Clinical trial NCT00306202: Study of Dasatinib in Children and Adolescents With Relapsed or Refractory Leukemia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Leukemia
Keywords: Relapsed and Refractory Leukemia
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
Collaborators: name: Innovative Therapies For Children with Cancer Consortium
First posted: 2006-03-23
Enrollment: 63
Sex: ALL
Minimum age (years): 12
Maximum age (years): 20
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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.

Primary outcomes:
measure: Recommended Phase II Dose of Dasatinib in Children and Adolescents With Relapsed or Refractory Leukemia
timeFrame: 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])
Secondary outcomes:
measure: 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.
timeFrame: 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])
measure: Number of Participants With Dose-limiting Toxicity (DLT)
timeFrame: 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])
measure: Number of Participants With Hematology Abnormalities by NCI CTCAE Version 3.0
timeFrame: 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])
measure: Number of Participants With Serum Chemistry Abnormalities (Calcium, Magnesium, and Phosphate) by NCI CTCAE Version 3.0
timeFrame: 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])
measure: Number of Participants With Serum Chemistry Abnormalities (Liver and Renal Function) by NCI CTCAE Version 3.0
timeFrame: 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])
measure: 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)
timeFrame: 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])
measure: Number of Participants With Major Cytogenetic Response (MCyR) in Stratum 1 (Ph+ CP-CML) Within First 12 and 24 Weeks
timeFrame: After completion of Week 12 and 24 (measured at Weeks 13 and 25)
measure: Best Cytogenetic Response (CyR) in Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML)
timeFrame: 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])
measure: Percentage of Participants With Complete Cytogenetic Response (CCyR) or Major Cytogenetic Response (MCyR) at Recommended Phase II Dose
timeFrame: 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])
measure: Time to Major Cytogenetic Response (MCyR) in Responders: Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML)
timeFrame: 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).
measure: Duration of Major Cytogenetic Response (MCyR) in Responders (Stratum 1 [Ph+ CP-CML] and Stratum 2/3 [Ph+ ALL or AP/BP-CML])
timeFrame: 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)
measure: Duration of Complete Cytogenetic Response (CCyR) in Responders: Stratum 1 [Ph+ CP-CML] and Stratum 2/3 [Ph+ ALL or AP/BP-CML]
timeFrame: 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)
measure: 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)
timeFrame: 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])
measure: Number of Participants With Major Hematologic Response (MaHR) in Stratum 2/3 (Ph+ ALL or AP/BP-CML) Within First 6 and 24 Weeks
timeFrame: After completion of Week 6 and 24 (measured at weeks 7 and 25)
measure: Best Hematologic Response (HR) At Any Time: Stratum 1 (Ph+ CP-CML)
timeFrame: 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])
measure: Best Hematologic Response (HR) At Any Time: Stratum 2/3 (Ph+ ALL or AP/BP-CML)
timeFrame: 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])
measure: Best Hematologic Response (HR) At Any Time: Stratum 4 (Ph- ALL/AML)
timeFrame: 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])
measure: Time to Major Hematologic Response (MaHR): Stratum 2/3 (PH+ ALL or AP/BP-CML)
timeFrame: 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).
measure: Time to Complete Hematologic Response (CHR): Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ALL or AP/BP-CML)
timeFrame: 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).
measure: Duration of Major Hematologic Response (MaHR): Stratum 2/3 (Ph+ALL or AP/BP-CML)
timeFrame: From the date of first confirmed MaHR to date of progression, death, or last tumor assessment (maximum participant duration of response of 37 months).
measure: Duration of Complete Hematologic Response (CHR): Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ALL or AP/BP-CML)
timeFrame: From the date of first confirmed CHR to date of progression, death, or last tumor assessment (maximum participant duration of response of 50 months).
measure: Percentage of Participants With Confirmed Hematologic Response (HR) at Recommended Phase II Dose: Stratum 1 (Ph+ CP-CML)
timeFrame: 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])
measure: Percentage of Participants With Confirmed Hematologic Response (HR) at Recommended Phase II Dose: Stratum 2/3 (Ph+ALL or AP/BP-CML)
timeFrame: 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])
measure: Number of Participants With Molecular Responses in Stratum 1 (Ph+ CP-CML)
timeFrame: 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])
measure: Number of Participants With Major Molecular Response (MMR) in Stratum 2/3 (Ph+ ALL or AP/BP-CML)
timeFrame: 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])
measure: Progression Free Survival (PFS)
timeFrame: 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])
measure: Overall Survival (OS)
timeFrame: 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])
measure: Dasatinib Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) by Age Group
timeFrame: 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).
measure: Dasatinib Plasma Pharmacokinetic Parameter: Terminal Half-life (T 1/2) by Age Group
timeFrame: 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).
measure: Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Observed Maximum Plasma Concentration (Cmax) by Age Group
timeFrame: 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).
measure: 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
timeFrame: 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).
measure: 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
timeFrame: 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).
measure: Dasatinib Plasma Pharmacokinetic Parameter: Observed Maximum Plasma Concentration (Cmax) by Dose Level and Age Group
timeFrame: 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).
measure: Dasatinib Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) By Dose Level and Age Group
timeFrame: 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).
measure: 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
timeFrame: 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).
measure: 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
timeFrame: 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).
measure: Dasatinib Plasma Pharmacokinetic Parameter: Terminal Half-life (T 1/2) by Dose Level and Age Group
timeFrame: 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).
measure: Dasatinib Metabolite (BMS-582691) Plasma Pharmacokinetic Parameter: Observed Maximum Plasma Concentration (Cmax) by Dose Level and Age Group
timeFrame: 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).
measure: Dasatinib Metabolite (BMS-582691) Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) By Dose Level and Age Group
timeFrame: 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).
measure: 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
timeFrame: 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).
measure: Concentration of Dasatinib in Cerebrospinal Fluid (CSF) by Dose Level and Age Group
timeFrame: 4 hours after oral dose
measure: Number of Participants With BCR-ABL Mutations at Baseline: Stratum1 Ph+ CP-CML and Stratum 2/3 Ph+ALL or AP/BP-CML
timeFrame: At baseline (within 3 weeks before initiation of study therapy)
measure: Number of Participants With BCR-ABL Mutations at End-of-Treatment: Stratum1 Ph+ CP-CML and Stratum2/3 Ph+ ALL or AP/BP-CML
timeFrame: 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])
measure: Number of Participants With FLT3 and KIT Mutations in Stratum4 Ph- ALL/AML at Baseline
timeFrame: At baseline (within 3 weeks before initiation of study therapy)
measure: Number of Participants With FLT3 and KIT Mutations in Stratum4 Ph- ALL/AML at End-Of-Treatment
timeFrame: At EOT (Median duration of therapy in months: Stratum 4=1.14 [Range: 0.03-3.38])
Other outcomes:
measure: Number of Participants With Hematologic Toxicity at Baseline by NCI CTCAE Version 3.0
timeFrame: At baseline (within 1 week before initiation of study therapy)
measure: Number of Participants With Serum Chemistry Abnormalities (Liver and Renal Function) at Baseline by NCI CTCAE Version 3.0
timeFrame: At baseline (within 1 week before initiation of study therapy)
measure: Number of Participants With Serum Chemistry Abnormalities (Calcium, Magnesium, and Phosphate) at Baseline by NCI CTCAE Version 3.0
timeFrame: At baseline (within 1 week before initiation of study therapy)
Locations:
city: Vienna
country: Austria
facility: Local Institution
city: Nantes
country: France
facility: Local Institution
city: Paris Cedex 10
country: France
facility: Local Institution
city: Paris Cedex 12
country: France
facility: Local Institution
city: Berlin
country: Germany
facility: Local Institution
city: Frankfurt
country: Germany
facility: Local Institution
city: Hannover
country: Germany
facility: Local Institution
city: Monza (mi)
country: Italy
facility: Local Institution
city: Rotterdam
country: Netherlands
facility: Local Institution
city: Manchester
country: United Kingdom
facility: Local Institution
state: Greater Manchester
city: Bristol
country: United Kingdom
facility: Local Institution
state: Somerset
city: Sutton
country: United Kingdom
facility: Local Institution
state: Surrey
city: Birmingham
country: United Kingdom
facility: Local Institution
state: West Midlands
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: Zwaan CM, Rizzari C, Mechinaud F, Lancaster DL, Lehrnbecher T, van der Velden VH, Beverloo BB, den Boer ML, Pieters R, Reinhardt D, Dworzak M, Rosenberg J, Manos G, Agrawal S, Strauss L, Baruchel A, Kearns PR. Dasatinib in children and adolescents with relapsed or refractory leukemia: results of the CA180-018 phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium. J Clin Oncol. 2013 Jul 1;31(19):2460-8. doi: 10.1200/JCO.2012.46.8280. Epub 2013 May 28.