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

Study Overview
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Brief Summary
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To assess the safety of dasatinib (BMS-354825) in subjects with Imatinib resistant or intolerant chronic myelogenous leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) who are resistant or intolerant to treatment and will continue study drug after completing the previous Phase I/II study (CA180031/NCT00337454)

Official Title
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A Study to Document the Long-Term Safety and Efficacy of BMS-354825 in Subjects With Imatinib Resistant or Intolerant Chronic Myelogenous Leukemia and Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Who Are Resistant or Intolerant to Previous Treatment and Have Completed the Previous Phase I/II Protocol (CA180-031/NCT00337454)

Conditions
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Chronic Myelogenous Leukemia, Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who were eligible and completed the previous Phase I and II study (CA180031/NCT00337454) and for whom the principal investigator has deemed that continuation of study drug is in the best interest of the subject Exclusion Criteria: Women who are pregnant or breastfeeding Subjects who are eligible and willing to undergo transplantation at pre-study Non-hematologic intolerance to Dasatinib (BMS-354825) in the previous Phase I and II study (CA180031/NCT00337454)

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dasatinib (CML-CP)<br>CML - Chronic Phase | Drug: dasatinib<br>* Tablet, Oral, (50mg, 70mg or 90mg BID on a continuous daily dosing schedule), allowed to modify within the range of 50 mg twice daily (BID) to 90 mg BID<br>* Other names: BMS-354825;|
| Experimental: dasatinib (CML-AP/BP)<br>CML - Accelerated Phase and Blast Phase | Drug: dasatinib<br>* Tablet, Oral, (50mg, 70mg or 90mg BID on a continuous daily dosing schedule), allowed to modify within the range of 50 mg twice daily (BID) to 90 mg BID<br>* Other names: BMS-354825;|
| Experimental: dasatinib (Ph+ ALL)<br>Ph+ Acute Lymphoblastic Leukemia | Drug: dasatinib<br>* Tablet, Oral, (50mg, 70mg or 90mg BID on a continuous daily dosing schedule), allowed to modify within the range of 50 mg twice daily (BID) to 90 mg BID<br>* Other names: BMS-354825;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuation | 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Chronic Phase CML (CML-CP): Percentage of Participants With Cytogenetic Response | 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). | At baseline, every 24 weeks thereafter (including study CA180031/NCT00337454) | 
| Participants With CML-Accelerated or Blast Phase (AP/BP): Percentage of Participants With Cytogenetic Response | 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). | At baseline, every 12 weeks up to 2 years on study (including study CA180031/NCT00337454), every 24 weeks thereafter | 
| Participants With Ph+ Acute Lymphoblastic Leukemia (Ph+ ALL): Percentage of Participants With Cytogenetic Response | 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). | At baseline, every 12 weeks up to 2 years on study (including study CA180031/NCT00337454), every 24 weeks thereafter | 
| Participants With CML-CP: Time to Complete Cytogenetic Response (CCyR) | 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. | At baseline, every 24 weeks thereafter (including study CA180031/NCT00337454), | 
| Participants With CML-AP/BP and Ph+ ALL: Time to Complete Cytogenetic Response (CCyR) | 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. | At baseline, every 12 weeks up to 2 years on study (including study CA180031/NCT00337454), every 24 weeks thereafter | 
| Participants With CML-CP: Duration of Complete Cytogenetic Response (CCyR) | 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. | At baseline, every 24 weeks thereafter (including study CA180031/NCT00337454) | 
| Participants With CML-AP/BP and Ph+ALL: Duration of Complete Cytogenetic Response (CCyR) | 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. | At baseline, every 12 weeks up to 2 years on study (including study CA180031/NCT00337454), every 24 weeks thereafter | 
| Participants With CML-CP: Time to Major Cytogenetic Response (MCyR) | 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). | At baseline, every 24 weeks thereafter (including study CA180031/NCT00337454) | 
| Participants With CML-AP/BP and Ph+ALL: Time to Major Cytogenetic Response (MCyR) | 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). | At baseline, every 12 weeks up to 2 years on study (including study CA180031/NCT00337454), every 24 weeks thereafter | 
| Participants With CML-CP: Duration of Major Cytogenetic Response (MCyR) | 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. | At baseline, every 24 weeks thereafter (including study CA180031/NCT00337454) | 
| Participants With CML-AP/BP and Ph+ ALL: Duration of Major Cytogenetic Response (MCyR) | 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. | At baseline, every 12 weeks up to 2 years on study (including study CA180031/NCT00337454), every 24 weeks thereafter | 
| Participants With CML-CP: Percentage of Participants With Complete Hematologic Response (CHR) | 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. | 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 | 
| Participants With CML-AP/BP: Percentage of Participants With Hematologic Response | 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). | 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 | 
| Participants With Ph+ ALL: Percentage of Participants With Hematologic Response | 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). | 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 | 
| Time to Complete Hematologic Response (CHR) in Chronic Phase CML, Accelerated or Blast Phase CML, and Ph+ALL | 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. | 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 | 
| Duration of Complete Hematologic Response (CHR) in Chronic Phase CML, Accelerated or Blast Phase CML, and Ph+ALL | 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. | 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 | 
| Time to Major Hematologic Response (MaHR) in Accelerated or Blast Phase CML, and Ph+ALL | 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. | 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 | 
| Duration of Major Hematologic Response (MaHR) in Accelerated or Blast Phase CML, and Ph+ALL | 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. | 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 | 
| Time to Overall Hematologic Response (OHR) in Accelerated or Blast Phase CML, and Ph+ALL | 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. | 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 | 
| Duration of Overall Hematologic Response (OHR) in Accelerated or Blast Phase CML, and Ph+ALL | 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. | 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 | 
| Participants With Detectable Mutations of RNA (mRNA) of BCR-ABL at Baseline and at Best Achievement | 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. | At baseline, every 12 weeks up to 2 years on study (including study CA180031/NCT00337454), every 24 weeks thereafter, and at discontinuation | 
| Status of Point Mutations of BCR-ABL at Baseline (BL) and End of Study (EOS) | Point mutations of BCR-ABL detected or undetected in the Quantitative real-time PCR polymerase chain reaction (RQ-PCR) products | At baseline and discontinuation--the study period was extended until the launch of dasatinib in Japan, January 2009. | 
| Collection of Blood Samples for Pharmacokinetic Analysis of Dasatinib Twice Daily (BID) That Will Contribute to Population Pharmacokinetic Modeling | Blood samples for pharmacokinetic analysis of Dasatinib BID that will contribute to population pharmacokinetic modeling were collected. | 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 |