Chronic Myelogenous Leukemia (CML) - Follow on: Study of BMS-354825 in Subjects With CML
- Registration Number
- NCT00123474
- Lead Sponsor
- Bristol-Myers Squibb
- Brief Summary
This is a phase III study of BMS-354825 in subjects with chronic phase Philadelphia chromosome or BCR-ABL positive chronic myelogenous leukemia, who are resistant or intolerant to imatinib mesylate (Gleevec).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 724
- Subjects with Philadelphia chromosome positive (Ph+) (or BCR/ABL+) chronic phase chronic myeloid leukemia whose disease has primary or acquired hematologic resistance to imatinib mesylate or who are intolerant of imatinib mesylate.
- Men and women, 18 years 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.
- Women who are pregnant or breastfeeding
- Subjects who are eligible and willing to undergo transplantation during the screening period
- 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
- 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 2 dasatinib - 1 dasatinib - 3 dasatinib - 4 dasatinib -
- Primary Outcome Measures
Name Time Method Percent of Participants With Major Cytogenetic Response (MCyR) at 6 Months Follow-Up 6 months Cytogenetic response (CyR) was based on the number of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase on a Bone Marrow (BM) sample. The criteria for CyR were as follows: Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM; Partial cytogenetic response (PCyR): \>0 to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: \>35 to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: \>65 to 95% Ph+ cells in metaphase in BM; No cytogenetic response: \>95 to 100% Ph+ cells in metaphase in BM; Best CyR was defined as the best response obtained at any time during the study; MCyR was defined as a best CyR of complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Baseline=closest to, but no later than, the first day of study drug for treated participants and closest to, but no later than, the date of randomization, for those who were randomized but who never received treatment, unless otherwise specified.
- Secondary Outcome Measures
Name Time Method Time to MCyR in Participants With MCyR at 6 Months Follow-Up 6 months Time to MCyR was defined as the time from the first dosing date until criteria were first met for CCyR or PCyR, whichever occurred first. Non-responders were censored at the maximum time of all participants in their respective group (ie, maximum between time to MCyR response for responders and time to last cytogenetic assessment for non-responders).
Time to CHR in Participants With CHR at 6 Months Follow-Up 6 months Time to CHR was defined as the time from the first dosing date until criteria are first met for the response. Non-responders were censored at the maximum time of all participants in their respective group (ie, maximum between time to CHR response for responders and time to last hematologic assessment for non-responders).
Time to MCyR in Participants With MCyR at 24 Months Follow-Up 24 months Time to MCyR was defined as the time from the first dosing date until criteria were first met for CCyR or PCyR, whichever occurred first. Non-responders were censored at the maximum time of all participants in their respective group (ie, maximum between time to MCyR response for responders and time to last cytogenetic assessment for non-responders). Cytogenetic assessments were not done after the 2 Year Follow-up.
Time to CHR in Participants With CHR At 24 Months Follow-Up 24 months Time to CHR was defined as the time from the first dosing date until criteria are first met for the response. Non-responders were censored at the maximum time of all participants in their respective group (ie, maximum between time to CHR response for responders and time to last hematologic assessment for non-responders). Cytogenetic assessments were not done after the 2 Year Follow-up.
Number of Participants With MCyR Whose Disease Progressed by 24 Months 24 months Progression in a participant=participant achieved a CHR and no longer met the criteria consistently over consecutive 2-weeks after starting their maximum dose; had no CHR after receiving their maximum dose and had an increase in white blood count (WBC) defined as a doubling of the count from the lowest value to \>20,000/mm\^3 or an increase by \> 50,000/mm\^3 on two assessments performed at least 2 weeks apart; participant met criteria of accelerated or blast phase CML at any time; had a MCyR and subsequently no longer met the criteria for MCyR after starting their maximum dose; had a ≥ 30% absolute increase in the number of Ph+ metaphases. Although a related secondary endpoint was estimated duration of MCyR, medium duration of MCyR could not be estimated because the majority of participants with MCyR continued to respond, or could not be reliably estimated because of the large number of censored participants. Cytogenetic assessments were not done after the 24 month follow-up.
Number of Participants With CHR Whose Disease Progressed by 24 Months 24 months Progression in a participant=achieved a CHR and subsequently no longer met the criteria consistently over a consecutive 2-week period after starting their maximum dose; had no CHR after receiving their maximum dose and had an increase in white blood count (WBC) defined as a doubling of the count from the lowest value to \>20,000/mm\^3 or an increase by \> 50,000/mm\^3 on two assessments performed at least 2 weeks apart; met the criteria of accelerated or blast phase CML at any time; had a MCyR and subsequently no longer met the criteria for MCyR after starting their maximum dose; had a ≥ 30% absolute increase in the number of Ph+ metaphases. Although a related secondary endpoint was estimated duration of CHR, medium duration of CHR could not be estimated because the majority of participants with CHR continued to respond, or could not be reliably estimated because of the large number of censored participants.
Number of Participants With MCyR and Baseline BCR-ABL Gene Mutation - All Treated Participants Baseline up to 24 months BCR-ABL mutations were assessed in participants prior to the start of study drug (baseline) and at the time of disease progression or at end of therapy. Quantification of BCR-ABL transcripts in peripheral blood was evaluated using quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR, RT-PCR).
Percent of Participants With MCyR At or Prior to 24 Months Follow-Up 24 months CyR was based on the number of Ph+ metaphases among cells in metaphase on a Bone Marrow (BM) sample. The criteria for CyR were as follows: CCyR: 0% Ph+ cells in metaphase in BM; PCyR: \>0 to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: \>35 to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: \>65 to 95% Ph+ cells in metaphase in BM; No cytogenetic response: \>95 to 100% Ph+ cells in metaphase in BM; Best CyR was defined as the best response obtained at any time during the study; MCyR was defined as a best CyR of CCyR or PCyR. Baseline=closest to, but no later than, the first day of study drug for treated participants and closest to, but no later than, the date of randomization, for those who were randomized but who never received treatment, unless otherwise specified.
Percent of Participants With Complete Hematologic Response (CHR) at 6 and 24 Months Follow-Up 6 months, 24 months A complete hematologic response (CHR) was obtained when all the following criteria were met: White Blood Cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets \< 450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); \< 5% myelocytes plus metamyelocytes in PB; Basophils in PB \< 20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date.
Percent of Imatinib-Resistant Participants With Progression Free Survival (PFS) at 24, 36, 48, 60, 72, and 84 Months Follow-Up 24, 36, 48, 60, 72, and 84 months PFS= time from randomization until: CHR achieved and participant subsequently no longer met criteria for CHR over 2 weeks; no CHR after receiving maximum dose and an increase in WBC (ie, doubling of the count from the lowest value to \> 20,000/mm\^3 or an increase by \> 50,000/mm\^3 on 2 assessments performed 2 weeks apart); participant met criteria of accelerated phase or blast phase CML; participant had MCyR and subsequently no longer met criteria for MCyR after starting maximum dose; participant had a ≥ 30% absolute increase in number of Ph+ metaphases. Deaths without a reported prior progression were considered to have progressed on the date of death; those who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. When first progression reported during follow-up, it was censored at last on-study assessment. If the first progression reported during follow-up was death, participant considered to have progressed at date of death.
Percent of Imatinib-Resistant Participants With Overall Survival (OS) at 24, 36, 48, 60, 72, and 84 Months Follow-Up 24, 36, 48, 60, 72, and 84 months Overall survival (OS) was defined as the time from randomization until death. Survival data were collected for up to 5 years on participants who had discontinued dasatinib treatment. Participants who did not die or who were lost to follow-up were censored on the last date the participant was known to be alive.
Percent of Participants Intolerant to Imatinib With MCyR at 6 Months and at 24 Months Follow-Up, by QD and BID Schedules and by Total Daily Dose 6 months, 24 months 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; PCyR: \>0 to 35% Ph+ cells in metaphase in BM; Minor cytogenetic response: \>35 to 65% Ph+ cells in metaphase in BM; Minimal cytogenetic response: \>65 to 95% Ph+ cells in metaphase in BM; No cytogenetic response: \>95 to 100% Ph+ cells in metaphase in BM; Best CyR was defined as the best response obtained at any time during the study; MCyR was defined as a best CyR of CCyR or PCyR.
Percent of Participants Intolerant to Imatinib With CHR at 6 Months and at 24 Months Follow-Up 6 months, 24 months A CHR was obtained when all the following criteria were met: White Blood Cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets \< 450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); \< 5% myelocytes plus metamyelocytes in PB; Basophils in PB \< 20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date.
Percent of Imatinib Intolerant Participants With Progression Free Survival After 24, 36, 48, 60, 72, and 84 Months of Follow-Up 24, 36, 48, 60, 72, and 84 months PFS= time from randomization until: CHR achieved and participant subsequently no longer met criteria for CHR over 2 weeks; no CHR after receiving maximum dose and an increase in WBC (ie, doubling of the count from the lowest value to \> 20,000/mm\^3 or an increase by \> 50,000/mm\^3 on 2 assessments performed 2 weeks apart); participant met criteria of accelerated phase or blast phase CML; participant had MCyR and subsequently no longer met criteria for MCyR after starting maximum dose; participant had a ≥ 30% absolute increase in number of Ph+ metaphases. Deaths without a reported prior progression were considered to have progressed on the date of death; those who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. When first progression reported during follow-up, it was censored at last on-study assessment. If the first progression reported during follow-up was death, participant considered to have progressed at date of death.
Percent of Imatinib Intolerant Participants With Overall Survival After 24, 36, 48, 60, 72, and 84 Months of Follow-up 24, 36, 48, 60, 72, and 84 months Overall survival (OS) was defined as the time from randomization until death. Survival data were collected for up to 5 years on participants who had discontinued dasatinib treatment. Participants who did not die or who were lost to follow-up were censored on the last date the participant was known to be alive.
Percent of All Randomized Participants With Cytogenic and Hematologic Response by Dosing Schedule (QD or BID) and by Total Daily Dose (100 mg or 140 mg) at 6 Months Follow-Up 6 months Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM. Partial cytogenetic response (PCyR): \>0 to 35% Ph+ cells in metaphase in BM. MCyR: best cytogenetic response of CCyR or PCyR. A complete hematologic response (CHR) was obtained when all the following criteria were met: White Blood Cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets \< 450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); \< 5% myelocytes plus metamyelocytes in PB; Basophils in PB \< 20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date.
Percent of All Randomized Participants With Cytogenic and Hematologic Response by Dosing Schedule (QD or BID) and by Total Daily Dose (100 mg or 140 mg) at 24 Months Follow-Up 24 months Complete cytogenetic response (CCyR): 0% Ph+ cells in metaphase in BM. Partial cytogenetic response (PCyR): \>0 to 35% Ph+ cells in metaphase in BM. MCyR: best cytogenetic response of CCyR or PCyR. A complete hematologic response (CHR) was obtained when all the following criteria were met: White Blood Cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets \< 450,000/mm³; No blasts or promyelocytes in peripheral blood (PB); \< 5% myelocytes plus metamyelocytes in PB; Basophils in PB \< 20%; No extramedullary involvement (including no splenomegaly or hepatomegaly). Hematologic responses were counted anytime following 14 days after the dosing start date. No cytogenic assessments were made after 2 years of follow-up.
Percent of Participants With Progression Free Survival (PFS) at 24, 36, 48, 60, 72, and 84 Months Follow-Up by Dose Schedule and Total Daily Dose - All Randomized Participants 24, 36, 48, 60, 72, and 84 months PFS= time from randomization until: CHR achieved and participant subsequently no longer met criteria for CHR over 2 weeks; no CHR after receiving maximum dose and an increase in WBC (ie, doubling of the count from the lowest value to \> 20,000/mm\^3 or an increase by \> 50,000/mm\^3 on 2 assessments performed 2 weeks apart); participant met criteria of accelerated phase or blast phase CML; participant had MCyR and subsequently no longer met criteria for MCyR after starting maximum dose; participant had a ≥ 30% absolute increase in number of Ph+ metaphases. Deaths without a reported prior progression were considered to have progressed on the date of death; those who neither progressed nor died were censored on the date of their last cytogenetic or hematologic assessment. When first progression reported during follow-up, it was censored at last on-study assessment. If the first progression reported during follow-up was death, participant considered to have progressed at date of death.
Percent of Participants Overall Survival at 24, 36, 48, 60, 72, and 84 Months Follow-Up - All Randomized Participants 24, 36, 48, 60, 72, and 84 months Overall survival (OS) was defined as the time from randomization until death. Survival data were collected for up to 5 years on participants who had discontinued dasatinib treatment. Participants who did not die or who were lost to follow-up were censored on the last date the participant was known to be alive.
Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) That Led to Treatment Discontinuation at 24 Months of Follow-up Baseline to 30 days post last dose, up to 24 months AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Baseline=closest to, but no later than, the first day of study drug for treated participants.
Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) That Led toTreatment Discontinuation After 7 Year Follow-up Baseline to 30 days post last dose, up to 7 years (study closure July 2014) AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Baseline=closest to, but no later than, the first day of study drug for treated participants. After the 2-year analysis and Protocol Amendment 02, those on a BID dosing schedule were allowed to switch to a QD dosing schedule. Due to the large number of participants switching from BID dosing to QD dosing, the abbreviated dosing data collection method incorporated in Amendment 03, the overall safety data are presented for the 100 mg QD group and combined for the other treatment groups.
Trial Locations
- Locations (41)
Kaiser Permanente Medical Center
🇺🇸Vallejo, California, United States
University Of Maryland
🇺🇸Baltimore, Maryland, United States
Western Pennsylvania Cancer Institute
🇺🇸Pittsburgh, Pennsylvania, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Seattle Cancer Care Alliance
🇺🇸Seattle, Washington, United States
The University Of Texas Md Anderson Cancer Center
🇺🇸Houston, Texas, United States
Nevada Cancer Institute
🇺🇸Las Vegas, Nevada, United States
Emory University School Of Medicine
🇺🇸Atlanta, Georgia, United States
Georgia Cancer Specialists
🇺🇸Atlanta, Georgia, United States
Indiana University Cancer Center
🇺🇸Indianapolis, Indiana, United States
Ventura County Hematology-Oncology Specialists
🇺🇸Oxnard, California, United States
Ucla Dept. Of Medicine
🇺🇸Los Angeles, California, United States
Georgetown University Med Ctr
🇺🇸Washington, District of Columbia, United States
Ut Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Northwestern University Feinberg School Of Medicine
🇺🇸Chicago, Illinois, United States
Oncology Hematology Associates Of Central Illinois, Pc
🇺🇸Peoria, Illinois, United States
Washington Cancer Institute At Washington Hospital Center
🇺🇸Washington, District of Columbia, United States
Pacific Shores Medical Group
🇺🇸Long Beach, California, United States
University Of Chicago
🇺🇸Chicago, Illinois, United States
Dana Faber Cancer Institute
🇺🇸Boston, Massachusetts, United States
University Of Miami
🇺🇸Miami, Florida, United States
Washington University School Of Medicine
🇺🇸Saint Louis, Missouri, United States
The Cancer Institute Of New Jersey
🇺🇸New Brunswick, New Jersey, United States
Gwinnett Hospital System Inc.
🇺🇸Lawrenceville, Georgia, United States
New York Presbyterian Hospital
🇺🇸New York, New York, United States
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
University Of Alabama At Birmingham
🇺🇸Birmingham, Alabama, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
Pacific Cancer Medical Center Inc
🇺🇸Anaheim, California, United States
Central Hematology Oncology Medical Group Inc.
🇺🇸Alhambra, California, United States
Loma Linda University Cancer Center
🇺🇸Loma Linda, California, United States
The Cancer Center At Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Local Institution
🇬🇧Glasgow, United Kingdom
University Of Florida
🇺🇸Gainesville, Florida, United States
Md Anderson Cancer Center Orlando
🇺🇸Orlando, Florida, United States
University Of Kentucky
🇺🇸Lexington, Kentucky, United States
Nebraska Methodist Hospital
🇺🇸Omaha, Nebraska, United States
Devetten, Marcel
🇺🇸Omaha, Nebraska, United States
University Of North Carolina At Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
University Of Kansas Medical Center
🇺🇸Westwood, Kansas, United States