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Dasatinib (BMS-354825) in Subjects With Myeloid Blast Phase Chronic Myeloid Leukemia Resistant to or Intolerant of Imatinib Mesylate

Sponsor
Bristol-Myers Squibb (Industry)
Overall Status
Completed
CT.gov ID
NCT00101816
Collaborator
(none)
124
Enrollment
62
Locations
1
Arm
39
Duration (Months)
2
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to see what effect an investigational drug (BMS-354825) has on subjects who are currently in the myeloid blast phase of chronic myeloid leukemia (CML) and who are either resistant to or intolerant of imatinib mesylate. Another purpose of the study is to see what side effects this drug may have on subjects.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
124 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase II Study of BMS-354825 in Subjects With Myeloid Blast Phase Chronic Myeloid Leukemia Resistant to or Intolerant of Imatinib Mesylate
Study Start Date :
Dec 1, 2004
Actual Primary Completion Date :
Aug 1, 2006
Actual Study Completion Date :
Mar 1, 2008

Arms and Interventions

Arm Intervention/Treatment
Experimental: 1

Drug: Dasatinib
Tablets, Oral, 70 mg, twice daily, Until disease progression or intolerable toxicity, switch to the roll-over study or study closure.
Other Names:
  • BMS-354825
  • Sprycel

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Major and Overall Hematologic Response (MaHR and OHR) [Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment]

      MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). Criteria for MaHR are specified in Outcome Measure 2. OHR=best confirmed response of MaHR or minor HR (MiHR). MiHR= <15% blasts in bone marrow and <15% blasts in peripheral blood (PB); <30% blasts + promyelocytes in bone marrow and <30% blasts + promyelocytes in PB; <20% basophils in PB; no extramedullary disease other than spleen and liver. Confirmed hematologic response=response confirmed ≥4 weeks after first documented event with no concomitant use of anagrelide or hydroxyurea.

    Secondary Outcome Measures

    1. Median Duration of Major Hematologic Response (MaHR) [Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment]

      MaHR=best confirmed response of CHR or NEL. CHR=white blood cells ≤ institutional upper limit of normal (iULN); absolute neutrophil count (ANC) ≥1000/mm3; platelets ≥100,000/mm3; no blasts/promyelocytes in peripheral blood (PB); bone marrow blasts ≤5%; <5% myelocytes+metamyelocytes in PB; PB basophils ≤ iULN; no extramedullary involvement. NEL=WBC ≤ iULN; no blasts/promyelocytes in PB; bone marrow blasts ≤5%; <5% myelocytes+metamyelocytes in PB; PB basophils ≤ iULN; no extramedullary involvement; at least 1 of the following: ANC ≥500/mm3 & <1000/mm3; platelets ≥20,000/mm3 & <100,000/mm3.

    2. Median Duration of Overall Hematologic Response (OHR) [Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment]

      OHR=best confirmed response of MaHR or MiHR. MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). Criteria for MaHR are specified in Outcome Measure 2. Criteria for MiHR are specified in Outcome Measure 1. Maintaining a response was defined as no 2 consecutive records of non-response (ie, a single record of non-response between 2 assessments of response was not considered a loss of response).

    3. Time to MaHR and OHR [Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment]

      Median time from first dosing to date of OHR and/or MaHR in subjects who achieved OHR and MaHR. MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). OHR=best confirmed response of MaHR or minor hematologic response (MiHR). Criteria for MaHR are specified in Outcome Measure 2. Criteria for MiHR are specified in Outcome Measure 1.

    4. Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response [Baseline (within 4 weeks of therapy start); Every month for Cycles 1-3; Every 12 weeks for Cycles 4+; end of treatment]

      Best confirmed cytogenetic response. Determination of cytogenetic response is based on the prevalence (percentage) of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase in a bone marrow sample (aspirates/biopsies).

    5. Number of Participants With CHR or NEL, MiHR, or no Hematologic Response [Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycles 1 and 2; After every 2nd cycle for Cycles 3+; at end of treatment]

      Best confirmed hematologic response. Confirmed hematologic response=response that is confirmed after at least 4 weeks with no concomitant use of anagrelide or hydroxyurea use during this interval. Criteria for complete hematologic response (CHR) or No Evidence of Leukemia (NEL) are specified in Outcome Measure 2. Criteria for minor hematologic response (MiHR) are specified in Outcome Measure 1.

    6. Number of Participants Achieving Major Molecular Response (MMR) [Baseline, every 12 weeks, and at time of Complete Cytogenetic Response (CCyR) for quantitative Polyermase Chain Reaction (qPCR) analysis]

      Number of participants who achieved an MMR at any time during the treatment period. MMR was calulated by measuring BCR-ABL transcripts in blood during treatment using quantitative reverse transcription-polymerase chain reaction (RT-PCR). BCR-ABL=the fused gene found in subjects with this type of Chronic Myeloid Leukemia (CML).

    7. MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations [baseline, at time of disease progression]

      MaHR and MCyR in subjects with mutations at baseline, including imatinib-resistant mutations (IRM) and specific BCR-ABL mutations (SBAM). Criteria for MaHR are specified in Outcome Measure 2. MCyR=rate of complete cytogenetic responses + the rate of partial cytogenetic responses, as defined in Outcome Measure 5. BCR-ABL=the fused gene found in subjects with this type of CML. This table contains those mutations observed in at least 3 participants. The categories "1 IRM w/2-4-fold increase in resistance" and "≥1 IRM w/≥5-fold increase in resistance" refer to increase in resistance to imatinib.

    8. Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G) [Baseline, Every 2 weeks for the first 3 cycles, following every 4-week cycle, and once at follow-up]

      Number of subjects with minimally significant changes from baseline in the health-related quality of life questionnaire FACT-G. FACT-G=27 questions in 4 domains: physical, social/family, emotional, & functional well-being (PWB, SWB, EWB, FWB). Score range: 0-108; higher scores=better health-related quality of life. Total Score change of 7 or more=minimal clinical important change; PWB, EWB, & FWB score change of 3 or more, & SWB score change of 2 or more=minimal clinical important change.

    9. Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs [Continuously throughout study, from pre-treatment visit through end of study (due to death, unacceptable toxicity, treatment failure, etc) and follow-up period]

      AE=any new untoward medical occurrence or worsening of a pre-existing medical condition regardless of causal relationship with treatment. SAE=any untoward medical occurrence at any dose that: results in death; is life-threatening; requires or prolongs inpatient hospitalization; results in persistent or significant disability; is cancer; is congenital anomaly/birth defect; results in drug dependency/abuse; is an important medical event. Graded by National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. (1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening/disabling, 5=Death)

    10. Pharmacokinetics (PK) of Dasatinib - Maximum Observed Plasma Concentration (Cmax) [Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.]

      The Cmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared.

    11. Pharmacokinetics (PK) of Dasatinib - Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point Within the Dosing Interval of 12 h or 24 h(AUC[0-T]) [Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.]

      The AUC(0-T) was calculated using the mixed log-linear trapezoidal algorithm in Kinetica™. In the calculation of AUC(0-T), predose concentrations that were < lower limit of qualtitation were assigned a value of zero.

    12. Pharmacokinetics (PK) of Dasatinib - Time to Maximum Observed Plasma Concentration (Tmax) [Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.]

      The Tmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared.

    13. Pharmacokinetics (PK) of Dasatinib - Plasma Half-life (T-HALF) [Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.]

      The T-HALF was calculated as Ln2/Lz,where Lz was the absolute value of the slope of the terminal log-linear phase.

    14. Pharmacokinetics (PK) of Dasatinib's Metabolite BMS-582691 - Maximum Observed Plasma Concentration (Cmax) [Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.]

      The Cmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared.

    15. Pharmacokinetics (PK) of Dasatinib's Metabolite BMS-582691 - Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point Within the Dosing Interval of 12 h (AUC[0-T]) [Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.]

      The AUC(0-T) was calculated using the mixed log-linear trapezoidal algorithm in Kinetica™. In the calculation of AUC(0-T), predose concentrations that were less than the lower limit of quantitation (LLQ) were assigned a value of zero.

    16. Pharmacokinetics (PK) of Dasatinib's Metabolite BMS-582691 - Time to Maximum Observed Plasma Concentration (Tmax) [Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.]

      The Tmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared.

    17. Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Plasma Half-life (T-HALF) [Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.]

      The T-HALF was calculated as Ln2/Lz,where Lz was the absolute value of the slope of the terminal log-linear phase.

    18. Population PK of Dasatinib [Day 8 immediately prior to the first daily dose and between 30 minutes to 3 hours following this dose.]

      Population pharmacokinetic analysis was not done because it is not meaningful for this single study

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Subjects with myeloid blast phase chronic myeloid leukemia

    • Subjects who are either resistant or intolerant of imatinib mesylate

    Exclusion Criteria:

    • Subjects who are eligible and willing to undergo transplantation

    • Serious uncontrolled medical disorder or active infection

    • Uncontrolled or significant heart problems, such as congestive heart failure, recent heart attack, etc

    • Subjects receiving medications that may affect heart rhythm

    • Other malignancy/cancer other than CML

    • History of significant bleeding disorder unrelated to CML

    • Pregnant or breastfeeding women (subjects must avoid becoming pregnant)

    • Subjects received imatinib within 7 days, interferon or cytarabine within 14 days, a targeted anticancer medication within 14 days, an antineoplastic agent (other than hydroxyurea or anagrelide) within 28 days, or any other investigation medication in 28 days

    • Subject is receiving medications that affect platelet function or an anticoagulant

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Local Institution Birmingham Alabama United States
    2 Local Institution Anaheim California United States
    3 Local Institution Los Angeles California United States
    4 Local Institution Stanford California United States
    5 Local Institution Vallejo California United States
    6 Local Institution Denver Colorado United States
    7 Local Institution Jacksonville Florida United States
    8 Local Institution Tampa Florida United States
    9 Local Institution Atlanta Georgia United States
    10 Local Institution Chicago Illinois United States
    11 Local Institution Kansas City Kansas United States
    12 Local Institution Baltimore Maryland United States
    13 Local Institution Boston Massachusetts United States
    14 Local Institution Detroit Michigan United States
    15 Local Institution St. Louis Missouri United States
    16 Local Institution Hackensack New Jersey United States
    17 Local Institution New Brunswick New Jersey United States
    18 Local Institution New York New York United States
    19 Local Institution Portland Oregon United States
    20 Local Institution Pittsburgh Pennsylvania United States
    21 Local Institution Nashville Tennessee United States
    22 Local Institution Houston Texas United States
    23 Local Institution Seattle Washington United States
    24 Local Institution Adelaide South Australia Australia
    25 Local Institution Wien Austria
    26 Local Institution B-Leuven Belgium
    27 Local Institution Edegem Belgium
    28 Local Institution Montreal Quebec Canada
    29 Local Institution Aarhus Denmark
    30 Local Institution Helsinki Finland
    31 Local Institution Lille France
    32 Local Institution Lyon Cedex 03 France
    33 Local Institution Nantes France
    34 Local Institution Paris Cedex 10 France
    35 Local Institution Pessac France
    36 Local Institution Poitiers Cedex France
    37 Local Institution Strasbourg Cedex France
    38 Local Institution Hamburg Germany
    39 Local Institution Mainz Germany
    40 Local Institution Mannheim Germany
    41 Local Institution Ramat-Gan Israel
    42 Local Institution Bologna Italy
    43 Local Institution Napoli Italy
    44 Local Institution Orbassano Italy
    45 Local Institution Roma Italy
    46 Local Institution Jeollanam-Do Korea, Republic of
    47 Local Institution Kyunggi-Do Korea, Republic of
    48 Local Institution Seoul Korea, Republic of
    49 Local Institution Nijmegen Netherlands
    50 Local Institution Rotterdam Netherlands
    51 Local Institution Trondheim Norway
    52 Local Institution Quezon City Philippines
    53 Local Institution Singapore Singapore
    54 Local Institution Gothenburg Sweden
    55 Local Institution Lund Sweden
    56 Local Institution Umea Sweden
    57 Local Institution Uppsala Sweden
    58 Local Institution Basel Switzerland
    59 Local Institution Taipei Taiwan
    60 Local Institution Taoyuan Taiwan
    61 Local Institution Glasgow Central United Kingdom
    62 Local Institution London Greater London United Kingdom

    Sponsors and Collaborators

    • Bristol-Myers Squibb

    Investigators

    • Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    , ,
    ClinicalTrials.gov Identifier:
    NCT00101816
    Other Study ID Numbers:
    • CA180-006
    • NCT00108719
    First Posted:
    Jan 14, 2005
    Last Update Posted:
    Aug 10, 2010
    Last Verified:
    Jun 1, 2010
    Keywords provided by , ,
    Myeloid blast phase Chronic Myeloid Leukemia (CML)
    Additional relevant MeSH terms:
    Leukemia
    Leukemia, Myeloid
    Leukemia, Myelogenous, Chronic, BCR-ABL Positive
    Blast Crisis
    Dasatinib

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail A total of 124 participants were enrolled in this study; 15 were never treated (11 participants did not meet inclusion criteria; 3 participants died; 1 participant failed screening).
    Arm/Group Title Imatinib-intolerant Imatinib-resistant
    Arm/Group Description Defined as: i) Toxicity that was considered at least possibly related to imatinib ≤400 mg/day that led to a discontinuation of imatinib therapy ii) Ability to tolerate only <400 mg/day imatinib. A subject who tolerated 400 mg/day imatinib, but was intolerant of higher doses was not considered imatinib-intolerant. Receiving oral dasatinib at a starting dose of 70 mg twice daily (BID), with dose modifications as necessary for the management of disease progression or toxicity. Defined as any of the following: i) Subjects initially diagnosed with chronic phase chronic myeloid leukemia (CML) who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥400 mg/day. ii) Subjects initially diagnosed with accelerated phase CML who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). iii) Subjects initially diagnosed with myeloid blast phase CML who meet the criteria for myeloid phase blast crisis after at least 4 weeks of treatment prescribed at a dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). Each of these definitions includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance). Oral dasatinib 70 mg BID, with dose modifications as necessary to manage disease progression or toxicity.
    Period Title: Overall Study
    STARTED 10 99
    COMPLETED 10 99
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title Imatinib-intolerant Imatinib-resistant Total
    Arm/Group Description Defined as: i) Toxicity that was considered at least possibly related to imatinib ≤400 mg/day that led to a discontinuation of imatinib therapy ii) Ability to tolerate only <400 mg/day imatinib. A subject who tolerated 400 mg/day imatinib, but was intolerant of higher doses was not considered imatinib-intolerant. Receiving oral dasatinib at a starting dose of 70 mg twice daily (BID), with dose modifications as necessary for the management of disease progression or toxicity. Defined as any of the following: i) Subjects initially diagnosed with chronic phase chronic myeloid leukemia (CML) who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥400 mg/day. ii) Subjects initially diagnosed with accelerated phase CML who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). iii) Subjects initially diagnosed with myeloid blast phase CML who meet the criteria for myeloid phase blast crisis after at least 4 weeks of treatment prescribed at a dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). Each of these definitions includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance). Oral dasatinib 70 mg BID, with dose modifications as necessary to manage disease progression or toxicity. Total of all reporting groups
    Overall Participants 10 99 109
    Age, Customized (participants) [Number]
    Between 21 and 45 years
    1
    10%
    35
    35.4%
    36
    33%
    Between 46 and 65 years
    7
    70%
    46
    46.5%
    53
    48.6%
    Between 66 and 75 years
    1
    10%
    18
    18.2%
    19
    17.4%
    >75 years
    1
    10%
    0
    0%
    1
    0.9%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    60.5
    (10.9)
    50.4
    (14.0)
    51.4
    (14.0)
    Sex: Female, Male (Count of Participants)
    Female
    3
    30%
    60
    60.6%
    63
    57.8%
    Male
    7
    70%
    39
    39.4%
    46
    42.2%
    Race/Ethnicity, Customized (Number) [Number]
    Asian
    0
    0%
    18
    18.2%
    18
    16.5%
    Black or African American
    0
    0%
    13
    13.1%
    13
    11.9%
    White
    10
    100%
    67
    67.7%
    77
    70.6%
    Other
    0
    0%
    1
    1%
    1
    0.9%
    Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) (Number) [Number]
    Score=0
    1
    10%
    21
    21.2%
    22
    20.2%
    Score=1
    6
    60%
    39
    39.4%
    45
    41.3%
    Score=2
    2
    20%
    33
    33.3%
    35
    32.1%
    Score=3
    0
    0%
    2
    2%
    2
    1.8%
    Score=4
    0
    0%
    0
    0%
    0
    0%
    Score=5
    0
    0%
    0
    0%
    0
    0%
    Not Reported
    1
    10%
    4
    4%
    5
    4.6%
    Functional Assessment of Cancer Therapy-General (FACT-G) (units on a scale) [Mean (Standard Deviation) ]
    Total FACT-G
    65.6
    (7.1)
    69.2
    (16.0)
    68.9
    (15.4)
    Physical Well Being
    17.2
    (3.8)
    16.4
    (6.3)
    16.5
    (6.1)
    Social/Family Well-Being
    20.1
    (23.6)
    22.1
    (4.7)
    21.9
    (4.7)
    Emotional Well-Being
    15.3
    (2.1)
    16.8
    (5.3)
    16.7
    (5.2)
    Functional Well-Being
    13.0
    (4.5)
    13.9
    (5.9)
    13.8
    (5.7)

    Outcome Measures

    1. Primary Outcome
    Title Major and Overall Hematologic Response (MaHR and OHR)
    Description MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). Criteria for MaHR are specified in Outcome Measure 2. OHR=best confirmed response of MaHR or minor HR (MiHR). MiHR= <15% blasts in bone marrow and <15% blasts in peripheral blood (PB); <30% blasts + promyelocytes in bone marrow and <30% blasts + promyelocytes in PB; <20% basophils in PB; no extramedullary disease other than spleen and liver. Confirmed hematologic response=response confirmed ≥4 weeks after first documented event with no concomitant use of anagrelide or hydroxyurea.
    Time Frame Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment

    Outcome Measure Data

    Analysis Population Description
    All treated subjects
    Arm/Group Title Imatinib-intolerant Imatinib-resistant Total
    Arm/Group Description Defined as: i) Toxicity that was considered at least possibly related to imatinib ≤400 mg/day that led to a discontinuation of imatinib therapy ii) Ability to tolerate only <400 mg/day imatinib. A subject who tolerated 400 mg/day imatinib, but was intolerant of higher doses was not considered imatinib-intolerant. Receiving oral dasatinib at a starting dose of 70 mg twice daily (BID), with dose modifications as necessary for the management of disease progression or toxicity. Defined as any of the following: i) Subjects initially diagnosed with chronic phase chronic myeloid leukemia (CML) who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥400 mg/day. ii) Subjects initially diagnosed with accelerated phase CML who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). iii) Subjects initially diagnosed with myeloid blast phase CML who meet the criteria for myeloid phase blast crisis after at least 4 weeks of treatment prescribed at a dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). Each of these definitions includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance). Oral dasatinib 70 mg BID, with dose modifications as necessary to manage disease progression or toxicity.
    Measure Participants 10 99 109
    MaHR
    2
    20%
    34
    34.3%
    36
    33%
    OHR
    4
    40%
    50
    50.5%
    54
    49.5%
    2. Secondary Outcome
    Title Median Duration of Major Hematologic Response (MaHR)
    Description MaHR=best confirmed response of CHR or NEL. CHR=white blood cells ≤ institutional upper limit of normal (iULN); absolute neutrophil count (ANC) ≥1000/mm3; platelets ≥100,000/mm3; no blasts/promyelocytes in peripheral blood (PB); bone marrow blasts ≤5%; <5% myelocytes+metamyelocytes in PB; PB basophils ≤ iULN; no extramedullary involvement. NEL=WBC ≤ iULN; no blasts/promyelocytes in PB; bone marrow blasts ≤5%; <5% myelocytes+metamyelocytes in PB; PB basophils ≤ iULN; no extramedullary involvement; at least 1 of the following: ANC ≥500/mm3 & <1000/mm3; platelets ≥20,000/mm3 & <100,000/mm3.
    Time Frame Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved MaHR
    Arm/Group Title Participants Acheiving MaHR
    Arm/Group Description MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL)
    Measure Participants 36
    Median (Full Range) [months]
    22.4
    3. Secondary Outcome
    Title Median Duration of Overall Hematologic Response (OHR)
    Description OHR=best confirmed response of MaHR or MiHR. MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). Criteria for MaHR are specified in Outcome Measure 2. Criteria for MiHR are specified in Outcome Measure 1. Maintaining a response was defined as no 2 consecutive records of non-response (ie, a single record of non-response between 2 assessments of response was not considered a loss of response).
    Time Frame Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved OHR
    Arm/Group Title Participants Acheiving OHR
    Arm/Group Description OHR=best confirmed response of major or minor hematologic response
    Measure Participants 54
    Median (95% Confidence Interval) [months]
    14.7
    4. Secondary Outcome
    Title Time to MaHR and OHR
    Description Median time from first dosing to date of OHR and/or MaHR in subjects who achieved OHR and MaHR. MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL). OHR=best confirmed response of MaHR or minor hematologic response (MiHR). Criteria for MaHR are specified in Outcome Measure 2. Criteria for MiHR are specified in Outcome Measure 1.
    Time Frame Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycle 1 and 2; After every 2nd cycle during Cycles 3+; at end of treatment

    Outcome Measure Data

    Analysis Population Description
    Participants who achieved OHR and MaHR
    Arm/Group Title Participants Acheiving MaHR Participants Acheiving OHR
    Arm/Group Description MaHR=best confirmed response of complete hematologic response (CHR) or No Evidence of Leukemia (NEL) OHR=best confirmed response of major or minor hematologic response (MaHR or MiHR).
    Measure Participants 36 54
    Median (95% Confidence Interval) [days]
    63.5
    30.0
    5. Secondary Outcome
    Title Number of Participants With Complete, Partial, Minor, Minimal, or No Cytogenetic Response
    Description Best confirmed cytogenetic response. Determination of cytogenetic response is based on the prevalence (percentage) of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase in a bone marrow sample (aspirates/biopsies).
    Time Frame Baseline (within 4 weeks of therapy start); Every month for Cycles 1-3; Every 12 weeks for Cycles 4+; end of treatment

    Outcome Measure Data

    Analysis Population Description
    All treated subjects
    Arm/Group Title Imatinib-intolerant Imatinib-resistant Total
    Arm/Group Description Defined as: i) Toxicity that was considered at least possibly related to imatinib ≤400 mg/day that led to a discontinuation of imatinib therapy ii) Ability to tolerate only <400 mg/day imatinib. A subject who tolerated 400 mg/day imatinib, but was intolerant of higher doses was not considered imatinib-intolerant. Receiving oral dasatinib at a starting dose of 70 mg twice daily (BID), with dose modifications as necessary for the management of disease progression or toxicity. Defined as any of the following: i) Subjects initially diagnosed with chronic phase chronic myeloid leukemia (CML) who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥400 mg/day. ii) Subjects initially diagnosed with accelerated phase CML who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). iii) Subjects initially diagnosed with myeloid blast phase CML who meet the criteria for myeloid phase blast crisis after at least 4 weeks of treatment prescribed at a dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). Each of these definitions includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance). Oral dasatinib 70 mg BID, with dose modifications as necessary to manage disease progression or toxicity.
    Measure Participants 10 99 109
    Complete (0% Ph+ metaphases)
    2
    20%
    27
    27.3%
    29
    26.6%
    Partial (>0% to 35% Ph+ metaphases)
    0
    0%
    8
    8.1%
    8
    7.3%
    Minor (>35% to 65% Ph+ metaphases)
    0
    0%
    3
    3%
    3
    2.8%
    Minimal (>65% to 95% Ph+ metaphases)
    0
    0%
    11
    11.1%
    11
    10.1%
    No Response (>95% to 100% Ph+ metaphases)
    4
    40%
    28
    28.3%
    32
    29.4%
    Unable to Determine
    4
    40%
    22
    22.2%
    26
    23.9%
    6. Secondary Outcome
    Title Number of Participants With CHR or NEL, MiHR, or no Hematologic Response
    Description Best confirmed hematologic response. Confirmed hematologic response=response that is confirmed after at least 4 weeks with no concomitant use of anagrelide or hydroxyurea use during this interval. Criteria for complete hematologic response (CHR) or No Evidence of Leukemia (NEL) are specified in Outcome Measure 2. Criteria for minor hematologic response (MiHR) are specified in Outcome Measure 1.
    Time Frame Baseline (within 72 hours of therapy start); Cycle 1/Day 1; Weekly during Cycles 1 and 2; After every 2nd cycle for Cycles 3+; at end of treatment

    Outcome Measure Data

    Analysis Population Description
    All treated subjects
    Arm/Group Title Imatinib-intolerant Imatinib-resistant Total
    Arm/Group Description Defined as: i) Toxicity that was considered at least possibly related to imatinib ≤400 mg/day that led to a discontinuation of imatinib therapy ii) Ability to tolerate only <400 mg/day imatinib. A subject who tolerated 400 mg/day imatinib, but was intolerant of higher doses was not considered imatinib-intolerant. Receiving oral dasatinib at a starting dose of 70 mg twice daily (BID), with dose modifications as necessary for the management of disease progression or toxicity. Defined as any of the following: i) Subjects initially diagnosed with chronic phase chronic myeloid leukemia (CML) who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥400 mg/day. ii) Subjects initially diagnosed with accelerated phase CML who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). iii) Subjects initially diagnosed with myeloid blast phase CML who meet the criteria for myeloid phase blast crisis after at least 4 weeks of treatment prescribed at a dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). Each of these definitions includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance). Oral dasatinib 70 mg BID, with dose modifications as necessary to manage disease progression or toxicity.
    Measure Participants 10 99 109
    Complete
    2
    20%
    26
    26.3%
    28
    25.7%
    No evidence of leukemia
    0
    0%
    8
    8.1%
    8
    7.3%
    Minor
    2
    20%
    16
    16.2%
    18
    16.5%
    No response
    6
    60%
    49
    49.5%
    55
    50.5%
    7. Secondary Outcome
    Title Number of Participants Achieving Major Molecular Response (MMR)
    Description Number of participants who achieved an MMR at any time during the treatment period. MMR was calulated by measuring BCR-ABL transcripts in blood during treatment using quantitative reverse transcription-polymerase chain reaction (RT-PCR). BCR-ABL=the fused gene found in subjects with this type of Chronic Myeloid Leukemia (CML).
    Time Frame Baseline, every 12 weeks, and at time of Complete Cytogenetic Response (CCyR) for quantitative Polyermase Chain Reaction (qPCR) analysis

    Outcome Measure Data

    Analysis Population Description
    treated participants with or without CCyR who were assessed for major molecular response
    Arm/Group Title Imatinib-intolerant Imatinib-resistant Total
    Arm/Group Description Defined as: i) Toxicity that was considered at least possibly related to imatinib ≤400 mg/day that led to a discontinuation of imatinib therapy ii) Ability to tolerate only <400 mg/day imatinib. A subject who tolerated 400 mg/day imatinib, but was intolerant of higher doses was not considered imatinib-intolerant. Receiving oral dasatinib at a starting dose of 70 mg twice daily (BID), with dose modifications as necessary for the management of disease progression or toxicity. Defined as any of the following: i) Subjects initially diagnosed with chronic phase chronic myeloid leukemia (CML) who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥400 mg/day. ii) Subjects initially diagnosed with accelerated phase CML who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). iii) Subjects initially diagnosed with myeloid blast phase CML who meet the criteria for myeloid phase blast crisis after at least 4 weeks of treatment prescribed at a dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). Each of these definitions includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance). Oral dasatinib 70 mg BID, with dose modifications as necessary to manage disease progression or toxicity.
    Measure Participants 3 45 48
    MMR in Assessed Subjects with CCyR (n=2; n=17)
    2
    20%
    11
    11.1%
    13
    11.9%
    MMR in Assessed Subjects without CCyR (n=1; n=28)
    0
    0%
    1
    1%
    1
    0.9%
    8. Secondary Outcome
    Title MaHR and Major Cytogenetic Response (MCyR) Among Participants With Baseline BCR-ABL Point Mutations
    Description MaHR and MCyR in subjects with mutations at baseline, including imatinib-resistant mutations (IRM) and specific BCR-ABL mutations (SBAM). Criteria for MaHR are specified in Outcome Measure 2. MCyR=rate of complete cytogenetic responses + the rate of partial cytogenetic responses, as defined in Outcome Measure 5. BCR-ABL=the fused gene found in subjects with this type of CML. This table contains those mutations observed in at least 3 participants. The categories "1 IRM w/2-4-fold increase in resistance" and "≥1 IRM w/≥5-fold increase in resistance" refer to increase in resistance to imatinib.
    Time Frame baseline, at time of disease progression

    Outcome Measure Data

    Analysis Population Description
    All subjects with baseline mutation data; n=the number of participants with the specified mutation. Baseline mutation data were reported for 103 of the 109 subjects (10/10 imatinib-intolerant and 93/99 imatinib-resistant). At baseline, 39 (42%) imatinib-resistant subjects and 3 imatinib-intolerant subject had imatinib-resistant mutations
    Arm/Group Title MaHR MCyR
    Arm/Group Description Participants acheiving MaHR, defined as best confirmed response of Complete Hematologic Response (CHR) or No Evidence of Leukemia (NEL) of Minore Hematologic Response (MiHR) Participants acheiving MCyR, defined as the rate of CCyR plus the rate of Partial Cytogenetic Response
    Measure Participants 103 103
    Participants with IRM (n=42)
    31
    310%
    29
    29.3%
    ≥1 IRM in P-loop (n=19)
    26
    260%
    26
    26.3%
    ≥1 IRM in activation loop (n=8)
    38
    380%
    13
    13.1%
    ≥1 IRM in other location (n=17)
    29
    290%
    35
    35.4%
    ≥1 IRM w/2-4-fold increase in resistance (n=4)
    75
    750%
    50
    50.5%
    ≥1 IRM w/≥5-fold increase in resistance (n=28)
    25
    250%
    25
    25.3%
    SBAM [M244V] at baseline (n=3)
    33
    330%
    33
    33.3%
    SBAM [G250E] at baseline (n=7)
    29
    290%
    14
    14.1%
    SBAM [Y253H] at baseline (n=6)
    50
    500%
    50
    50.5%
    SBAM [E255K/V] at baseline (n=5)
    0
    0%
    20
    20.2%
    SBAM [T315I] at baseline (n=5)
    0
    0%
    20
    20.2%
    SBAM [M351T/V] at baseline (n=3)
    67
    670%
    67
    67.7%
    SBAM [F359I/V] at baseline (n=3)
    0
    0%
    0
    0%
    SBAM [H396R] at baseline (n=4)
    25
    250%
    0
    0%
    SBAM [F486S] at baseline (n=4)
    0
    0%
    0
    0%
    9. Secondary Outcome
    Title Minimally Significant Changes From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G)
    Description Number of subjects with minimally significant changes from baseline in the health-related quality of life questionnaire FACT-G. FACT-G=27 questions in 4 domains: physical, social/family, emotional, & functional well-being (PWB, SWB, EWB, FWB). Score range: 0-108; higher scores=better health-related quality of life. Total Score change of 7 or more=minimal clinical important change; PWB, EWB, & FWB score change of 3 or more, & SWB score change of 2 or more=minimal clinical important change.
    Time Frame Baseline, Every 2 weeks for the first 3 cycles, following every 4-week cycle, and once at follow-up

    Outcome Measure Data

    Analysis Population Description
    Number of participants with FACT-G assessments at baseline and at least one assessment during treatment
    Arm/Group Title Imatinib-intolerant Imatinib-resistant Total
    Arm/Group Description Defined as: i) Toxicity that was considered at least possibly related to imatinib ≤400 mg/day that led to a discontinuation of imatinib therapy ii) Ability to tolerate only <400 mg/day imatinib. A subject who tolerated 400 mg/day imatinib, but was intolerant of higher doses was not considered imatinib-intolerant. Receiving oral dasatinib at a starting dose of 70 mg twice daily (BID), with dose modifications as necessary for the management of disease progression or toxicity. Defined as any of the following: i) Subjects initially diagnosed with chronic phase chronic myeloid leukemia (CML) who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥400 mg/day. ii) Subjects initially diagnosed with accelerated phase CML who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). iii) Subjects initially diagnosed with myeloid blast phase CML who meet the criteria for myeloid phase blast crisis after at least 4 weeks of treatment prescribed at a dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). Each of these definitions includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance). Oral dasatinib 70 mg BID, with dose modifications as necessary to manage disease progression or toxicity.
    Measure Participants 7 81 88
    Total Fact-G
    5
    50%
    46
    46.5%
    51
    46.8%
    Physical Well-Being
    5
    50%
    54
    54.5%
    59
    54.1%
    Social/Family Well-Being
    4
    40%
    35
    35.4%
    39
    35.8%
    Emotional Well-Being
    4
    40%
    37
    37.4%
    41
    37.6%
    Functional Well-Being
    3
    30%
    42
    42.4%
    45
    41.3%
    10. Secondary Outcome
    Title Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), AEs Leading to Discontinuation, Drug-Related AEs
    Description AE=any new untoward medical occurrence or worsening of a pre-existing medical condition regardless of causal relationship with treatment. SAE=any untoward medical occurrence at any dose that: results in death; is life-threatening; requires or prolongs inpatient hospitalization; results in persistent or significant disability; is cancer; is congenital anomaly/birth defect; results in drug dependency/abuse; is an important medical event. Graded by National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. (1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening/disabling, 5=Death)
    Time Frame Continuously throughout study, from pre-treatment visit through end of study (due to death, unacceptable toxicity, treatment failure, etc) and follow-up period

    Outcome Measure Data

    Analysis Population Description
    All treated subjects
    Arm/Group Title Imatinib-intolerant Imatinib-resistant Total
    Arm/Group Description Defined as: i) Toxicity that was considered at least possibly related to imatinib ≤400 mg/day that led to a discontinuation of imatinib therapy ii) Ability to tolerate only <400 mg/day imatinib. A subject who tolerated 400 mg/day imatinib, but was intolerant of higher doses was not considered imatinib-intolerant. Receiving oral dasatinib at a starting dose of 70 mg twice daily (BID), with dose modifications as necessary for the management of disease progression or toxicity. Defined as any of the following: i) Subjects initially diagnosed with chronic phase chronic myeloid leukemia (CML) who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥400 mg/day. ii) Subjects initially diagnosed with accelerated phase CML who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). iii) Subjects initially diagnosed with myeloid blast phase CML who meet the criteria for myeloid phase blast crisis after at least 4 weeks of treatment prescribed at a dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). Each of these definitions includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance). Oral dasatinib 70 mg BID, with dose modifications as necessary to manage disease progression or toxicity.
    Measure Participants 10 99 109
    Death Within 30 Days
    6
    60%
    38
    38.4%
    44
    40.4%
    Death
    6
    60%
    49
    49.5%
    55
    50.5%
    SAEs
    7
    70%
    80
    80.8%
    87
    79.8%
    AEs
    10
    100%
    99
    100%
    109
    100%
    AEs Leading to Discontinuation
    3
    30%
    39
    39.4%
    42
    38.5%
    Drug-Related AEs
    9
    90%
    91
    91.9%
    100
    91.7%
    11. Secondary Outcome
    Title Pharmacokinetics (PK) of Dasatinib - Maximum Observed Plasma Concentration (Cmax)
    Description The Cmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared.
    Time Frame Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.

    Outcome Measure Data

    Analysis Population Description
    26 participants had dense PK sampling on Day 1 and Day 8; parameters for 1 participant on Day 8 was excluded due to unreliable data. Participants with all concentration-time values < than the limit of quantitation were treated as missing for PK analysis. n= participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
    Arm/Group Title Study Day 1 Study Day 8
    Arm/Group Description
    Measure Participants 24 19
    Mean (Standard Deviation) [ng/mL]
    60.34
    (55.86)
    110.42
    (44.31)
    12. Secondary Outcome
    Title Pharmacokinetics (PK) of Dasatinib - Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point Within the Dosing Interval of 12 h or 24 h(AUC[0-T])
    Description The AUC(0-T) was calculated using the mixed log-linear trapezoidal algorithm in Kinetica™. In the calculation of AUC(0-T), predose concentrations that were < lower limit of qualtitation were assigned a value of zero.
    Time Frame Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.

    Outcome Measure Data

    Analysis Population Description
    26 participants had dense PK sampling on Day 1 and Day 8; parameters for 1 participant on Day 8 was excluded due to unreliable data. Participants with all concentration-time values < than the limit of quantitation were treated as missing for PK analysis. n= participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
    Arm/Group Title Study Day 1 Study Day 8
    Arm/Group Description
    Measure Participants 24 19
    Mean (Standard Deviation) [ng∙h/mL]
    161.17
    (150.29)
    295.92
    (169.20)
    13. Secondary Outcome
    Title Pharmacokinetics (PK) of Dasatinib - Time to Maximum Observed Plasma Concentration (Tmax)
    Description The Tmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared.
    Time Frame Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.

    Outcome Measure Data

    Analysis Population Description
    26 participants had dense PK sampling on Day 1 and Day 8; parameters for 1 participant on Day 8 was excluded due to unreliable data. Participants with all concentration-time values < than the limit of quantitation were treated as missing for PK analysis. n= participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
    Arm/Group Title Study Day 1 Study Day 8
    Arm/Group Description
    Measure Participants 24 19
    Mean (Standard Deviation) [hours]
    1.79
    (1.45)
    1.22
    (0.97)
    14. Secondary Outcome
    Title Pharmacokinetics (PK) of Dasatinib - Plasma Half-life (T-HALF)
    Description The T-HALF was calculated as Ln2/Lz,where Lz was the absolute value of the slope of the terminal log-linear phase.
    Time Frame Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.

    Outcome Measure Data

    Analysis Population Description
    26 participants had dense PK sampling on Day 1 and Day 8; parameters for 1 participant on Day 8 was excluded due to unreliable data. Participants with all concentration-time values < than the limit of quantitation were treated as missing for PK analysis. n= participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
    Arm/Group Title Study Day 1 Study Day 8
    Arm/Group Description
    Measure Participants 23 19
    Mean (Standard Deviation) [hours]
    3.71
    (1.78)
    4.26
    (2.15)
    15. Secondary Outcome
    Title Pharmacokinetics (PK) of Dasatinib's Metabolite BMS-582691 - Maximum Observed Plasma Concentration (Cmax)
    Description The Cmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared.
    Time Frame Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.

    Outcome Measure Data

    Analysis Population Description
    26 participants had dense PK sampling on Day 1 & Day 8; parameters for 1 participant on Day 1 & 1 on Day 8 were excluded due to unreliable data. Participants w/all concentration-time values <than limit of quantitation were treated as missing for PK analysis. n=participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
    Arm/Group Title Study Day 1 Study Day 8
    Arm/Group Description
    Measure Participants 14 18
    Mean (Standard Deviation) [ng/mL]
    2.44
    (1.32)
    3.87
    (1.67)
    16. Secondary Outcome
    Title Pharmacokinetics (PK) of Dasatinib's Metabolite BMS-582691 - Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point Within the Dosing Interval of 12 h (AUC[0-T])
    Description The AUC(0-T) was calculated using the mixed log-linear trapezoidal algorithm in Kinetica™. In the calculation of AUC(0-T), predose concentrations that were less than the lower limit of quantitation (LLQ) were assigned a value of zero.
    Time Frame Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.

    Outcome Measure Data

    Analysis Population Description
    26 participants had dense PK sampling on Day 1 & Day 8; parameters for 1 participant on Day 1 & 1 on Day 8 were excluded due to unreliable data. Participants w/all concentration-time values <than limit of quantitation were treated as missing for PK analysis. n=participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
    Arm/Group Title Imatinib-intolerant Imatinib-resistant
    Arm/Group Description Defined as: i) Toxicity that was considered at least possibly related to imatinib ≤400 mg/day that led to a discontinuation of imatinib therapy ii) Ability to tolerate only <400 mg/day imatinib. A subject who tolerated 400 mg/day imatinib, but was intolerant of higher doses was not considered imatinib-intolerant. Receiving oral dasatinib at a starting dose of 70 mg twice daily (BID), with dose modifications as necessary for the management of disease progression or toxicity. Defined as any of the following: i) Subjects initially diagnosed with chronic phase chronic myeloid leukemia (CML) who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥400 mg/day. ii) Subjects initially diagnosed with accelerated phase CML who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). iii) Subjects initially diagnosed with myeloid blast phase CML who meet the criteria for myeloid phase blast crisis after at least 4 weeks of treatment prescribed at a dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). Each of these definitions includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance). Oral dasatinib 70 mg BID, with dose modifications as necessary to manage disease progression or toxicity.
    Measure Participants 14 18
    Mean (Standard Deviation) [ng∙h/mL]
    7.08
    (7.80)
    13.81
    (11.96)
    17. Secondary Outcome
    Title Pharmacokinetics (PK) of Dasatinib's Metabolite BMS-582691 - Time to Maximum Observed Plasma Concentration (Tmax)
    Description The Tmax was obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria,which is also referred to as adjusted R-squared.
    Time Frame Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.

    Outcome Measure Data

    Analysis Population Description
    26 participants had dense PK sampling on Day 1 & Day 8; parameters for 1 participant on Day 1 & 1 on Day 8 were excluded due to unreliable data. Participants w/all concentration-time values <than limit of quantitation were treated as missing for PK analysis. n=participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
    Arm/Group Title Imatinib-intolerant Imatinib-resistant
    Arm/Group Description Defined as: i) Toxicity that was considered at least possibly related to imatinib ≤400 mg/day that led to a discontinuation of imatinib therapy ii) Ability to tolerate only <400 mg/day imatinib. A subject who tolerated 400 mg/day imatinib, but was intolerant of higher doses was not considered imatinib-intolerant. Receiving oral dasatinib at a starting dose of 70 mg twice daily (BID), with dose modifications as necessary for the management of disease progression or toxicity. Defined as any of the following: i) Subjects initially diagnosed with chronic phase chronic myeloid leukemia (CML) who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥400 mg/day. ii) Subjects initially diagnosed with accelerated phase CML who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). iii) Subjects initially diagnosed with myeloid blast phase CML who meet the criteria for myeloid phase blast crisis after at least 4 weeks of treatment prescribed at a dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). Each of these definitions includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance). Oral dasatinib 70 mg BID, with dose modifications as necessary to manage disease progression or toxicity.
    Measure Participants 14 18
    Mean (Standard Deviation) [hours]
    1.71
    (1.00)
    1.90
    (1.49)
    18. Secondary Outcome
    Title Pharmacokinetics (PK) of Dasatinib and Its Metabolite BMS-582691 - Plasma Half-life (T-HALF)
    Description The T-HALF was calculated as Ln2/Lz,where Lz was the absolute value of the slope of the terminal log-linear phase.
    Time Frame Collected on Days 1 and 8 at times as close as possible to the following time points (relative to drug administration): pre-dose, and following drug administration at 30 minutes, 1 hour, 1.5, 2, 3, 4, 5, 6, 8 and 10 hours.

    Outcome Measure Data

    Analysis Population Description
    26 participants had dense PK sampling on Day 1 & Day 8; parameters for 1 participant on Day 1 & 1 on Day 8 were excluded due to unreliable data. Participants w/all concentration-time values <than limit of quantitation were treated as missing for PK analysis. n=participants included in the statistical analyses of PK on Day 1 and Day 8, respectively.
    Arm/Group Title Study Day 1 Study Day 8
    Arm/Group Description
    Measure Participants 14 18
    Mean (Standard Deviation) [hours]
    4.95
    (3.93)
    4.38
    (3.97)
    19. Secondary Outcome
    Title Population PK of Dasatinib
    Description Population pharmacokinetic analysis was not done because it is not meaningful for this single study
    Time Frame Day 8 immediately prior to the first daily dose and between 30 minutes to 3 hours following this dose.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Imatinib-intolerant Imatinib-resistant Total
    Arm/Group Description Defined as: i) Toxicity that was considered at least possibly related to imatinib ≤400 mg/day that led to a discontinuation of imatinib therapy ii) Ability to tolerate only <400 mg/day imatinib. A subject who tolerated 400 mg/day imatinib, but was intolerant of higher doses was not considered imatinib-intolerant. Receiving oral dasatinib at a starting dose of 70 mg twice daily (BID), with dose modifications as necessary for the management of disease progression or toxicity. Defined as any of the following: i) Subjects initially diagnosed with chronic phase chronic myeloid leukemia (CML) who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥400 mg/day. ii) Subjects initially diagnosed with accelerated phase CML who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). iii) Subjects initially diagnosed with myeloid blast phase CML who meet the criteria for myeloid phase blast crisis after at least 4 weeks of treatment prescribed at a dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). Each of these definitions includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance). Oral dasatinib 70 mg BID, with dose modifications as necessary to manage disease progression or toxicity.
    Measure Participants 0 0 0

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Imatinib-intolerant Imatinib-resistant
    Arm/Group Description Defined as: i) Toxicity that was considered at least possibly related to imatinib ≤400 mg/day that led to a discontinuation of imatinib therapy ii) Ability to tolerate only <400 mg/day imatinib. A subject who tolerated 400 mg/day imatinib, but was intolerant of higher doses was not considered imatinib-intolerant. Receiving oral dasatinib at a starting dose of 70 mg twice daily (BID), with dose modifications as necessary for the management of disease progression or toxicity. Defined as any of the following: i) Subjects initially diagnosed with chronic phase chronic myeloid leukemia (CML) who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥400 mg/day. ii) Subjects initially diagnosed with accelerated phase CML who progressed to myeloid phase CML while on treatment with a prescribed imatinib dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). iii) Subjects initially diagnosed with myeloid blast phase CML who meet the criteria for myeloid phase blast crisis after at least 4 weeks of treatment prescribed at a dose of ≥600 mg/day (or 400 to <600 mg/day if subject is intolerant of ≥600 mg/day). Each of these definitions includes subjects who had no response to imatinib (primary resistance) and those who responded and subsequently progressed to myeloid blast phase (acquired resistance). Oral dasatinib 70 mg BID, with dose modifications as necessary to manage disease progression or toxicity.
    All Cause Mortality
    Imatinib-intolerant Imatinib-resistant
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Imatinib-intolerant Imatinib-resistant
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 7/10 (70%) 80/99 (80.8%)
    Blood and lymphatic system disorders
    ANAEMIA 0/10 (0%) 7/99 (7.1%)
    NEUTROPENIA 0/10 (0%) 4/99 (4%)
    LEUKOCYTOSIS 0/10 (0%) 3/99 (3%)
    PANCYTOPENIA 0/10 (0%) 1/99 (1%)
    SPLENOMEGALY 0/10 (0%) 1/99 (1%)
    THROMBOCYTOPENIA 2/10 (20%) 5/99 (5.1%)
    FEBRILE NEUTROPENIA 1/10 (10%) 10/99 (10.1%)
    Cardiac disorders
    ANGINA UNSTABLE 0/10 (0%) 1/99 (1%)
    NODAL ARRHYTHMIA 0/10 (0%) 1/99 (1%)
    SINUS TACHYCARDIA 0/10 (0%) 1/99 (1%)
    ATRIAL FIBRILLATION 0/10 (0%) 2/99 (2%)
    MYOCARDIAL ISCHAEMIA 0/10 (0%) 1/99 (1%)
    PERICARDIAL EFFUSION 0/10 (0%) 4/99 (4%)
    MYOCARDIAL INFARCTION 0/10 (0%) 2/99 (2%)
    CONGESTIVE CARDIOMYOPATHY 0/10 (0%) 1/99 (1%)
    CARDIAC FAILURE CONGESTIVE 0/10 (0%) 3/99 (3%)
    ACUTE MYOCARDIAL INFARCTION 1/10 (10%) 0/99 (0%)
    ARRHYTHMIA SUPRAVENTRICULAR 0/10 (0%) 1/99 (1%)
    LEFT VENTRICULAR DYSFUNCTION 0/10 (0%) 1/99 (1%)
    SUPRAVENTRICULAR TACHYCARDIA 0/10 (0%) 2/99 (2%)
    Gastrointestinal disorders
    NAUSEA 1/10 (10%) 3/99 (3%)
    ASCITES 0/10 (0%) 1/99 (1%)
    MELAENA 0/10 (0%) 1/99 (1%)
    VOMITING 1/10 (10%) 3/99 (3%)
    DIARRHOEA 0/10 (0%) 5/99 (5.1%)
    GASTRITIS 0/10 (0%) 2/99 (2%)
    STOMATITIS 0/10 (0%) 1/99 (1%)
    CONSTIPATION 0/10 (0%) 1/99 (1%)
    HAEMATOCHEZIA 0/10 (0%) 2/99 (2%)
    ABDOMINAL PAIN 1/10 (10%) 3/99 (3%)
    GINGIVAL BLEEDING 0/10 (0%) 1/99 (1%)
    NEUTROPENIC COLITIS 0/10 (0%) 1/99 (1%)
    ABDOMINAL PAIN LOWER 0/10 (0%) 1/99 (1%)
    LARGE INTESTINAL ULCER 0/10 (0%) 1/99 (1%)
    GASTROINTESTINAL HAEMORRHAGE 1/10 (10%) 9/99 (9.1%)
    LOWER GASTROINTESTINAL HAEMORRHAGE 0/10 (0%) 3/99 (3%)
    General disorders
    PAIN 0/10 (0%) 1/99 (1%)
    FATIGUE 0/10 (0%) 1/99 (1%)
    MALAISE 0/10 (0%) 1/99 (1%)
    PYREXIA 1/10 (10%) 17/99 (17.2%)
    ASTHENIA 0/10 (0%) 2/99 (2%)
    CHEST PAIN 0/10 (0%) 1/99 (1%)
    GENERALISED OEDEMA 0/10 (0%) 2/99 (2%)
    DISEASE PROGRESSION 0/10 (0%) 2/99 (2%)
    MUCOSAL INFLAMMATION 0/10 (0%) 1/99 (1%)
    NON-CARDIAC CHEST PAIN 0/10 (0%) 1/99 (1%)
    PERFORMANCE STATUS DECREASED 0/10 (0%) 1/99 (1%)
    Hepatobiliary disorders
    HEPATOSPLENOMEGALY 0/10 (0%) 1/99 (1%)
    CHOLECYSTITIS ACUTE 0/10 (0%) 1/99 (1%)
    CYTOLYTIC HEPATITIS 0/10 (0%) 1/99 (1%)
    Infections and infestations
    SEPSIS 0/10 (0%) 11/99 (11.1%)
    GANGRENE 0/10 (0%) 1/99 (1%)
    INFECTION 0/10 (0%) 5/99 (5.1%)
    PNEUMONIA 1/10 (10%) 6/99 (6.1%)
    CELLULITIS 0/10 (0%) 3/99 (3%)
    PHARYNGITIS 0/10 (0%) 1/99 (1%)
    SEPTIC SHOCK 0/10 (0%) 2/99 (2%)
    BRAIN ABSCESS 0/10 (0%) 1/99 (1%)
    LIVER ABSCESS 0/10 (0%) 1/99 (1%)
    ANAL INFECTION 0/10 (0%) 1/99 (1%)
    LUNG INFECTION 0/10 (0%) 1/99 (1%)
    PYELONEPHRITIS 0/10 (0%) 1/99 (1%)
    CATHETER SEPSIS 0/10 (0%) 1/99 (1%)
    PERIANAL ABSCESS 0/10 (0%) 1/99 (1%)
    ASCITES INFECTION 0/10 (0%) 1/99 (1%)
    LOCALISED INFECTION 0/10 (0%) 1/99 (1%)
    DIARRHOEA INFECTIOUS 0/10 (0%) 1/99 (1%)
    NEUTROPENIC INFECTION 0/10 (0%) 3/99 (3%)
    CYTOMEGALOVIRUS COLITIS 0/10 (0%) 1/99 (1%)
    URINARY TRACT INFECTION 0/10 (0%) 1/99 (1%)
    ENTEROCOLITIS INFECTIOUS 0/10 (0%) 1/99 (1%)
    CYTOMEGALOVIRUS INFECTION 0/10 (0%) 1/99 (1%)
    LOWER RESPIRATORY TRACT INFECTION 0/10 (0%) 1/99 (1%)
    Injury, poisoning and procedural complications
    FRACTURE 0/10 (0%) 1/99 (1%)
    FEMUR FRACTURE 1/10 (10%) 0/99 (0%)
    SUBDURAL HAEMATOMA 0/10 (0%) 3/99 (3%)
    Investigations
    TROPONIN I 0/10 (0%) 1/99 (1%)
    HAEMOGLOBIN 0/10 (0%) 1/99 (1%)
    HAEMOGLOBIN DECREASED 1/10 (10%) 1/99 (1%)
    CARDIAC ENZYMES INCREASED 0/10 (0%) 1/99 (1%)
    BLAST CELL COUNT INCREASED 0/10 (0%) 1/99 (1%)
    GRANULOCYTE COUNT DECREASED 0/10 (0%) 1/99 (1%)
    PLATELET AGGREGATION ABNORMAL 0/10 (0%) 1/99 (1%)
    BLOOD CREATINE PHOSPHOKINASE INCREASED 0/10 (0%) 1/99 (1%)
    ELECTROCARDIOGRAM QT CORRECTED INTERVAL PROLONGED 0/10 (0%) 2/99 (2%)
    Metabolism and nutrition disorders
    ANOREXIA 0/10 (0%) 1/99 (1%)
    DEHYDRATION 0/10 (0%) 1/99 (1%)
    HYPONATRAEMIA 0/10 (0%) 1/99 (1%)
    HYPERCALCAEMIA 0/10 (0%) 2/99 (2%)
    HYPERGLYCAEMIA 0/10 (0%) 1/99 (1%)
    DIABETES MELLITUS 0/10 (0%) 1/99 (1%)
    Musculoskeletal and connective tissue disorders
    BACK PAIN 0/10 (0%) 1/99 (1%)
    BONE PAIN 0/10 (0%) 1/99 (1%)
    ARTHRALGIA 0/10 (0%) 1/99 (1%)
    PAIN IN EXTREMITY 0/10 (0%) 1/99 (1%)
    VERTEBRAL COLUMN MASS 0/10 (0%) 1/99 (1%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    LEUKAEMIA 0/10 (0%) 1/99 (1%)
    TUMOUR PAIN 0/10 (0%) 1/99 (1%)
    MYELOFIBROSIS 0/10 (0%) 1/99 (1%)
    BLAST CELL CRISIS 1/10 (10%) 2/99 (2%)
    TUMOUR LYSIS SYNDROME 0/10 (0%) 2/99 (2%)
    BLAST CELL PROLIFERATION 0/10 (0%) 2/99 (2%)
    CHRONIC MYELOID LEUKAEMIA 1/10 (10%) 18/99 (18.2%)
    BLAST CRISIS IN MYELOGENOUS LEUKAEMIA 0/10 (0%) 9/99 (9.1%)
    Nervous system disorders
    APHASIA 1/10 (10%) 0/99 (0%)
    HEADACHE 0/10 (0%) 3/99 (3%)
    MYELITIS 0/10 (0%) 1/99 (1%)
    CONVULSION 0/10 (0%) 1/99 (1%)
    CEREBRAL ISCHAEMIA 0/10 (0%) 1/99 (1%)
    CEREBRAL HAEMORRHAGE 0/10 (0%) 4/99 (4%)
    MENINGITIS NONINFECTIVE 1/10 (10%) 1/99 (1%)
    TRANSIENT ISCHAEMIC ATTACK 0/10 (0%) 1/99 (1%)
    INTRACRANIAL PRESSURE INCREASED 1/10 (10%) 0/99 (0%)
    DEPRESSED LEVEL OF CONSCIOUSNESS 0/10 (0%) 1/99 (1%)
    Renal and urinary disorders
    HAEMATURIA 0/10 (0%) 1/99 (1%)
    RENAL FAILURE 0/10 (0%) 3/99 (3%)
    NEPHROLITHIASIS 0/10 (0%) 1/99 (1%)
    RENAL IMPAIRMENT 0/10 (0%) 1/99 (1%)
    Respiratory, thoracic and mediastinal disorders
    COUGH 0/10 (0%) 3/99 (3%)
    DYSPNOEA 1/10 (10%) 6/99 (6.1%)
    ORTHOPNOEA 0/10 (0%) 1/99 (1%)
    CHYLOTHORAX 0/10 (0%) 1/99 (1%)
    PNEUMONITIS 0/10 (0%) 6/99 (6.1%)
    PLEURAL EFFUSION 3/10 (30%) 17/99 (17.2%)
    LUNG INFILTRATION 0/10 (0%) 4/99 (4%)
    LUNG CONSOLIDATION 0/10 (0%) 1/99 (1%)
    RESPIRATORY FAILURE 1/10 (10%) 0/99 (0%)
    PULMONARY HYPERTENSION 1/10 (10%) 2/99 (2%)
    ACUTE RESPIRATORY FAILURE 0/10 (0%) 1/99 (1%)
    ACUTE RESPIRATORY DISTRESS SYNDROME 0/10 (0%) 1/99 (1%)
    Skin and subcutaneous tissue disorders
    RASH 0/10 (0%) 1/99 (1%)
    PURPURA 0/10 (0%) 2/99 (2%)
    PETECHIAE 0/10 (0%) 2/99 (2%)
    DECUBITUS ULCER 0/10 (0%) 1/99 (1%)
    URTICARIA VESICULOSA 0/10 (0%) 1/99 (1%)
    HAEMORRHAGE SUBCUTANEOUS 0/10 (0%) 1/99 (1%)
    ACUTE FEBRILE NEUTROPHILIC DERMATOSIS 0/10 (0%) 2/99 (2%)
    Surgical and medical procedures
    INTESTINAL STOMA 0/10 (0%) 1/99 (1%)
    STEM CELL TRANSPLANT 0/10 (0%) 1/99 (1%)
    BONE MARROW TRANSPLANT 0/10 (0%) 2/99 (2%)
    Vascular disorders
    FLUSHING 0/10 (0%) 1/99 (1%)
    THROMBOPHLEBITIS 0/10 (0%) 1/99 (1%)
    Other (Not Including Serious) Adverse Events
    Imatinib-intolerant Imatinib-resistant
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 10/10 (100%) 97/99 (98%)
    Blood and lymphatic system disorders
    ANAEMIA 1/10 (10%) 14/99 (14.1%)
    LEUKOPENIA 1/10 (10%) 3/99 (3%)
    NEUTROPENIA 1/10 (10%) 13/99 (13.1%)
    SPLENOMEGALY 1/10 (10%) 4/99 (4%)
    THROMBOCYTOPENIA 0/10 (0%) 17/99 (17.2%)
    FEBRILE NEUTROPENIA 0/10 (0%) 6/99 (6.1%)
    Cardiac disorders
    TACHYCARDIA 1/10 (10%) 7/99 (7.1%)
    TACHYARRHYTHMIA 1/10 (10%) 0/99 (0%)
    ATRIAL FIBRILLATION 1/10 (10%) 1/99 (1%)
    PERICARDIAL EFFUSION 0/10 (0%) 7/99 (7.1%)
    LEFT VENTRICULAR DYSFUNCTION 1/10 (10%) 0/99 (0%)
    Eye disorders
    DRY EYE 1/10 (10%) 0/99 (0%)
    EYE OEDEMA 1/10 (10%) 1/99 (1%)
    EYELID OEDEMA 1/10 (10%) 4/99 (4%)
    EYE HAEMORRHAGE 0/10 (0%) 6/99 (6.1%)
    RETINAL HAEMORRHAGE 1/10 (10%) 1/99 (1%)
    CONJUNCTIVAL HAEMORRHAGE 1/10 (10%) 8/99 (8.1%)
    Gastrointestinal disorders
    NAUSEA 3/10 (30%) 34/99 (34.3%)
    ASCITES 0/10 (0%) 5/99 (5.1%)
    VOMITING 6/10 (60%) 37/99 (37.4%)
    DIARRHOEA 5/10 (50%) 60/99 (60.6%)
    DYSPEPSIA 0/10 (0%) 11/99 (11.1%)
    GASTRITIS 0/10 (0%) 5/99 (5.1%)
    PROCTALGIA 1/10 (10%) 4/99 (4%)
    STOMATITIS 3/10 (30%) 14/99 (14.1%)
    ANAL FISSURE 1/10 (10%) 0/99 (0%)
    CONSTIPATION 2/10 (20%) 21/99 (21.2%)
    HAEMORRHOIDS 2/10 (20%) 7/99 (7.1%)
    HAEMATOCHEZIA 1/10 (10%) 5/99 (5.1%)
    ABDOMINAL PAIN 0/10 (0%) 22/99 (22.2%)
    INGUINAL HERNIA 1/10 (10%) 0/99 (0%)
    LIP HAEMORRHAGE 1/10 (10%) 0/99 (0%)
    GINGIVAL BLEEDING 0/10 (0%) 5/99 (5.1%)
    MOUTH HAEMORRHAGE 1/10 (10%) 6/99 (6.1%)
    RECTAL HAEMORRHAGE 1/10 (10%) 4/99 (4%)
    ABDOMINAL DISCOMFORT 0/10 (0%) 5/99 (5.1%)
    ABDOMINAL PAIN UPPER 2/10 (20%) 16/99 (16.2%)
    GASTROINTESTINAL DISORDER 1/10 (10%) 0/99 (0%)
    GASTROINTESTINAL HAEMORRHAGE 0/10 (0%) 10/99 (10.1%)
    General disorders
    PAIN 1/10 (10%) 12/99 (12.1%)
    CHILLS 0/10 (0%) 12/99 (12.1%)
    OEDEMA 1/10 (10%) 9/99 (9.1%)
    FATIGUE 3/10 (30%) 34/99 (34.3%)
    PYREXIA 8/10 (80%) 62/99 (62.6%)
    ASTHENIA 5/10 (50%) 25/99 (25.3%)
    CHEST PAIN 2/10 (20%) 13/99 (13.1%)
    FACE OEDEMA 1/10 (10%) 4/99 (4%)
    HYPOTHERMIA 1/10 (10%) 0/99 (0%)
    PITTING OEDEMA 1/10 (10%) 1/99 (1%)
    LOCALISED OEDEMA 3/10 (30%) 4/99 (4%)
    OEDEMA PERIPHERAL 3/10 (30%) 35/99 (35.4%)
    GENERALISED OEDEMA 1/10 (10%) 2/99 (2%)
    MUCOSAL INFLAMMATION 1/10 (10%) 5/99 (5.1%)
    INFLUENZA LIKE ILLNESS 2/10 (20%) 1/99 (1%)
    Hepatobiliary disorders
    CHOLELITHIASIS 1/10 (10%) 0/99 (0%)
    HYPERBILIRUBINAEMIA 1/10 (10%) 0/99 (0%)
    GALLBLADDER ENLARGEMENT 1/10 (10%) 0/99 (0%)
    HEPATIC FUNCTION ABNORMAL 1/10 (10%) 0/99 (0%)
    Immune system disorders
    ALLERGY TO ARTHROPOD BITE 1/10 (10%) 0/99 (0%)
    Infections and infestations
    RHINITIS 1/10 (10%) 4/99 (4%)
    PNEUMONIA 1/10 (10%) 3/99 (3%)
    ORAL HERPES 0/10 (0%) 5/99 (5.1%)
    PHARYNGITIS 1/10 (10%) 3/99 (3%)
    FOLLICULITIS 0/10 (0%) 5/99 (5.1%)
    GASTROENTERITIS 1/10 (10%) 6/99 (6.1%)
    NASOPHARYNGITIS 1/10 (10%) 7/99 (7.1%)
    ORAL CANDIDIASIS 0/10 (0%) 7/99 (7.1%)
    VAGINAL INFECTION 1/10 (10%) 1/99 (1%)
    LOCALISED INFECTION 1/10 (10%) 1/99 (1%)
    CLOSTRIDIAL INFECTION 1/10 (10%) 1/99 (1%)
    FUNGAL SKIN INFECTION 1/10 (10%) 0/99 (0%)
    URINARY TRACT INFECTION 1/10 (10%) 8/99 (8.1%)
    UPPER RESPIRATORY TRACT INFECTION 0/10 (0%) 7/99 (7.1%)
    URINARY TRACT INFECTION BACTERIAL 1/10 (10%) 0/99 (0%)
    ESCHERICHIA URINARY TRACT INFECTION 1/10 (10%) 1/99 (1%)
    Injury, poisoning and procedural complications
    CONTUSION 1/10 (10%) 4/99 (4%)
    SKIN LACERATION 1/10 (10%) 1/99 (1%)
    Investigations
    CARDIAC MURMUR 1/10 (10%) 1/99 (1%)
    WEIGHT DECREASED 5/10 (50%) 25/99 (25.3%)
    WEIGHT INCREASED 2/10 (20%) 21/99 (21.2%)
    ASPARTATE AMINOTRANSFERASE INCREASED 0/10 (0%) 5/99 (5.1%)
    ELECTROCARDIOGRAM QT CORRECTED INTERVAL PROLONGED 1/10 (10%) 0/99 (0%)
    Metabolism and nutrition disorders
    ANOREXIA 3/10 (30%) 25/99 (25.3%)
    HYPOKALAEMIA 0/10 (0%) 6/99 (6.1%)
    HYPOCALCAEMIA 1/10 (10%) 3/99 (3%)
    FLUID OVERLOAD 1/10 (10%) 2/99 (2%)
    DECREASED APPETITE 1/10 (10%) 3/99 (3%)
    Musculoskeletal and connective tissue disorders
    MYALGIA 1/10 (10%) 11/99 (11.1%)
    MYOSITIS 1/10 (10%) 0/99 (0%)
    BACK PAIN 0/10 (0%) 15/99 (15.2%)
    BONE PAIN 1/10 (10%) 16/99 (16.2%)
    ARTHRALGIA 1/10 (10%) 15/99 (15.2%)
    MUSCULAR WEAKNESS 1/10 (10%) 5/99 (5.1%)
    PAIN IN EXTREMITY 0/10 (0%) 17/99 (17.2%)
    MUSCULOSKELETAL PAIN 0/10 (0%) 6/99 (6.1%)
    Nervous system disorders
    COMA 1/10 (10%) 1/99 (1%)
    APHASIA 1/10 (10%) 2/99 (2%)
    HEADACHE 3/10 (30%) 31/99 (31.3%)
    LETHARGY 1/10 (10%) 1/99 (1%)
    DIZZINESS 2/10 (20%) 14/99 (14.1%)
    CONVULSION 0/10 (0%) 6/99 (6.1%)
    SOMNOLENCE 1/10 (10%) 2/99 (2%)
    PARAESTHESIA 0/10 (0%) 5/99 (5.1%)
    HYPOAESTHESIA 1/10 (10%) 2/99 (2%)
    Psychiatric disorders
    ANXIETY 1/10 (10%) 8/99 (8.1%)
    INSOMNIA 2/10 (20%) 13/99 (13.1%)
    AGITATION 1/10 (10%) 0/99 (0%)
    DEPRESSION 0/10 (0%) 8/99 (8.1%)
    DEPRESSED MOOD 2/10 (20%) 1/99 (1%)
    CONFUSIONAL STATE 1/10 (10%) 1/99 (1%)
    Reproductive system and breast disorders
    NIPPLE PAIN 1/10 (10%) 0/99 (0%)
    VAGINAL HAEMORRHAGE 1/10 (10%) 0/99 (0%)
    Respiratory, thoracic and mediastinal disorders
    COUGH 3/10 (30%) 40/99 (40.4%)
    RALES 0/10 (0%) 5/99 (5.1%)
    HYPOXIA 3/10 (30%) 2/99 (2%)
    DYSPNOEA 4/10 (40%) 30/99 (30.3%)
    EPISTAXIS 0/10 (0%) 21/99 (21.2%)
    HAEMOPTYSIS 1/10 (10%) 6/99 (6.1%)
    PNEUMONITIS 0/10 (0%) 6/99 (6.1%)
    NASAL DISORDER 1/10 (10%) 0/99 (0%)
    PLEURITIC PAIN 1/10 (10%) 2/99 (2%)
    PLEURAL EFFUSION 3/10 (30%) 34/99 (34.3%)
    PRODUCTIVE COUGH 0/10 (0%) 8/99 (8.1%)
    PULMONARY OEDEMA 1/10 (10%) 5/99 (5.1%)
    THROAT TIGHTNESS 1/10 (10%) 0/99 (0%)
    DYSPNOEA EXERTIONAL 0/10 (0%) 7/99 (7.1%)
    RESPIRATORY FAILURE 1/10 (10%) 1/99 (1%)
    PULMONARY THROMBOSIS 1/10 (10%) 0/99 (0%)
    PHARYNGOLARYNGEAL PAIN 0/10 (0%) 7/99 (7.1%)
    PULMONARY HYPERTENSION 1/10 (10%) 0/99 (0%)
    RESPIRATORY TRACT CONGESTION 1/10 (10%) 1/99 (1%)
    Skin and subcutaneous tissue disorders
    ACNE 0/10 (0%) 6/99 (6.1%)
    RASH 2/10 (20%) 25/99 (25.3%)
    PURPURA 1/10 (10%) 4/99 (4%)
    ERYTHEMA 2/10 (20%) 8/99 (8.1%)
    PRURITUS 0/10 (0%) 10/99 (10.1%)
    PETECHIAE 1/10 (10%) 12/99 (12.1%)
    ECCHYMOSIS 0/10 (0%) 10/99 (10.1%)
    SKIN ULCER 1/10 (10%) 0/99 (0%)
    SKIN LESION 1/10 (10%) 4/99 (4%)
    NIGHT SWEATS 1/10 (10%) 9/99 (9.1%)
    HYPERHIDROSIS 2/10 (20%) 4/99 (4%)
    SPIDER NAEVUS 1/10 (10%) 0/99 (0%)
    SWELLING FACE 1/10 (10%) 0/99 (0%)
    PERIORBITAL OEDEMA 1/10 (10%) 8/99 (8.1%)
    Vascular disorders
    HAEMATOMA 1/10 (10%) 7/99 (7.1%)
    HYPOTENSION 1/10 (10%) 13/99 (13.1%)
    HYPERTENSION 0/10 (0%) 12/99 (12.1%)
    PERIPHERAL ISCHAEMIA 1/10 (10%) 0/99 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.

    Results Point of Contact

    Name/Title BMS Study Director
    Organization Bristol-Myers Squibb
    Phone
    Email Clinical.Trials@bms.com
    Responsible Party:
    , ,
    ClinicalTrials.gov Identifier:
    NCT00101816
    Other Study ID Numbers:
    • CA180-006
    • NCT00108719
    First Posted:
    Jan 14, 2005
    Last Update Posted:
    Aug 10, 2010
    Last Verified:
    Jun 1, 2010