Phase I Study of SRC/ABL Tyrosine Kinase Inhibitor Dasatinib [BMS-354825] in Children and Adolescents With Relapsed or Refractory Leukemia, Protocol ITCC 005

简要总结

主要结局

次要结局

• 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)(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 Dose-limiting Toxicity (DLT)(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 Major Cytogenetic Response (MCyR) in Stratum 1 (Ph+ CP-CML) Within First 12 and 24 Weeks(After completion of Week 12 and 24 (measured at Weeks 13 and 25))
• Time to Major Cytogenetic Response (MCyR) in Responders: Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML)(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).)
• Number of Participants With Serum Chemistry Abnormalities (Calcium, Magnesium, and Phosphate) by NCI CTCAE Version 3.0(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 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.(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(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 (Liver and Renal Function) by NCI CTCAE Version 3.0(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)(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]))
• Best Cytogenetic Response (CyR) in Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML)(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]))
• Duration of Complete Cytogenetic Response (CCyR) in Responders: Stratum 1 [Ph+ CP-CML] and Stratum 2/3 [Ph+ ALL or AP/BP-CML](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))
• Percentage of Participants With Complete Cytogenetic Response (CCyR) or Major Cytogenetic Response (MCyR) at Recommended Phase II Dose(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]))
• Duration of Major Cytogenetic Response (MCyR) in Responders (Stratum 1 [Ph+ CP-CML] and Stratum 2/3 [Ph+ ALL or AP/BP-CML])(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))
• Dasatinib Plasma Pharmacokinetic Parameter: Terminal Half-life (T 1/2) by Age Group(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).)
• Number of Participants With Major Hematologic Response (MaHR) in Stratum 2/3 (Ph+ ALL or AP/BP-CML) Within First 6 and 24 Weeks(After completion of Week 6 and 24 (measured at weeks 7 and 25))
• Best Hematologic Response (HR) At Any Time: Stratum 2/3 (Ph+ ALL or AP/BP-CML)(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]))
• Duration of Complete Hematologic Response (CHR): Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ALL or AP/BP-CML)(From the date of first confirmed CHR to date of progression, death, or last tumor assessment (maximum participant duration of response of 50 months).)
• Duration of Major Hematologic Response (MaHR): Stratum 2/3 (Ph+ALL or AP/BP-CML)(From the date of first confirmed MaHR to date of progression, death, or last tumor assessment (maximum participant duration of response of 37 months).)
• Number of Participants With Molecular Responses in Stratum 1 (Ph+ CP-CML)(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]))
• Progression Free Survival (PFS)(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]))
• Best Hematologic Response (HR) At Any Time: Stratum 4 (Ph- ALL/AML)(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)(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).)
• Number of Participants With Major Molecular Response (MMR) in Stratum 2/3 (Ph+ ALL or AP/BP-CML)(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]))
• 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(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(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(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).)
• Number of Participants With BCR-ABL Mutations at Baseline: Stratum1 Ph+ CP-CML and Stratum 2/3 Ph+ALL or AP/BP-CML(At baseline (within 3 weeks before initiation of study therapy))
• Time to Complete Hematologic Response (CHR): Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ALL or AP/BP-CML)(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).)
• Percentage of Participants With Confirmed Hematologic Response (HR) at Recommended Phase II Dose: Stratum 1 (Ph+ CP-CML)(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)(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]))
• Overall Survival (OS)(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(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(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(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(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(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(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(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(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(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).)
• Number of Participants With BCR-ABL Mutations at End-of-Treatment: Stratum1 Ph+ CP-CML and Stratum2/3 Ph+ ALL or AP/BP-CML(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(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(At EOT (Median duration of therapy in months: Stratum 4=1.14 [Range: 0.03-3.38]))
• Concentration of Dasatinib in Cerebrospinal Fluid (CSF) by Dose Level and Age Group(4 hours after oral dose)
• Best Hematologic Response (HR) At Any Time: Stratum 1 (Ph+ CP-CML)(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]))