Advanced Chronic Myelogenous Leukemia (CML) - Follow On: Study of BMS-354825 in Subjects With CML

Study Overview
=================
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).

Official Title
-----------------
A Randomized Two-Arm, Multicenter, Open-Label Phase III Study of BMS-354825 Administered Orally at a Dose of 70 mg Twice Daily or 140 mg Once Daily in Subjects With Chronic Myeloid Leukemia in Accelerated Phase or in Myeloid or Lymphoid Blast Phase or With Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Who Are Resistant or Intolerant to Imatinib Mesylate (Gleevec)

Conditions
-----------------
Myeloid Leukemia, Chronic, Accelerated Phase, Leukemia, Lymphoblastic, Acute, Philadelphia-Positive

Intervention / Treatment
-----------------
* Drug: dasatinib
* Drug: dasatinib


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dasatinib Twice a Day (BID)<br>70 mg dasatinib twice a day (BID) | Drug: dasatinib<br>* Tablets, Oral, 140 mg QD, indefinitely, survival study<br>* Other names: BMS-354825;|
| Experimental: dasatinib Once a Day (QD)<br>140 mg dasatinib once a day (QD) | Drug: dasatinib<br>* Tablets, Oral, 70 mg BID, indefinitely, survival study<br>* Other names: BMS-354825;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Randomization up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Randomization up to 2 years | 
| 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. | Randomization up to 2 years | 
| 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. | Day 1 up to 6 months (time of primary endpoint), 2 years | 
| 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. | Day 1 up to 5 years | 
| 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. | Randomization up to 6 Months, 2 Years | 
| 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. | Randomization up to 6 months, 2 years | 
| 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. | Randomization up to 6 Months, 2 Years | 
| 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. | Randomization up to 6 Months, 2 Years | 
| 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. | Randomization up to 5 Years | 
| 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. | Randomization up to 5 Years | 
| 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. | 24 months, 36 months, 48 months, 60 months | 
| 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. | Day 1 to Year 7 | 
| 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. | Baseline to Year 2 | 
| 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. | Day 1 up to Year 7 | 
| 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. | Baseline to Year 2 | 
| 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). | Baseline to Year 2 | 
| 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. | Baseline up to Year 2 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Accelerated Phase Chronic Myeloid Leukemia, Lymphoid Blast Phase Chronic Myeloid Leukemia, Myeloid Blast Phase Chronic Myeloid Leukemia, Philadelphia Positive Acute Lymphoblastic Leukemia