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

Phase 3

Completed

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

Interventions: Drug: dasatinib

Registration Number: NCT00123487

Lead Sponsor: Bristol-Myers Squibb

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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 638

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
dasatinib Once a Day (QD)	dasatinib	140 mg dasatinib once a day (QD)
dasatinib Twice a Day (BID)	dasatinib	70 mg dasatinib twice a day (BID)

Primary Outcome Measures

Name	Time	Method
Percent of Participants With Major Hematologic Response (MaHR) With 6 Months of Follow-up From Date of Last Enrollment - Randomized Population	Randomization up to 6 months	MaHR defined by either complete hematologic response (CHR) or no evidence of leukemia (NEL). CHR defined as: white blood cells (WBC) ≤ upper limit of normal (ULN); absolute neutrophil count (ANC) ≥ 1,000/mm\^3; platelets ≥ 100,000/mm\^3; no blasts or promyelocytes in peripheral blood (PB); bone marrow (BM) blasts ≤ 5%; \<5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by same criteria as CHR except that platelets and ANC had to satisfy at least one of the following (note that both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \< 100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. After Year 2, Amendment 3 allowed participants to switch from the BID to the QD dosing schedule. Percentage: number of participants with MaHR/number of randomized participants.

Secondary Outcome Measures

Name	Time	Method
Median Time to Major Hematologic Response (MaHR) - Randomized Population	Day 1 up to 6 months (time of primary endpoint), 2 years	A participants' time to MaHR was defined as the time from the first dosing date until criteria are first met for CHR or NEL, whichever occurred first. Non-responders were censored at the maximum of the date of last hematologic or cytogenetic assessment. Median time was measured in months.
Number of Participants With Maximal QTcF Intervals up to Year 2 in Treated Participants	Baseline up to Year 2	A12-lead ECG was obtained at baseline (baseline=within 2 weeks prior to randomization) and once between Day 8 and 29. Additional ECGs were done at the Investigator's discretion. ECGs were read centrally. QT Interval corrected with Fridericia formula was measured in msec.
Number of Participants With Best Cytogenic Response (CyR) - Randomized Population	Randomization up to 6 Months, 2 Years	Cytogenetic assessments were performed only for the first 2 years of study. CyR was based on the number of Ph+ metaphases among cells in metaphase on a BM sample. The criteria for CyR were as follows: Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM; Partial cytogenetic response (PCyR): 1% to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: 36% to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: 66% to 95% Ph+ cells in metaphase in BM; No cytogenetic response: 96% to 100% Ph+ cells in metaphase in BM.
Median Overall Survival (OS) - Randomized Population	Randomization up to 5 Years	OS was defined as time from randomization until date of death. Participants who had not died or who were lost to follow-up were censored on the last date on which the participant was known to be alive. Median duration was measured in months.
Number of Participants With Normal Baseline Versus Worst Grade 3/4 Hematology Laboratory Abnormalities up to Year 2 in Treated Participants	Baseline to Year 2	Laboratory abnormalities were graded according to the National Cancer Institute Common Terminology Criteria (NCI CTC) version 3.0. CTC Grade 3 and 4 criteria are defined as follows: White blood cells (WBC): Grade (Gr) 3:\<2.0 to 1.0\10\^9/L, Gr 4:\<1.0\10\^9/L. Absolute neutrophil count (ANC): Gr 3:\<1.0 to 0.5\10\^9/L, Gr 4:\<0.5\10\^9/L. Platelet count Gr 3:\<50.0 to 25.0\*10\^9/L, Gr 4:\<25.0 to 10\^9/L. Hemoglobin Gr 3:\<8.0 to 6.5 g/dL, Gr 4:\<6.5 g/dL. Baseline was laboratory value obtained within 2 weeks prior to randomization.
Percent of Participants With Major Hematological Response (MaHR) With 2 Years of Follow-up From Date of Last Enrollment - Randomized Population	Randomization up to 2 years	A MaHR was defined as a participant having either CHR or NEL. CHR was defined as: WBC ≤ ULN; ANC ≥ 1,000/mm\^3; - platelets ≥ 100,000/mm\^3; - no blasts or promyelocytes in PB; BM blasts ≤ 5%; \< 5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by the same criteria as CHR except that platelets and ANC had to satisfy at least one of the following (both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \< 100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. After Year 2, Amendment 3 allowed participants to switch from the BID to the QD dosing schedule. Percent: number of participants with MaHR /number of participants randomized.
Percent of Participants With Major Hematologic Response (MaHR) by Disease Group - Randomized Population	Randomization up to 2 years	MaHR was defined by either complete hematologic response (CHR) or no evidence of leukemia (NEL). CHR defined as: white blood cells (WBC) ≤ upper limit of normal (ULN); absolute neutrophil count (ANC) ≥ 1,000/mm\^3; platelets ≥ 100,000/mm\^3; no blasts or promyelocytes in peripheral blood (PB); bone marrow (BM) blasts ≤ 5%; \<5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by same criteria as CHR except that platelets and ANC had to satisfy at least one parameter of the following (note that both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \< 100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. After Year 2, Amendment 3 allowed participants to switch from the BID to the QD dosing schedule.. Percentage: participants with MaHR/randomized participants.
Number of Participants With Best Confirmed Hematologic Response, Major Hematologic Response (MaHR) and Overall Hematologic Response - Randomized Population	Randomization up to 6 months, 2 years	Type of hematologic response: CHR defined as: WBC ≤ ULN; ANC ≥ 1,000/mm\^3; - platelets ≥ 100,000/mm\^3; - no blasts or promyelocytes in PB; BM blasts ≤ 5%; \< 5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by the same criteria as CHR except that platelets and ANC had to satisfy at least one of the following (note that both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \<100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. Minor Hematologic Response (MiHR): \<15% blasts in BM and in PB; \< 30% blasts + promyelocytes in BM and PB; \< 20% basophils in PB; No extra-medullary disease other than spleen and liver. Major hematologic response (MaHR ) was CHR or NEL. Overall hematologic response was CHR or NEL or MiHR.
Percent of Participants With Major Cytogenetic Response (MCyR) - Randomized Population	Randomization up to 6 Months, 2 Years	Cytogenetic assessments were performed only for the first 2 years of study. CyR was based on the number of Ph+ metaphases among cells in metaphase on a BM sample. The criteria for CyR were as follows: Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM; Partial cytogenetic response (PCyR): 1% to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: 36% to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: 66% to 95% Ph+ cells in metaphase in BM; No cytogenetic response: 96% to 100% Ph+ cells in metaphase in BM; Major cytogenetic response (MCyR) was defined as CCyR or PCyR. Percentage: number of participants with MCyR and denominator is number of randomized participants.
Median Progression Free Survival (PFS) - Randomized Population	Randomization up to 5 Years	PFS was defined as: Time from randomization until any of the following: Progression of disease (per investigator), or death. For those with blast phase CML or Ph+ ALL, disease progression was: loss of OHR; no decrease from on-study baseline percent blasts in PB or BM on all assessments over a 4-week period after starting maximum dose; absolute increase of at least 50% in PB blast count over a 2-week period after starting maximum dose. For those with accelerated phase CML: the list above also included: Development of blast phase CML at any time after initiation of therapy and development of extra-medullary sites other than spleen or liver. Participants who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. Median duration was measured in months.
Progression Free Survival (PFS) and Overall Survival (OS) at 24, 36, 48, and 60 Months - Randomized Population	24 months, 36 months, 48 months, 60 months	PFS was defined as time from randomization until any of the following: Progression of disease (per investigator), or death. For those with blast phase CML or Ph+ ALL, disease progression was: loss of OHR; no decrease from on-study baseline percent blasts in PB or BM on all assessments over a 4-week period after starting maximum dose; absolute increase of at least 50% in PB blast count over a 2-week period after starting maximum dose. For those with accelerated phase CML: the list above also included: Development of blast phase CML at any time after initiation of therapy and development of extra-medullary sites other than spleen or liver. Participants who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. OS was defined as time from randomization until date of death. Participants who had not died or were lost to follow-up were censored on the last date they were known to be alive. Median duration was measured in months.
Number of Participants With Grade 4 Myelosuppression Determined From Hematology Evaluations	Day 1 up to Year 7	Laboratory abnormalities were graded according to the National Cancer Institute Common Terminology Criteria (NCI CTC) Version 3.0. Grade 4 hematology evaluations used to determine myelosuppression included: WBC: \<1.0\10\^9/L. ANC: \<0.5\10\^9/L. Platelet count \<25.0 to 10\^9/L.
Median Duration of a Major Hematologic Response (MaHR) in Those Participants Who Achieved a MaHR During the Study	Day 1 up to 5 years	MaHR was defined by either CHR or no evidence of leukemia NEL. CHR was defined as: WBC ≤ ULN; ANC ≥ 1,000/mm\^3; - platelets ≥ 100,000/mm\^3; - no blasts or promyelocytes in PB; BM blasts ≤ 5%; \< 5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by the same criteria as CHR except that platelets and ANC had to satisfy at least one of the following (note that both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \< 100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. Median duration was measured in months.
Percent of Participants With Overall Hematologic Response - Randomized Population	Randomization up to 6 Months, 2 Years	Overall Hematologic Response (OHR) was defined as CHR, NEL or minor hematologic response (MiHR). CHR was defined as: WBC ≤ ULN; ANC ≥ 1,000/mm\^3; - platelets ≥ 100,000/mm\^3; - no blasts or promyelocytes in PB; BM blasts ≤ 5%; \< 5% myelocytes plus metamyelocytes in PB; basophils in PB \< 20%; no extra-medullar involvement (including no hepatomegaly or splenomegaly). NEL defined by the same criteria as CHR except that platelets and ANC had to satisfy at least one of the following (note that both lower limits had to be satisfied): platelets ≥ 20,000/mm\^3 and \< 100,000/mm\^3; ANC \> 500/mm\^3 and \<1,000/mm\^3. MiHR defined as: \< 15% blasts in BM and in PB; \< 30% blasts + promyelocytes in BM and PB; \< 20% basophils in PB; No extra-medullary disease other than spleen and liver. Percentage: participants with OHR/ randomized participants.
Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation and Drug-related Fluid Retention AEs, up to Year 7 in Treated Participants	Day 1 to Year 7	With protocol Amendment 6, the duration of the study was extended for 2 additional years (7 years total) for participants who continued to have clinical benefit and no feasible alternate access to dasatinib. However, after Year 5 the requirement to follow participants for survival and to collect other efficacy data was removed from the protocol for the remainder of the study. Only AEs and SAEs were collected up to Year 7. On-study AEs and SAEs were graded by severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. The investigator AE terms were coded and grouped by preferred term and system organ class using the Medical Dictionary for Regulatory Activities (MedDRA), version 16.0.
Number of Participants With Normal Baseline Versus Worst Grade 3/4 Biochemistry Laboratory Abnormalities up to Year 2 in Treated Participants	Baseline to Year 2	Laboratory abnormalities were graded according to the NCI CTC version 3.0. Grade 3 and 4 criteria were defined as follows: Upper limit of normal (ULN). Alanine transaminase (ALT) Grade (Gr) 3: \>5.0 to 20.0\ULN; Gr 4: \>20.0\ULN. Aspartate aminotransferase (AST) Gr 3: \>5.0 to 20.0\ULN; Gr 4: \>20.0\ULN. Total bilirubin Gr 3: \>3.0 to 10..0\ULN; Gr 4: \>10.0.0\ULN. Serum creatinine (H) Gr 3: \>3.0 to 6.0\ULN; Gr 4: \>6.0\ULN. Calcium (L) Gr3: 6.0-7.0; Gr 4: \<6.0 mg/dL; Phosphorus (L): Gr 3: \<2.0 - 1.0 mg/dL , Gr 4: \<1.0 mg/dL. Non-hematologic laboratory results were not collected beyond Year 2. Baseline values were obtained within 2 weeks prior to randomization.
Number of Participants With Changes From Baseline in QT Interval Corrected With Fridericia Formula (QTcF) up to Year 2 in Treated Participants	Baseline to Year 2	A12-lead electrocardiogram (ECG) was obtained at baseline (baseline=within 2 weeks prior to randomization) and once between Days 8 and 29. Additional ECGs were done at the Investigator's discretion. ECGs were read centrally. The QT interval corrected with Fridericia formula is presented with categories of changes from baseline (BL) in milliseconds (msec).

Trial Locations

Locations (27): The University Of North Carolina At Chapel Hill
🇺🇸
Chapel Hill, North Carolina, United States
Washington University School Of Medicine
🇺🇸
Saint Louis, Missouri, United States
Emory University School Of Medicine
🇺🇸
Atlanta, Georgia, United States
Ucla Dept. Of Medicine
🇺🇸
Los Angeles, California, United States
Loma Linda University Cancer Center
🇺🇸
Loma Linda, California, United States
Local Institution
🇬🇧
Liverpool, United Kingdom
Northwestern University
🇺🇸
Chicago, Illinois, United States
The University Of Chicago
🇺🇸
Chicago, Illinois, United States
Indiana University Cancer Center
🇺🇸
Indianapolis, Indiana, United States
Dana Faber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
Western Pennsylvania Cancer Institute
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Pittsburgh, Pennsylvania, United States
The University Of Texas Md Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Seattle Cancer Care Alliance
🇺🇸
Seattle, Washington, United States
New York Presbyterian Hospital
🇺🇸
New York, New York, United States
University Of Alabama At Birmingham
🇺🇸
Birmingham, Alabama, United States
University Of Miami
🇺🇸
Miami, Florida, United States
Oregon Health & Sci Univ
🇺🇸
Portland, Oregon, United States
University Of Kentucky
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Lexington, Kentucky, United States
Devetten, Marcel
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Omaha, Nebraska, United States
Washington Cancer Institute At Washington Hospital Center
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Washington, District of Columbia, United States
University Of Maryland
🇺🇸
Baltimore, Maryland, United States
Karmanos Cancer Center
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Detroit, Michigan, United States
Sarah Cannon Research Institute
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Nashville, Tennessee, United States
The Cancer Institute Of New Jersey
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New Brunswick, New Jersey, United States
Nebraska Methodist Hospital
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Omaha, Nebraska, United States
The Cancer Center At Hackensack University Medical Center
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Hackensack, New Jersey, United States