every 24 weeks >2 years; at discontinuation

Population: OHR was computed only for subjects whose best response is CHR or MaHR or Minor HR (MiHR).