Overview

This trial is active, not recruiting.

Condition leukemia
Treatments dasatinib
Phase phase 1
Target BCR-ABL
Sponsor Bristol-Myers Squibb
Collaborator ITCC
Start date March 2006
End date May 2011
Trial size 58 participants
Trial identifier NCT00306202, 2005-002882-35, CA180-018, Protocol ITCC 005

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation non-randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Participants with imatinib-resistant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP)
dasatinib Sprycel
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).
(Experimental)
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)
dasatinib Sprycel
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.
(Experimental)
Participants with second or subsequent relapse of Ph- ALL or Ph- AML
dasatinib Sprycel
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.

Primary Outcomes

Measure
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])

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.
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])
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])
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])
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])
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])
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])
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)
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])
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])
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).
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)
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)
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])
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)
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])
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])
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])
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).
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).
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).
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).
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])
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])
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])
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])
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])
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])
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Concentration of Dasatinib in Cerebrospinal Fluid (CSF) by Dose Level and Age Group
time frame: 4 hours after oral dose
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)
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])
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)
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])

Eligibility Criteria

Male or female participants from 12 months up to 20 years old.

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.

Additional Information

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
Trial information was received from ClinicalTrials.gov and was last updated in August 2015.
Information provided to ClinicalTrials.gov by Bristol-Myers Squibb.