Leukemia, Pediatric
Conditions
Brief summary
The purpose of this study is to determine whether Dasatinib when added to standard chemotherapy is effective and safe in the treatment of pediatric philadelphia chromosome positive acute lymphoblastic leukemia
Interventions
DRUGDasatinib
Tablets, Oral, 60 mg/m2, Once daily, 2 years or until unacceptable toxicity
Sponsors
Children's Oncology Group
EsPhALL
Bristol-Myers Squibb
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com. Inclusion Criteria: * Newly diagnosed Philadelphia chromosome positive Acute Lymphoblastic Leukemia (ALL) * Age \>1 year and \< less than 18 years old * Induction chemotherapy ≤ 14 days according to institutional standard of care * Adequate liver, renal and cardiac function
Exclusion criteria
* Prior treatment with a Oncogene fusion protein (BCR-ABL) inhibitor * Extramedullary involvement of the testicles * Active systemic bacterial, fungal or viral infection * Down syndrome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 3-year Event-free Survival (EFS) Rate | From first dose to 3 years following first dose | 3-year EFS rate is defined as the percentage of participants without event after 3 years since the start of study treatment. Events for EFS are defined as ANY first one of the following: * Lack of complete response in bone marrow * Relapse at any site * Development of second malignant neoplasm * Death from any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Adverse Events | From first dose to 100 days following last dose (up to approximately 23 months) | Number of participants experiencing different types of all causality all grade adverse events |
| Event-Free Survival (EFS) Rate (Kaplan-Meier Estimates) | From first dose to 3 years or 5 years following first dose | Overall estimation of the EFS of dasatinib plus chemotherapy was performed utilizing the Kaplan-Meier (KM) Product Limit method. The 3-year and 5-year EFS rates were computed with the corresponding 95% CI's using Greenwood's formula. Analyses of EFS included KM plots with number of patients at risk. Participants who neither relapse nor die or who are lost to follow-up were censored on the date of their last bone marrow, CSF assessment or physical exam, whichever occurred last. |
| Complete Remission Rate | From first dose to End of Induction Period Ia (up to 5 weeks) or Ib (up to 9 weeks) or End of Consolidation Period (up to 22 weeks) | Complete Remission rate is defined as the percentage of participants achieving a complete remission, i.e. \< 5% lymphoblasts in bone marrow and in CSF, with no evidence of other extramedullary disease. Complete remission will be assessed at the end of Induction IA, end of induction IB and end of the consolidation period for all treated participants. |
| Percentage of Participants Negative for Minimal Residual Disease (MRD) | From first dose to End of Induction Period Ia (up to 5 weeks) or Ib (up to 9 weeks) or End of Consolidation Period (up to 22 weeks) | MRD was by real-time qPCR for clone-specific immunoglobulin and T-cell receptor gene rearrangements (IG/TCR). Participants were declared as MRD negative if the MRD level is undetectable providing the assay lower limit of quantification is at least 0.1% |
| Percentage of Participants With BCR-ABL Mutations at Baseline and at Time of Disease Progression or Relapse | At baseline (prior to start of study treatment) and at disease progression or relapse (up to approximately 3 years) | A BCR-ABL mutation is defined as the presence of a detectable amino acid substitution in the ABL kinase domain, assessed by Real-time quantitative PCR. |
Countries
Australia, Canada, Italy, Puerto Rico, United Kingdom, United States
Participant flow
Pre-assignment details
106 participants were treated with dasatinib.
Participants by arm
| Arm | Count |
|---|---|
| Dasatinib Cohort Children and adolescents newly diagnosed with Philadelphia chromosome positive acute lymphocytic leukemia (Ph+ ALL) treated with standard multiagent chemotherapy and Dasatinib (either in tablets or Powder For Oral Suspension (PFOS)) at a dose of 60 mg/m2 daily. | 106 |
| Total | 106 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Follow-up Phase | Death | 14 |
| Follow-up Phase | Follow-up no longer required per protocol | 70 |
| Follow-up Phase | Lost to Follow-up | 7 |
| Follow-up Phase | Other and not reported reasons | 5 |
| Follow-up Phase | Withdrawal by Subject | 4 |
| Treatment Phase | Adverse Event | 8 |
| Treatment Phase | Death | 2 |
| Treatment Phase | Lack of Efficacy | 3 |
| Treatment Phase | Other reasons | 9 |
| Treatment Phase | Study Drug Toxicity | 2 |
| Treatment Phase | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Dasatinib Cohort |
|---|---|
| Age, Continuous | 9.29 Years STANDARD_DEVIATION 4.467 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 27 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 85 Participants |
| Sex: Female, Male Female | 49 Participants |
| Sex: Female, Male Male | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 21 / 106 |
| other Total, other adverse events | 106 / 106 |
| serious Total, serious adverse events | 101 / 106 |
Outcome results
Primary
3-year Event-free Survival (EFS) Rate
3-year EFS rate is defined as the percentage of participants without event after 3 years since the start of study treatment. Events for EFS are defined as ANY first one of the following: * Lack of complete response in bone marrow * Relapse at any site * Development of second malignant neoplasm * Death from any cause
Time frame: From first dose to 3 years following first dose
Population: All treated partcipants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dasatinib Cohort | 3-year Event-free Survival (EFS) Rate | 66.0 Percentage of Participants |
Comparison: Difference in 3-year binomial EFS rate in all treated participants (dasatinib plus chemotherapy) vs. chemotherapy alone in AIEOP-BFM 2000 historical controlp-value: 0.03290% CI: [3.9, 29.8]Chi-squared
Comparison: Difference in 3-year binomial EFS rate for all treated participants (dasatinib plus chemotherapy) vs. continuous imatinib plus chemotherapy in the Amended EsPhALL Trial Historical Controlp-value: 0.27190% CI: [-3.3, 17.2]Chi-squared
p-value: 0.15790% CI: [-22.7, 1.2]Chi-squared
Secondary
Complete Remission Rate
Complete Remission rate is defined as the percentage of participants achieving a complete remission, i.e. \< 5% lymphoblasts in bone marrow and in CSF, with no evidence of other extramedullary disease. Complete remission will be assessed at the end of Induction IA, end of induction IB and end of the consolidation period for all treated participants.
Time frame: From first dose to End of Induction Period Ia (up to 5 weeks) or Ib (up to 9 weeks) or End of Consolidation Period (up to 22 weeks)
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib Cohort | Complete Remission Rate | End of Induction period Ia | 65.1 Percentage of Partcipants |
| Dasatinib Cohort | Complete Remission Rate | End of Induction period Ib | 88.7 Percentage of Partcipants |
| Dasatinib Cohort | Complete Remission Rate | End of Consolidation period | 93.4 Percentage of Partcipants |
Secondary
Event-Free Survival (EFS) Rate (Kaplan-Meier Estimates)
Overall estimation of the EFS of dasatinib plus chemotherapy was performed utilizing the Kaplan-Meier (KM) Product Limit method. The 3-year and 5-year EFS rates were computed with the corresponding 95% CI's using Greenwood's formula. Analyses of EFS included KM plots with number of patients at risk. Participants who neither relapse nor die or who are lost to follow-up were censored on the date of their last bone marrow, CSF assessment or physical exam, whichever occurred last.
Time frame: From first dose to 3 years or 5 years following first dose
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib Cohort | Event-Free Survival (EFS) Rate (Kaplan-Meier Estimates) | 3-year EFS Estimate | 65.5 Percentage of Participants |
| Dasatinib Cohort | Event-Free Survival (EFS) Rate (Kaplan-Meier Estimates) | 5-year EFS Estimate | 53.1 Percentage of Participants |
Secondary
Number of Participants Experiencing Adverse Events
Number of participants experiencing different types of all causality all grade adverse events
Time frame: From first dose to 100 days following last dose (up to approximately 23 months)
Population: All treated participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dasatinib Cohort | Number of Participants Experiencing Adverse Events | Adverse Events (AEs) | 106 Participants |
| Dasatinib Cohort | Number of Participants Experiencing Adverse Events | Drug-related AEs | 88 Participants |
| Dasatinib Cohort | Number of Participants Experiencing Adverse Events | AEs leading to discontinuation | 7 Participants |
| Dasatinib Cohort | Number of Participants Experiencing Adverse Events | Serious Adverse Events (SAEs) | 101 Participants |
| Dasatinib Cohort | Number of Participants Experiencing Adverse Events | Deaths | 15 Participants |
Secondary
Percentage of Participants Negative for Minimal Residual Disease (MRD)
MRD was by real-time qPCR for clone-specific immunoglobulin and T-cell receptor gene rearrangements (IG/TCR). Participants were declared as MRD negative if the MRD level is undetectable providing the assay lower limit of quantification is at least 0.1%
Time frame: From first dose to End of Induction Period Ia (up to 5 weeks) or Ib (up to 9 weeks) or End of Consolidation Period (up to 22 weeks)
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib Cohort | Percentage of Participants Negative for Minimal Residual Disease (MRD) | End of Induction period Ia | 28.3 Percentage of Participants |
| Dasatinib Cohort | Percentage of Participants Negative for Minimal Residual Disease (MRD) | End of Induction period Ib | 52.8 Percentage of Participants |
| Dasatinib Cohort | Percentage of Participants Negative for Minimal Residual Disease (MRD) | End of Consolidation period | 71.7 Percentage of Participants |
Secondary
Percentage of Participants With BCR-ABL Mutations at Baseline and at Time of Disease Progression or Relapse
A BCR-ABL mutation is defined as the presence of a detectable amino acid substitution in the ABL kinase domain, assessed by Real-time quantitative PCR.
Time frame: At baseline (prior to start of study treatment) and at disease progression or relapse (up to approximately 3 years)
Population: All treated participants with available measurements
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib Cohort | Percentage of Participants With BCR-ABL Mutations at Baseline and at Time of Disease Progression or Relapse | At Disease Progression or Relapse | 6.5 Percentage of participants |
| Dasatinib Cohort | Percentage of Participants With BCR-ABL Mutations at Baseline and at Time of Disease Progression or Relapse | At Baseline | 1.3 Percentage of participants |