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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00123474
First received: July 21, 2005
Last updated: July 29, 2015
Last verified: July 2015
  Purpose

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).


Condition Intervention Phase
Myeloid Leukemia, Chronic, Chronic-Phase
Drug: dasatinib
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Two-by-Two, Multicenter, Open-Label Phase III Study of BMS-354825 Administered Orally at a Dose of 50 mg or 70 mg Twice Daily or 100 mg or 140 mg Once Daily in Subjects With Chronic Phase Philadelphia Chromosome or BCR-ABL Positive Chronic Myelogenous Leukemia Who Are Resistant or Intolerant to Imatinib Mesylate (Gleevec)

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Percent of Participants With Major Cytogenetic Response (MCyR) After at Least 6 Months Follow-Up [ Time Frame: Baseline and after at least 6 months follow-up ] [ Designated as safety issue: No ]
    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:
  • Percent of Participants With MCyR At or Prior to 24 Months Follow-Up [ Time Frame: Baseline and after at least 24 months follow-up ] [ Designated as safety issue: No ]
    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) After at Least 6 and 24 Months Follow-Up [ Time Frame: Baseline and after at least 6 and 24 months follow-up ] [ Designated as safety issue: No ]
    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.

  • Time to MCyR in Participants With MCyR After At Least 6 Months Follow-Up [ Time Frame: Baseline and after at least 6 months follow-up ] [ Designated as safety issue: No ]
    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 After at Least 6 Months Follow-Up [ Time Frame: Baseline and after at least 6 months follow-up ] [ Designated as safety issue: No ]
    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 After at Least 24 Months Follow-Up [ Time Frame: Baseline and after at least 24 months follow-up ] [ Designated as safety issue: No ]
    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 After at Least 24 Months Follow-Up [ Time Frame: Baseline and after at least 24 months follow-up ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and after at least 24 months follow-up ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and after at least 24 months follow-up ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline to Year 2 ] [ Designated as safety issue: No ]
    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 Imatinib-Resistant Participants With Progression Free Survival (PFS) After at Least 24, 36, 48, 60, 72, and 84 Months Follow-Up [ Time Frame: Baseline and after 84 months follow-up ] [ Designated as safety issue: No ]
    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) After at Least 24, 36, 48, 60, 72, and 84 Months Follow-Up [ Time Frame: Baseline and after 84 months follow-up ] [ Designated as safety issue: No ]
    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 After at Least 6 Months and After at Least 24 Months Follow-Up, by QD and BID Schedules and by Total Daily Dose [ Time Frame: Baseline and after at Least 6 Months and 24 Months Follow-Up ] [ Designated as safety issue: No ]
    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 After at Least 6 Months and After at Least 24 Months Follow-Up [ Time Frame: Baseline and after at Least 6 Months and 24 Months Follow Up ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and after 84 months follow-up ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and after 84 months follow-up ] [ Designated as safety issue: No ]
    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) After at Least 6 Months Follow-Up [ Time Frame: Baseline and after at least 6 months follow-up ] [ Designated as safety issue: No ]
    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) After at Least 24 Months Follow-Up [ Time Frame: Baseline and after at least 24 months follow-up ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and after 84 Months Follow-up ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline up to 84 Months Follow-up ] [ Designated as safety issue: No ]
    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.

  • Baseline and After 2 Years Follow-Up: Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) That Led to Treatment Discontinuation [ Time Frame: Baseline and after 2 Years Follow-Up ] [ Designated as safety issue: Yes ]
    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.

  • Baseline and After 7 Years Follow-Up and Study Closure: Number of Participants With Death, Serious Adverse Events (SAEs), Adverse Events (AEs) That Led toTreatment Discontinuation [ Time Frame: Baseline to 30 days post last dose;7 years follow up; study closure July 2014 ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 724
Study Start Date: July 2005
Study Completion Date: July 2014
Primary Completion Date: September 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: dasatinib
Tablets, Oral, 50 mg BID, indefinitely, survival study
Other Names:
  • Sprycel
  • BMS-354825
Experimental: 2 Drug: dasatinib
Tablets, Oral, 70 mg BID, indefinitely, survival study
Other Names:
  • Sprycel
  • BMS-354825
Experimental: 3 Drug: dasatinib
Tablets, Oral, 100 mg QD, indefinitely, survival study
Other Names:
  • Sprycel
  • BMS-354825
Experimental: 4 Drug: dasatinib
Tablets, Oral, 140 mg QD, indefinitely, survival study
Other Names:
  • Sprycel
  • BMS-354825

  Eligibility

Ages Eligible for Study:   18 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com.

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00123474

  Show 137 Study Locations
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00123474     History of Changes
Other Study ID Numbers: CA180-034
Study First Received: July 21, 2005
Results First Received: June 29, 2015
Last Updated: July 29, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Bristol-Myers Squibb:
Chronic Phase Chronic Myelogenous Leukemia

Additional relevant MeSH terms:
Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Leukemia, Myeloid, Chronic-Phase
Bone Marrow Diseases
Hematologic Diseases
Myeloproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Dasatinib
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on August 27, 2015