A Phase II Study of Dasatinib in Children and Adolescents With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia (CML) or With Ph+ Leukemias Resistant or Intolerant to Imatinib

Study Overview
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Brief Summary
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The purpose of this study is to determine whether dasatinib is safe and effective in children and adolescents with newly diagnosed chronic myeloid leukemia (CML), or in children with Ph+ acute lymphoblastic leukemia (ALL), accelerated or blast phases CML who relapse after imatinib or who are resistant or intolerant to imatinib. The side effects of this oral investigational drug in children and adolescents will be evaluated

Official Title
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A Phase II Study of Dasatinib Therapy in Children and Adolescents With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia or With Ph+ Leukemias Resistant or Intolerant to Imatinib

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Dasatinib


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com. Inclusion Criteria: CP-CML who prove resistant or intolerant to imatinib (Cohort 1) Ph+ ALL, AP-CML, or BP-CML who are resistant or intolerant to or who relapse after imatinib therapy (Cohort 2) Newly diagnosed, treatment naive CP-CML (Cohort 3) Lansky or Karnofsky scale >50 Life expectancy ≥12 weeks Adequate hepatic and renal function Written informed consent Target Population for the PK substudy must obtain written informed consent from subject, or from parents or legal guardians for minor subjects, according to local law and regulation Target Population for the PK substudy subjects must have CP-CML and be taking daily dasatinib (tablets or PFOS) either as part of Cohort 1 or Cohort 3 of this protocol. Patients receiving commercial dasatinib tablets outside of this protocol may be invited to participate in this PK substudy Target Population for the PK substudy subjects with CP-CML who are tolerating dasatinib tablet dose of at least 60 mg/m2 or dasatinib PFOS dose of at least 72 mg/m2 Target Population for the PK substudy prior exposure to imatinib or other TKI therapy is permissible Target Population for the PK substudy subjects must meet relevant inclusion criteria Exclusion Criteria: Eligibility for potentially-curative therapy including hematopoietic stem-cell transplantation Symptomatic CNS involvement (other than signs and symptoms caused by leptomeningeal disease) Isolated extramedullary disease Prior therapy with Dasatinib Target Population for the PK substudy subjects participating in the PK substudy must comply with the relevant exclusion criteria Target Population for the PK substudy subjects are not allowed to use proton pump inhibitors, H2 antagonists, CYP3A4 inhibitors and inducers when entering the PK substudy Other inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Imatinib-resistant/intolerant CP-CML<br>Dasatinib 60 mg/m² tablet every day (QD) [with a maximum dose of 100 mg QD for subjects with high BSA] for minimum of 24 months, may continue as long as deriving clinical benefit OR Dasatinib 72 mg/m² powder for oral suspension (PFOS) QD [with a maximum dose of 120 mg QD for subjects with high BSA] for minimum of 24 months, may continue as long as deriving clinical benefit | Drug: Dasatinib<br> <br> * Other names: Sprycel (BMS-354825);|
| Experimental: Cohort 2: Ph+ALL or AP- or BP-CML<br>Dasatinib 80 mg/m² tablet QD [with a maximum dose of 140 mg QD for subjects with high BSA] for minimum of 24 months, may continue as long as deriving clinical benefit OR Dasatinib 96 mg/m² PFOS QD [with a maximum dose of 170 mg QD for subjects with high BSA] for minimum of 24 months, may continue as long as deriving clinical benefit | Drug: Dasatinib<br> <br> * Other names: Sprycel (BMS-354825);|
| Experimental: Cohort 3: Newly diagnosed, treatment naïve CP-CML<br>Dasatinib 60 mg/m² tablet QD [with a maximum dose of 100 mg QD for subjects with high BSA] for minimum of 24 months, may continue as long as deriving clinical benefit OR Dasatinib 72 mg/m² PFOS QD [with a maximum dose of 120 mg QD for subjects with high BSA] for minimum of 24 months, may continue as long as deriving clinical benefit | Drug: Dasatinib<br> <br> * Other names: Sprycel (BMS-354825);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Cytogenetic Response (MCyR) Rate | Major Cytogenetic Response (MCyR) rate is defined as the proportion of all treated participants who achieved a complete (0%) or partial (1%-35% Ph+ metaphases in at least 20 metaphases in bone marrow) cytogenetic response, expressed as percentage. The denominator of the MCyR response rate consists of all treated participants in Cohort 1, and the numerator is all participants in Cohort 1 achieving MCyR. 95% confidence interval was calculated by Clopper-Pearson exact method. | From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months) | 
| Complete Hematologic Response (CHR) Rate | Complete Hematologic Response (CHR) rate is defined as the proportion of all treated participants who achieve a confirmed CHR while on-study, expressed as percentage. CHR is defined as including no more than 5% blasts in bone marrow and normal white blood cell count without blasts in peripheral blood, expressed as percentage. The denominator of the CHR response rate consists of all treated participants in Cohort 2, and the numerator is all participants in Cohort 2 achieving CHR. 95% confidence interval was calculated by Clopper-Pearson exact method. | From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months) | 
| Complete Cytogenetic Response (CCyR) Rate | Complete Cytogenetic Response (CCyR) rate is defined as the proportion of all treated participants who achieve a CCyR while on-study, expressed as a percentage. CCyR rate is defined as 0% Ph+ metaphases in at least 20 metaphases in bone marrow. The denominator of the CCyR response rate consists of all treated participants in Cohort 3, and the numerator is all participants in Cohort 3 achieving CCyR. 95% confidence interval was calculated by Clopper-Pearson exact method. | From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Cytogenetic Response (MCyR) Rate in Cohort 2 | Major Cytogenetic Response (MCyR) rate was defined as the proportion of all treated participants who achieved a complete (0%) or partial (1%-35% Ph+ metaphases in at least 20 metaphases in bone marrow) cytogenetic response. The percentage of treated participants in each arm with MCyR is reported. | From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months) | 
| Complete Hematologic Response (CHR) Rate in Cohorts 1 and 3 | Complete Hematologic Response (CHR) rate defined as the proportion of all treated participants who achieve a confirmed CHR while on-study. CHR is defined as including no more than 5% blasts in bone marrow and normal white blood cell count without blasts in peripheral blood. The percentage of treated participants in each arm with CHR is reported. | From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months) | 
| Rate of Best Cytogenetic Response | The number of participants achieving their best on-study cytogenetic response was reported as a percentage of all treated participants in that arm. (Based on >=20 Metaphases) | From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months) | 
| Time to Major Cytogenetic Response (MCyR) | Time to MCyR is defined as the time from first dose of dasatinib until the first day MCyR criteria are met, computed only for participants whose best response is MCyR. (Based on >=20 Metaphases) | From first dose until MCyR criteria are met (assessed up to September 2016, approximately 90 months) | 
| Duration of Major Cytogenetic Response (MCyR) | Duration of MCyR will be computed from the first day criteria are met for MCyR until the date progressive disease (PD) is reported (or treatment is discontinued for PD) or death. Participants who neither discontinue due to PD nor die will be censored on the date of their last hematologic or cytogenetic assessment, whichever comes last. (Based on >=20 Metaphases) | From first day criteria are met for MCyR until the date PD is reported or death (assessed up to September 2016, approximately 90 months) | 
| Time to Complete Cytogenetic Response (CCyR) | Time to CCyR is defined as the time from first dose of dasatinib until the first day CCyR criteria are met, computed only for participants whose best response is CCyR. (Based on >=20 Metaphases) | From first dose until CCyR criteria are met, assessed up to September 2016 (approximately 90 months) | 
| Duration of Complete Cytogenetic Response (CCyR) | Duration of CCyR will be computed from the first day criteria are met for CCyR until the date progressive disease (PD) is reported (or treatment is discontinued for PD) or death. Participants who neither discontinue due to PD nor die will be censored on the date of their last hematologic or cytogenetic assessment, whichever comes last. (Based on >=20 Metaphases) | From first day criteria are met for CCyR until the date of progressive disease or death (assessed up to September 2016, approximately 90 months) | 
| Progression-Free Survival (PFS) Rate at 2 Years | PFS is defined as time from the first dosing date until the time PD is first documented by the investigator or death. Participants who die without a reported date of progression will be considered to have progressed on the date of death. Participants who neither progress nor die will be censored on the date of their last cytogenetic or hematologic assessment. The percentages of progression-free participants at 2 years are based on Kaplan-Meier estimation. Disease Progression was defined as any of the following criteria: -For CP-CML, progression to AP-CML or BP-CML while at highest tolerated dose -Increasing WBC -Loss of CHR (defined as any of the following: WBC count rises to >20.0x10^9/L; Platelet count rises to >600x10^9/L; appearance of extramedullary disease; appearance of >5% myelocytes+metamyelocytes in blood; appearance of blasts/promyelocytes in peripheral blood) -Loss of MCyR or increase in Ph+ bone marrow cells by >=30% from nadir -Death from any case during treatment | 2 years | 
| Time to Complete Hematologic Response (CHR) | Time to CHR is defined as the time from first dose of dasatinib until the first day CHR criteria are met, provided they are confirmed 4 weeks later, computed only for participants whose best response is CHR. | From first dose until CHR criteria are met, assessed up to September 2016 (approximately 90 months) | 
| Duration of Complete Hemotologic Response (CHR) | Duration of CHR will be computed from the first day all criteria are met for CHR, provided they are confirmed 4 weeks later, until the date progressive disease (PD) is reported (or treatment is discontinued for PD) or death. Participants who neither discontinue due to PD nor die will be censored on the date of their last hematologic assessment. | From first day criteria are met for CHR until date of disease progression or death (assessed up to September 2016, approximately 90 months) | 
| Disease-Free Survival Rate at 2 Years | Disease free survival is defined as time from CCyR for participants with newly diagnosed chronic phase CML and for participants with chronic phase CML who are resistant or intolerant to imatinib (cohort 3 and cohort 1), and as time from CHR for participants with advanced phase CML and PH + ALL (cohort 2) until the time progression is first documented by the investigator or death from any cause. The percentages of disease-free participants at 2 years are based on Kaplan-Meier estimation. (CML: Chronic Myeloid Leukemia) | 2 years | 
| Overall Survival (OS) Rate at 2 Years | OS is defined as time from the first dosing date until the time of death. All participants will be followed yearly for survival for up to 5 years after treatment discontinuation. Participants who have not died or who are lost to follow-up will be censored on the last date the participant is known to be alive. The percentages of surviving participants at 2 years are based on Kaplan-Meier estimation. | 2 years | 
| Major Molecular Response (MMR) Rate | Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (qPCR). MMR for participants with the p210 BCR-ABL transcript variant was defined as a ratio BCR-ABL/ABL <= 10-3 or 0.1% on the international scale. In this study, ABL was used as the control-gene. For a participant with the p190 BCR-ABL transcript variant (occurring in Cohort 2 only), on-study assessments were compared to the participant's individual baseline BCR-ABL/ABL ratio and a reduction to < 0.1% or a 3-log reduction from baseline was considered an MMR. | From date of first treatment to date of MMR (assessed up to September 2016, approximately 90 months) | 
| Complete Molecular Response (CMR) Rate | Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (qPCR). (CMR) is defined as absence of BCR-ABL rearrangements by real-time qPCR analysis. The percentage of treated participants with CMR is reported by arm. | From date of first treatment to date of CMR (assessed up to September 2016, approximately 90 months) | 
| Major Cytogenetic Response (MCyR) Rate up to 2 Years | Major Cytogenetic Response (MCyR) rate is defined as the proportion of all treated participants who achieved a complete (0%) or partial (1%-35% Ph+ metaphases in at least 20 metaphases in bone marrow) cytogenetic response. The percentage of treated participants with MCyR is reported by arm. | 24 months | 
| Complete Cytogenetic Response (CCyR) Rate up to 2 Years | Complete Cytogenetic Response (CCyR) rate is defined as the proportion of all treated participants who achieve a CCyR while on-study. CCyR rate is defined as 0% Ph+ metaphases in at least 20 metaphases in bone marrow. The percentage of treated participants with CCyR is reported by arm. | 24 months | 
| Major Molecular Response (MMR) Rate up to 2 Years | Molecular response will be assessed using BCR-ABL transcript levels measurement by real-time qPCR. MMR for participants with the p210 BCR-ABL transcript variant is defined according to the recommendations of Hughes et al. as a ratio BCR-ABL/ABL <= 10-3 or 0.1% on the international scale proposed by the authors. The standardized baseline, as established in the IRIS trial, is taken to represent 100% on the international scale and a 3-log reduction in ratio (BCR-ABL transcripts/ABL or BCR) from the standardized baseline (MMR) is fixed at 0.1%. In this study, ABL or other housekeeping gene, will be used as the control-gene. For a participant with the p190 BCR-ABL transcript variant, on-study assessments will be compared to the participant's individual baseline BCR-ABL/ABL ratio and a reduction to < 0.1% or a 3-log reduction from baseline will be considered an MMR. The percentage of treated participants with MMR is reported by arm. | 24 months | 
| Complete Molecular Response (CMR) Rate up to 2 Years | Molecular response will be assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (qPCR). (CMR) is defined as absence of BCR-ABL rearrangements by real-time qPCR analysis. The percentage of treated participants with CMR is reported by arm. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Pediatric