Study of Dasatinib in Children and Adolescents With Relapsed or Refractory Leukemia

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
ITCC
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00306202
First received: March 21, 2006
Last updated: August 5, 2014
Last verified: August 2014
  Purpose

The purpose of this clinical research study was to establish a recommended phase 2 once daily (QD) dose of dasatinib and to assess the efficacy of the investigational drug for relapsed or refractory (resistant to previous treatment) leukemia in children and adolescents. The side effects that this oral investigational drug may have in children, and the levels of the drug in the blood, will be studied at different doses.


Condition Intervention Phase
Leukemia
Drug: Dasatinib
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of SRC/ABL Tyrosine Kinase Inhibitor Dasatinib [BMS-354825] in Children and Adolescents With Relapsed or Refractory Leukemia, Protocol ITCC 005

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Recommended Phase II Dose of Dasatinib in Children and Adolescents With Relapsed or Refractory Leukemia [ Time Frame: From the date of first dose to end-of-treatment (EOT) (Median duration of therapy in months: Stratum 1=24.11 [Range:2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38]) ] [ Designated as safety issue: Yes ]
    The recommended phase 2 dasatinib dose was determined based on efficacy, safety, and pharmacokinetic data obtained at the prespecified dose levels.


Secondary Outcome Measures:
  • Number of Participants With Related Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. [ Time Frame: From the date of first dose until at least 30 days after the last dose of study drug (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38]) ] [ Designated as safety issue: Yes ]

    AE: New untoward medical occurrence or worsening of a preexisting medical condition that does not have causal relationship with this treatment. SAE: Untoward medical event that at any dose: results in death, persistent or significant disability/incapacity, drug dependency/abuse; life-threatening, an important medical event, a congenital anomaly/birth defect; requires inpatient hospitalization/prolongs existing hospitalization.

    Grade 3 = Severe; Grade 4 = Life-threatening or disabling.


  • Number of Participants With Dose-limiting Toxicity (DLT) [ Time Frame: From the date of first dose until at least 30 days after the last dose of study drug (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38]) ] [ Designated as safety issue: Yes ]

    DLTs: AEs which were at least possibly drug-related occurring within first 3 weeks of dasatinib therapy (toxicities occurring after 21 days were also considered) and are:-

    • Any nonhematologic clinically-apparent toxicity of Grade(GR)≥3 occurring despite appropriate medical management and GR4 laboratory abnormality/GR3 lasting ≥7 days
    • GR4 neutropenia or thrombocytopenia lasting ≥7 days and not explained by the presence of leukemia after hematopoietic reconstitution
    • Any clinically important toxicity of GR≥2 requiring treatment discontinuation or interruption ≥7 days.

  • Number of Participants With Hematology Abnormalities by NCI CTCAE Version 3.0 [ Time Frame: Days 8, 15, 22, 29, 36, 43, then every 3 weeks, then every 3 months after 1 Year, EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38]) ] [ Designated as safety issue: Yes ]
    GR1=Mild; GR2=Moderate; GR3=Severe; GR4=Life-threatening or disabling. Normal ranges provided by local laboratory and may also vary from site to site. WBC: GR1=<LLN-3.0*10^9/L; GR2=<3.0-2.0*10^9/L; GR3=<2.0-1.0*10^9/L; GR4=<1.0*10^9/L. ANC: GR1=<LLN-1.5*10^9 /L; GR2=<1.5-1.0*10^9/L; GR3=<1.0-0.5*10^9/L; GR4=<0.5*10^9/L. Hemoglobin: GR1=<LLN-10.0g/dL; GR2=<10.0-8.0g/dL; GR3=<8.0-6.5g/dL; GR4=<6.5g/dL. Platelets: GR1=<LLN-75.0*10^9/L; GR2=<75.0-50.0*10^9/L; GR3=<50.0-25.0*10^9/L; GR4=<25.0*10^9/L.

  • Number of Participants With Serum Chemistry Abnormalities (Calcium, Magnesium, and Phosphate) by NCI CTCAE Version 3.0 [ Time Frame: Days 22 and 43, then every 12 weeks, then every 24 weeks after 24 months of treatment, EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38]) ] [ Designated as safety issue: Yes ]
    GR1=Mild; GR2=Moderate; GR3=Severe; GR4=Life-threatening or disabling. Normal ranges provided by local laboratory and may also vary from site to site. Low calcium: GR1=<LLN-8.0 mg/dL, GR2=<8.0-7.0 mg/dL, GR3=<7.0-6.0 mg/dL, GR4=<6.0 mg/dL; Low magnesium: GR1=<LLN-1.2 mg/dL, GR2=<1.2-0.9 mg/dL, GR3=<0.9-0.7 mg/dL, GR4=<0.7 mg/dL; Low phosphate: GR1=<LLN - 2.5 mg/dL, GR2=<2.5 - 2.0 mg/dL, GR3=<2.0 - 1.0 mg/dL, GR4=<1.0 mg/dL.

  • Number of Participants With Serum Chemistry Abnormalities (Liver and Renal Function) by NCI CTCAE Version 3.0 [ Time Frame: Days 22 and 43, then every 12 weeks, then every 24 weeks after 24 months of treatment, EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38]) ] [ Designated as safety issue: Yes ]
    GR1=Mild; GR2=Moderate; GR3=Severe; GR4=Life-threatening or disabling. Normal ranges provided by local laboratory and may also vary from site to site. AST and ALT: GR1=>ULN-2.5*ULN; GR2=>2.5-5.0*ULN; GR3=>5.0-20.0*ULN; GR4:>20.0*ULN. Total bilirubin:GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3-10*ULN, GR4=>10*ULN. Creatinine: GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3.0-6.0*ULN, GR4=>6.0*ULN.

  • Number of Participants With Major Cytogenetic Response (MCyR) at Any Time in Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML) [ Time Frame: Strata 1 and 2/3: At Week 7, 13, then every 12 weeks, and EOT; Stratum 2/3: Additionally at Week 4, 19, 31 (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]) ] [ Designated as safety issue: No ]

    Cytogenetic responses were based on the karyotype analysis of the percentage of Ph+ metaphases among cells in metaphase on a BM sample. At least 20 metaphase cells from a BM sample were evaluated.

    MCyR: A cytogenetic response that is either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR).

    CCyR: 0% Ph+ cells in metaphase in BM. PCyR: >0% to 35% Ph+ cells in metaphase in BM.


  • Number of Participants With Major Cytogenetic Response (MCyR) in Stratum 1 (Ph+ CP-CML) Within First 12 and 24 Weeks [ Time Frame: After completion of Week 12 and 24 (measured at Weeks 13 and 25) ] [ Designated as safety issue: No ]

    Cytogenetic responses were based on the karyotype analysis of the percentage of Ph+ metaphases among cells in metaphase on a BM sample. At least 20 metaphase cells from a BM sample were evaluated.

    MCyR: A cytogenetic response that was either CCyR or PCyR. CCyR: 0% Ph+ cells in metaphase in BM. PCyR: >0% to 35% Ph+ cells in metaphase in BM.


  • Best Cytogenetic Response (CyR) in Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML) [ Time Frame: Strata 1 and 2/3: At Weeks 7, 13, then every 12 weeks, and EOT; Stratum 2/3: Additionally at Weeks 4, 19, 25, 31 (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]) ] [ Designated as safety issue: No ]

    Best CyR was assessed based on the percentages of Ph+ metaphases of ≥20 analyzed metaphases in BM sample.

    Participants with complete, partial, minor, minimal, or no CyR. Refer to Outcome Measure 7 for definitions of CCyR and PCyR. Minor CyR:>35%-65% Ph+ cells in metaphase in BM. Minimal CyR:>65%-95% Ph+ cells in metaphase in BM. No CyR:>95%-100% Ph+ cells in metaphase in BM. Unable to determine:Participants without valid cytogenetic assessment (i.e., at least 1 metaphase observed and number of Ph+ metaphases smaller than total number of metaphases [%Ph+ <100%]).


  • Percentage of Participants With Complete Cytogenetic Response (CCyR) or Major Cytogenetic Response (MCyR) at Recommended Phase II Dose [ Time Frame: Strata 1 and 2/3: At Week 7, 13, then every 12 weeks, and EOT; Stratum 2/3: Additionally at Week 4, 19, 31 (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]) ] [ Designated as safety issue: No ]

    Cytogenetic responses were based on the karyotype analysis of the percentage of Ph+ metaphases among cells in metaphase on a BM sample. At least 20 metaphase cells from a BM sample were evaluated.

    MCyR: A cytogenetic response that was either CCyR or PCyR. CCyR: 0% Ph+ cells in metaphase in BM. PCyR: >0% to 35% Ph+ cells in metaphase in BM.


  • Time to Major Cytogenetic Response (MCyR) in Responders: Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML) [ Time Frame: Strata 1 and 2/3: At Weeks 7, 13, 25, 37, then every 12 weeks; Stratum 2/3: Additionally at Weeks 4, 19, 31; until first MCyR (maximum participant time to first MCyR of 92 days). ] [ Designated as safety issue: No ]
    Defined as time (in days) from the first dose of dasatinib until criteria were first met for MCyR. MCyR: A CyR that was either CCyR or PCyR. CCyR: 0% Ph+ cells in metaphase in BM. PCyR: >0% to 35% Ph+ cells in metaphase in BM. The Kaplan-Meier plot was used. A 2-sided, 95% confidence interval (CI) for the median was computed using the Brookmeyer and Crowley method.

  • Duration of Major Cytogenetic Response (MCyR) in Responders (Stratum 1 [Ph+ CP-CML] and Stratum 2/3 [Ph+ ALL or AP/BP-CML]) [ Time Frame: From the date of first MCyR assessment to date of progression, death, or last tumor assessment (maximum participant duration of response of 48.6 months) ] [ Designated as safety issue: No ]

    Defined as the time (in months) from the first day that all criteria were met for MCyR until the date of progression (based on the Investigator's assessment) or death (for participants whose best responses were MCyR and CCyR respectively).

    MCyR: A cytogenetic response that was either CCyR or PCyR. CCyR: 0% Ph+ cells in metaphase in BM. PCyR: >0% to 35% Ph+ cells in metaphase in BM. The Kaplan-Meier plot was used. A 2-sided, 95% CI for the median was computed using the Brookmeyer and Crowley method.


  • Duration of Complete Cytogenetic Response (CCyR) in Responders: Stratum 1 [Ph+ CP-CML] and Stratum 2/3 [Ph+ ALL or AP/BP-CML] [ Time Frame: From the date of first CCyR assessment to date of progression, death, or last tumor assessment (maximum participant duration of response of 45.1 months) ] [ Designated as safety issue: No ]

    Defined as time (in months) from the first day that all criteria were met for CCyR until the date of progression (based on the Investigator's assessment) or death (for participants whose best response was CCyR).

    CCyR = 0% Ph+ metaphases of ≥ 20 analyzed metaphases in BM aspiration. The Kaplan-Meier plot was used. A 2-sided, 95% CI for the median was computed using the Brookmeyer and Crowley method.


  • Number of Participants With Major Hematologic Response (MaHR) at Any Time in Stratum 2/3 (Ph+ ALL or AP/BP-CML) and Stratum 4 (Ph- ALL/AML) [ Time Frame: Days 8, 15, 22, 29, 36, 43; Weeks 4, 7, 13, 19, 25, 31, 37; at Week 10 (only stratum 4); then every 12 weeks upto 24 months; then once/year; EOT(Median duration of therapy in months: Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38]) ] [ Designated as safety issue: No ]

    Defined as participants having as best response complete hematologic response (CHR) or CHR with incomplete platelet recovery (CHRp).

    Criteria:

    CHR-WBC in Peripheral Blood (PB):≤ULN; Immature cells in PB:No blasts, promyelocytes, myelocytes, metamyelocytes; Platelet count (untransfused):≥100,000/mm^3 and ≤450,000/mm^3; ANC:≥ 1000/mm^3; Blasts in BM:<5%; Extra medullary disease:No extramedullary leukemia, including no hepato or splenomegaly (regardless of CNS involvement).

    CHRp-CHR except platelet count (untransfused) & ANC:20,000/mm^3 ≤platelet <100,000/mm^3 & /or 500/mm^3 ≤ANC ≤1000/mm^3.


  • Number of Participants With Major Hematologic Response (MaHR) in Stratum 2/3 (Ph+ ALL or AP/BP-CML) Within First 6 and 24 Weeks [ Time Frame: After completion of Week 6 and 24 (measured at weeks 7 and 25) ] [ Designated as safety issue: No ]

    Defined as participants having as best response a CHR or CHRp.

    Criteria:

    CHR-WBC in PB:≤ULN; Immature cells in PB:No blasts, promyelocytes, myelocytes, metamyelocytes; Platelet count (untransfused):≥100,000/mm^3 and ≤450,000/mm^3; ANC:≥ 1000/mm^3; Blasts in BM:<5%; Extra medullary disease:No extramedullary leukemia, including no hepato or splenomegaly (regardless of CNS involvement).

    CHRp-CHR except platelet count (untransfused) and ANC:20,000/mm^3 ≤platelet <100,000/mm^3 and /or 500/mm^3 ≤ANC ≤1000/mm^3.


  • Best Hematologic Response (HR) At Any Time: Stratum 1 (Ph+ CP-CML) [ Time Frame: Days 8, 15, 22, 29, 36, 43; Weeks 7, 13, 25, 37; then every 12 weeks upto 24 months; then once/year; EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]) ] [ Designated as safety issue: No ]

    HR: Determined by complete blood count (CBC), differential, and platelet count (PLT). Criteria for complete hematologic response (CHR):

    WBC in PB: <10,000/mm^3; Immature cells in PB: No blasts or promyelocytes (myelocytes + metamyelocytes) <5%; Basophils in PB: <5%; Platelet count (untransfused): <450,000/mm^3; Extra medullary disease: No extramedullary leukemia, including no splenomegaly.

    Unconfirmed HR = All criteria met. Confirmed HR = Criteria for HR fulfilled again at least 28 days after they first met with no concomitant use of anagrelide or hydroxyurea during this interval.


  • Best Hematologic Response (HR) At Any Time: Stratum 2/3 (Ph+ ALL or AP/BP-CML) [ Time Frame: Days 8, 15, 22, 29, 36, 43; Weeks 4, 7, 13, 19, 25, 31, 37; then every 12 weeks up to 24 months; then once/year; EOT (Median duration of therapy in months: Stratum 2/3=3.02 [Range: 0.53-37.72]) ] [ Designated as safety issue: No ]

    HR was determined by CBC, differential, and platelet count. Refer to outcome measure 15 for criteria for CHR and CHRp. Criteria for minor hematologic response (MiHR): CHRp except blasts in BM-≥5% and ≤15% blasts in BM.

    Unconfirmed HR = All criteria met. periph=peripheral. Confirmed HR = Criteria for HR fulfilled again at least 28 days after they first met with no concomitant use of anagrelide or hydroxyurea during this interval.


  • Best Hematologic Response (HR) At Any Time: Stratum 4 (Ph- ALL/AML) [ Time Frame: Days 8, 15, 22, 29, 36, 43; Weeks 4, 7, 10, 13, 19, 25, 31, 37; then every 12 weeks upto 24 months; then once/year; EOT (Median duration of therapy in months: Stratum 4=1.14 [Range: 0.03-3.38]) ] [ Designated as safety issue: No ]
    HR was determined by CBC, differential, and platelet count. Unable to determine = Participants without any valid hematologic assessments.

  • Time to Major Hematologic Response (MaHR): Stratum 2/3 (PH+ ALL or AP/BP-CML) [ Time Frame: Days 8, 15, 22, 29, 36, 43; Weeks 4, 7, 13, 19, 25, 31, 37; then every 12 weeks upto 24 months; then once/year; until confirmed MaHR (maximum participant time to first MaHR of 44 days). ] [ Designated as safety issue: No ]

    Defined as time (in days) from first dose of dasatinib until the first day MaHR criteria were met, provided they were confirmed later (after 28 days) with no concomitant use of anagrelide or hydroxyurea during this interval.

    MaHR: Defined as participants having as best response a CHR or CHRp. Refer to Outcome Measure 15 for criteria for CHR and CHRp. Estimated by the Kaplan-Meier method and a 2-sided, 95% CI for the median was computed using the Brookmeyer and Crowley method.


  • Time to Complete Hematologic Response (CHR): Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ALL or AP/BP-CML) [ Time Frame: Days 8, 15, 22, 29, 36, 43; Weeks 7, 13, 25, 37; at Week 4, 19, 31 (only stratum 2/3); then every 12 weeks upto 24 months; then once/year; until criteria was first met for CHR (maximum participant time to first CHR of 65 days). ] [ Designated as safety issue: No ]

    Time to CHR is the time (in days) from first dose of dasatinib until the first day CHR criteria were met, provided they were confirmed later after 28 days with no concomitant use of anagrelide or hydroxyurea during this interval.

    Refer to Outcome Measure 16 for criteria to CHR in Stratum 1 and to Outcome Measure 15 for criteria for CHR in Stratum 2/3.

    Estimated by the Kaplan-Meier method and a 2-sided 95% CI for median was computed using the Brookmeyer and Crowley method.


  • Duration of Major Hematologic Response (MaHR): Stratum 2/3 (Ph+ALL or AP/BP-CML) [ Time Frame: From the date of first confirmed MaHR to date of progression, death, or last tumor assessment (maximum participant duration of response of 37 months). ] [ Designated as safety issue: No ]

    Duration of MaHR is the time (in months) from the first day criteria were met for MaHR, provided they were confirmed later at least after 28 days with no concomitant use of anagrelide or hydroxyurea during this interval, until death or progression was first observed.

    MaHR: Defined as participants having as best response a CHR or CHRp. Refer to outcome measure 20 for criteria for CHR or CHRp. The Kaplan-Meier plot was used. A 2-sided, 95% CI for the median was computed using the Brookmeyer and Crowley method.


  • Duration of Complete Hematologic Response (CHR): Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ALL or AP/BP-CML) [ Time Frame: From the date of first confirmed CHR to date of progression, death, or last tumor assessment (maximum participant duration of response of 50 months). ] [ Designated as safety issue: No ]

    Duration of CHR is the time (in months) from the first day criteria were met for CHR, provided they were confirmed later (after 28 days) with no concomitant use of anagrelide or hydroxyurea during this interval until death or progression was first observed. Refer to Outcome Measure 20 for criteria for CHR (Stratum 1) and Outcome Measure 19 for CHR (Stratum 2/3).

    The Kaplan-Meier plot was used. A 2-sided, 95% CI for the median was computed using the Brookmeyer and Crowley method.


  • Percentage of Participants With Confirmed Hematologic Response (HR) at Recommended Phase II Dose: Stratum 1 (Ph+ CP-CML) [ Time Frame: Days 8, 15, 22, 29, 36, 43; Weeks 7, 13, 25, 37; then every 12 weeks upto 24 months; then once/year; EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]) ] [ Designated as safety issue: No ]

    A participant was said to have a confirmed HR if all the criteria for HR were fulfilled again at least 28 days after they first met with no concomitant use of anagrelide or hydroxyurea during this interval.

    HR observed in stratum 1 was CHR. Refer to Outcome Measure 20 for criteria for CHR.

    The Clopper and Pearson method was used to compute 95% exact CIs.


  • Percentage of Participants With Confirmed Hematologic Response (HR) at Recommended Phase II Dose: Stratum 2/3 (Ph+ALL or AP/BP-CML) [ Time Frame: Days 8, 15, 22, 29, 36, 43; Weeks 4, 7, 13, 19, 25, 31, 37; then every 12 weeks upto 24 months; then once/year; EOT (Median duration of therapy in months: Stratum 2/3=3.02 [Range: 0.53-37.72]) ] [ Designated as safety issue: No ]

    A participant is said to have a confirmed HR if criteria for HR were fulfilled again at least 28 days after they first met with no concomitant use of anagrelide or hydroxyurea during this interval.

    Confirmed HR observed in stratum 2/3 was either CHR or MaHR or overall hematologic response (OHR).

    Refer to Outcome Measure 19 for criteria for CHR and MaHR. OHR is defined as MaHR or MiHR. MiHR=CHRp except blasts in BM (≥ 5% and ≤ 15% blasts in BM). The Clopper and Pearson method was used to compute 95% exact CIs.


  • Number of Participants With Molecular Responses in Stratum 1 (Ph+ CP-CML) [ Time Frame: At baseline (within 3 weeks before initiation of study therapy), After hematologic response, EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]) ] [ Designated as safety issue: No ]

    Molecular response was calculated by measuring p210 variant of BCR-ABL transcripts in blood during treatment using quantitative polymerase chain reaction (qPCR) assay.

    Major molecular response (MMR): Ratio of the BCR-ABL to ABL <10^-3 or 0.1% on the international scale.

    Complete molecular response (CMR): Complete absence of BCR-ABL or the ratio is <10^-4.5 or 0.00316% on the international scale.

    Confirmed MMR or CMR = Criteria met again >6 weeks. BCR-ABL=the fused gene found in participants with this type of CML.


  • Number of Participants With Major Molecular Response (MMR) in Stratum 2/3 (Ph+ ALL or AP/BP-CML) [ Time Frame: At baseline (within 3 weeks before initiation of study therapy), After hematologic response, EOT (Median duration of therapy in months: Stratum 2/3=3.02 [Range: 0.53-37.72]) ] [ Designated as safety issue: No ]

    Molecular response was calculated by measuring BCR-ABL transcripts in blood during treatment using qPCR assay.

    MMR: Ratio of the BCR-ABL to ABL <10^-3 or a ≥3 log reduction from baseline in participants with p190 variant; ratio of the BCR-ABL to ABL <10^-3 on the international scale in participants with p210 variant.

    BCR-ABL=the fused gene found in participants with this type of CML.


  • Progression Free Survival (PFS) [ Time Frame: From the date of randomization to date of progression, death, last tumor assessment, or 5 years after EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38]) ] [ Designated as safety issue: No ]

    Time in months from 1st first dose until progression (resistance or refractory disease) or death was first documented by investigator.

    Progressive disease: Resistant disease for which investigator may electively stop treatment or refractory disease requiring cessation of study treatment.

    The PFS was estimated using the Kaplan-Meier product-limit method, and a two-sided 95% CI for the median PFS time was computed using the method of Brookmeyer and Crowley.


  • Overall Survival (OS) [ Time Frame: From start of study therapy until death or 5 years after EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38]) ] [ Designated as safety issue: No ]
    Defined as time in months from start of study therapy to death. The OS was estimated using the Kaplan-Meier product-limit method, and a two-sided 95% CI for the median OS time was computed using the Brookmeyer and Crowley method.

  • Dasatinib Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) by Age Group [ Time Frame: During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours). ] [ Designated as safety issue: No ]
    PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Tmax is the time taken to reach the maximum observed plasma concentration.

  • Dasatinib Plasma Pharmacokinetic Parameter: Terminal Half-life (T 1/2) by Age Group [ Time Frame: During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours). ] [ Designated as safety issue: No ]
    PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. T 1/2 is the time required for the concentration of the drug to reach half of its original value in plasma.

  • Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Observed Maximum Plasma Concentration (Cmax) by Age Group [ Time Frame: During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours). ] [ Designated as safety issue: No ]
    PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Dose Normalized Cmax is the maximum observed concentration of drug substance in plasma normalized for different dasatinib dose levels.

  • Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-T]) by Age Group [ Time Frame: During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours). ] [ Designated as safety issue: No ]
    PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC[0-T] is the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration, normalized by dasatinib dose level.

  • Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinite Time (AUC[INF]) by Age Group [ Time Frame: During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours). ] [ Designated as safety issue: No ]
    PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC (0-inf) is the area under the plasma concentration-time curve from time zero extrapolated to infinite time, normalized by dasatinib dose level.

  • Dasatinib Plasma Pharmacokinetic Parameter: Observed Maximum Plasma Concentration (Cmax) by Dose Level and Age Group [ Time Frame: During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours). ] [ Designated as safety issue: No ]
    PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Cmax is the maximum observed concentration of drug substance in plasma.

  • Dasatinib Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) By Dose Level and Age Group [ Time Frame: During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours). ] [ Designated as safety issue: No ]
    PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Tmax is the time taken to reach the maximum observed plasma concentration.

  • Dasatinib Plasma Pharmacokinetic Parameter: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-T]) by Dose Level and Age Group [ Time Frame: During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours). ] [ Designated as safety issue: No ]
    PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC(0-T) is the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration.

  • Dasatinib Plasma Pharmacokinetic Parameter: Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinite Time (AUC[INF]) by Dose Level and Age Group [ Time Frame: During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours). ] [ Designated as safety issue: No ]
    PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC(INF) is the area under the plasma concentration-time curve from time zero extrapolated to infinite time.

  • Dasatinib Plasma Pharmacokinetic Parameter: Terminal Half-life (T 1/2) by Dose Level and Age Group [ Time Frame: During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours). ] [ Designated as safety issue: No ]
    PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. T 1/2 is the time required for the concentration of the drug to reach half of its original value in plasma.

  • Dasatinib Metabolite (BMS-582691) Plasma Pharmacokinetic Parameter: Observed Maximum Plasma Concentration (Cmax) by Dose Level and Age Group [ Time Frame: During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours). ] [ Designated as safety issue: No ]
    PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Cmax is the maximum observed concentration of drug substance in plasma.

  • Dasatinib Metabolite (BMS-582691) Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) By Dose Level and Age Group [ Time Frame: During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours). ] [ Designated as safety issue: No ]
    PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Tmax is the time taken to reach the maximum observed plasma concentration.

  • Dasatinib Metabolite (BMS-582691) Plasma Pharmacokinetic Parameter: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-T]) by Dose Level and Age Group [ Time Frame: During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours). ] [ Designated as safety issue: No ]
    PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC(0-T) is the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration.

  • Concentration of Dasatinib in Cerebrospinal Fluid (CSF) by Dose Level and Age Group [ Time Frame: 4 hours after oral dose ] [ Designated as safety issue: No ]

    Concentration of dasatinib in CSF was assessed only in participants who had lumbar puncture during the treatment.

    y=years


  • Number of Participants With BCR-ABL Mutations at Baseline: Stratum1 Ph+ CP-CML and Stratum 2/3 Ph+ALL or AP/BP-CML [ Time Frame: At baseline (within 3 weeks before initiation of study therapy) ] [ Designated as safety issue: No ]
    BCR-ABL, also referred to as the Philadelphia chromosome, is formed from the fusion of the BCR gene on chromosome 22 with the ABL gene on chromosome 9.

  • Number of Participants With BCR-ABL Mutations at End-of-Treatment: Stratum1 Ph+ CP-CML and Stratum2/3 Ph+ ALL or AP/BP-CML [ Time Frame: At EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]) ] [ Designated as safety issue: No ]
    BCR-ABL = These are fused genes found in participants with this type of leukemia.

  • Number of Participants With FLT3 and KIT Mutations in Stratum4 Ph- ALL/AML at Baseline [ Time Frame: At baseline (within 3 weeks before initiation of study therapy) ] [ Designated as safety issue: No ]
    FLT3 and KIT = These are fused genes found in participants with this type of leukemia.

  • Number of Participants With FLT3 and KIT Mutations in Stratum4 Ph- ALL/AML at End-Of-Treatment [ Time Frame: At EOT (Median duration of therapy in months: Stratum 4=1.14 [Range: 0.03-3.38]) ] [ Designated as safety issue: No ]
    FLT3 and KIT = These are fused genes found in participants with this type of leukemia.


Other Outcome Measures:
  • Number of Participants With Hematologic Toxicity at Baseline by NCI CTCAE Version 3.0 [ Time Frame: At baseline (within 1 week before initiation of study therapy) ] [ Designated as safety issue: Yes ]

    GR1=Mild; GR2=Moderate; GR3=Severe; GR4=Life-threatening or disabling. Normal ranges provided by local laboratory and may also vary from site to site. White Blood Cell (WBC):GR1=<LLN-3.0*10^9/L; GR2=<3.0-2.0*10^9/L; GR3=<2.0-1.0*10^9/L; GR4=<1.0*10^9/L. Absolute Neutrophil Count (ANC): GR1=<LLN-1.5*10^9 /L; GR2=<1.5-1.0*10^9/L; GR3=<1.0-0.5*10^9/L; GR4=<0.5*10^9/L. Hemoglobin: GR1=<LLN-10.0g/dL; GR2=<10.0-8.0g/dL; GR3=<8.0-6.5g/dL; GR4=<6.5g/dL. Platelets: GR1=<LLN-75.0*10^9/L; GR2=<75.0-50.0*10^9/L; GR3=<50.0-25.0*10^9/L; GR4=<25.0*10^9/L.

    LLN=lower limit of normal.


  • Number of Participants With Serum Chemistry Abnormalities (Liver and Renal Function) at Baseline by NCI CTCAE Version 3.0 [ Time Frame: At baseline (within 1 week before initiation of study therapy) ] [ Designated as safety issue: Yes ]

    GR1=Mild; GR2=Moderate; GR3=Severe; GR4=Life-threatening or disabling. Normal ranges provided by local laboratory and may also vary from site to site. Aspartate aminotransferase (AST) and alanine aminotransferase(ALT): GR1=>ULN-2.5*ULN; GR2=>2.5-5.0*ULN; GR3=>5.0-20.0*ULN; GR4=>20.0*ULN. Total bilirubin:GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3-10*ULN, GR4=>10*ULN. Creatinine: GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3.0-6.0*ULN, GR4=>6.0*ULN.

    ULN=upper limit of normal.


  • Number of Participants With Serum Chemistry Abnormalities (Calcium, Magnesium, and Phosphate) at Baseline by NCI CTCAE Version 3.0 [ Time Frame: At baseline (within 1 week before initiation of study therapy) ] [ Designated as safety issue: Yes ]
    GR1=Mild; GR2=Moderate; GR3=Severe; GR4=Life-threatening or disabling. Normal ranges provided by local laboratory and may also vary from site to site. Low calcium: GR1=<LLN-8.0 mg/dL, GR2=<8.0-7.0 mg/dL, GR3=<7.0-6.0 mg/dL, GR4=<6.0 mg/dL; Low magnesium: GR1=<LLN-1.2 mg/dL, GR2=<1.2-0.9 mg/dL, GR3=<0.9-0.7 mg/dL, GR4=<0.7 mg/dL; Low phosphate: GR1=<LLN - 2.5 mg/dL, GR2=<2.5 - 2.0 mg/dL, GR3=<2.0 - 1.0 mg/dL, GR4=<1.0 mg/dL.


Enrollment: 58
Study Start Date: March 2006
Estimated Study Completion Date: October 2022
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Stratum 1 (Ph+ CP-CML)
Participants with imatinib-resistant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP)
Drug: Dasatinib

Tablets, Oral, If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Starting Dose Level of 60 mg/m^2; Escalated/Dose Level 2 of 80 mg/m^2. Once daily (QD), as long as clinical benefit was maintained.

Intra-participant dose escalation was allowed based on tolerance and on individual response. The starting dose for subsequent participants in a stratum may have been escalated depending on safety, assessed by prior intra-participant dose-escalation, and lack of efficacy in previous participants. Treatment courses were defined as 3 weeks (21 days plus any required delay); for participants who stayed on treatment > 12 months, courses after 12 months were defined in quartiles of 13 weeks. Participants were to be followed until death or up to 5 years after end-of-treatment (EOT).

Other Names:
  • Sprycel
  • BMS-354825
Experimental: Stratum 2/3 (Ph+ ALL or AP/BP-CML)
Participants with imatinib-resistant or imatinib-intolerant Ph+ CML in accelerated phase (AP), or in myeloid blast phase (MBP), or in lymphoid blast phase (LBP); or relapsed or refractory Ph+ acute lymphoblastic leukemia (ALL) after imatinib use; or second or subsequent relapse of Ph+ acute myeloid leukemia (AML)
Drug: Dasatinib

Tablets, Oral, If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Starting Dose Level of 60 mg/m^2; Escalated/Dose Level 2 of 80 mg/m^2. QD, as long as clinical benefit was maintained.

Intra-participant dose escalation was allowed based on tolerance and on individual response. The starting dose for subsequent participants in a stratum may have been escalated depending on safety, assessed by prior intra-participant dose-escalation, and lack of efficacy in previous participants. Treatment courses were defined as 3 weeks (21 days plus any required delay); for participants who stayed on treatment > 12 months, courses after 12 months were defined in quartiles of 13 weeks. Participants were to be followed until death or up to 5 years after EOT.

Other Names:
  • Sprycel
  • BMS-354825
Experimental: Stratum 4 (Ph- ALL/AML)
Participants with second or subsequent relapse of Ph- ALL or Ph- AML
Drug: Dasatinib

Tablets, Oral, If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Starting Dose Level of 60 mg/m^2; Escalated/Dose level 2 of 80 mg/m^2, Escalated/Dose level 3 of 100 mg/m^2, and Escalated/Dose level 4 of 120 mg/m^2. QD, as long as clinical benefit was maintained.

Intra-participant dose escalation was allowed based on tolerance and on individual response. The starting dose for subsequent participants in a stratum may have been escalated depending on safety, assessed by prior intra-participant dose-escalation, and lack of efficacy in previous participants. Treatment courses were defined as 3 weeks (21 days plus any required delay); for participants who stayed on treatment > 12 months, courses after 12 months were defined in quartiles of 13 weeks. Participants were to be followed until death or up to 5 years after EOT.

Other Names:
  • Sprycel
  • BMS-354825

  Eligibility

Ages Eligible for Study:   12 Months to 20 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:

  • Ph-positive (Ph+) Chronic Myelogenous Leukemia in chronic, accelerated or blast phase or Ph+ acute lymphoblastic leukemia (ALL) with imatinib-resistant disease or intolerance to imatinib.
  • Ph-negative acute leukemia in second or subsequent relapse
  • Age >1 and <21 years
  • Lansky or Karnofsky scale >60
  • Life expectancy >3 weeks
  • Adequate hepatic and renal function
  • Written informed consent

Exclusion Criteria:

  • Subjects for whom potentially-curative therapy was available, including electing immediate [ie, planned <45 days] stem-cell transplantation. Subjects in Stratum 1 were to have had an ongoing identical HLA donor search, and may have discontinued study if a donor became available.)
  • Subjects with symptomatic central nervous system (CNS) disease (eg, convulsions due to their CNS disease).
  • Subjects who had not recovered from acute toxicity of previous therapy.
  • Clinically-significant disorder of platelet function (eg, von Willebrand's disease) or ongoing gastrointestinal bleeding.
  • Serious uncontrolled medical disorder or active infection
  • Uncontrolled or significant cardiovascular disease
  • Use of any investigational agent or any other anticancer agent within 14 days prior to treatment start.
  • Prior therapy with dasatinib
  • Subjects taking medications that irreversibly inhibit platelet function or anticoagulants.
  • Subjects taking certain medications that are accepted to have a risk of causing QTc prolongation.
  • Women of Child Bearing Potential with a positive pregnancy test prior to study drug administration.
  • Expected noncompliance, or unable to have regular follow-up due to psychologic, social, familial, or geographic reasons.
  • Subjects who are compulsorily detained for legal reasons or treatment of either a psychiatric or physical (eg, 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: NCT00306202

Locations
Austria
Local Institution
Vienna, Austria, 1090
France
Local Institution
Nantes, France, 44093
Local Institution
Paris Cedex 10, France, 75475
Local Institution
Paris Cedex 12, France, 75571
Germany
Local Institution
Berlin, Germany, 13353
Local Institution
Frankfurt, Germany, 60590
Local Institution
Hannover, Germany, 30625
Italy
Local Institution
Monza (mi), Italy, 20052
Netherlands
Local Institution
Rotterdam, Netherlands, 3015 GJ
United Kingdom
Local Institution
Manchester, Greater Manchester, United Kingdom, M27 4HA
Local Institution
Bristol, Somerset, United Kingdom, BS2 8BJ
Local Institution
Sutton, Surrey, United Kingdom, SM2 5PT
Local Institution
Birmingham, West Midlands, United Kingdom, B4 6NH
Sponsors and Collaborators
Bristol-Myers Squibb
ITCC
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided by Bristol-Myers Squibb

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00306202     History of Changes
Other Study ID Numbers: CA180-018, Protocol ITCC 005, 2005-002882-35
Study First Received: March 21, 2006
Results First Received: June 11, 2012
Last Updated: August 5, 2014
Health Authority: United States: Food and Drug Administration
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Bristol-Myers Squibb:
Relapsed and Refractory Leukemia

Additional relevant MeSH terms:
Leukemia
Neoplasms by Histologic Type
Neoplasms
Dasatinib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 22, 2014