SNPMiner Trials (Home Page)
Report for Mutation V299L
Developed by Shray Alag, 2020.
SNP Clinical Trial Gene
There are 10 clinical trials
Clinical Trials
1 A Study of Complete Molecular Response for Chronic Myeloid Leukemia in Chronic Phase Patients, Treated With Dasatinib
The purpose of this study is to evaluate complete molecular response of Dasatinib in patients for Philadelphia chromosome-positive chronic myeloid leukemia
NCT01342679 Chronic Myeloid Leukemia Drug: dasatinib MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia
Inclusion Criteria: - Chronic Myeloid Leukemia in the Chronic Phase - 20 years old over - ECOG performance status (PS) score 0-2 - Patients for major molecular response (MMR) with no CMR - Adequate organ function (hepatic, renal and lung) - Signed written informed consent Exclusion Criteria: - A case with the double cancer of the activity - Women who are pregnant or breastfeeding - The case of Pleural effusion clearly - Patients with complications or a history of severe or uncontrolled cardiovascular failure following - have a Myocardial infarction within 6 months - have an Angina within 3 months - have a Congestive heart failure within 3 months - have a suspected congenital QT syndrome - have a QTc interval of more than 450msec at baseline - A serious uncontrolled medical disorder that would impair the ability of the subjects to receive protocol therapy - Prior treatment with dasatinib - Subjects with T315I, F317L and V299L BCR-ABL point mutations Inclusion Criteria: - Chronic Myeloid Leukemia in the Chronic Phase - 20 years old over - ECOG performance status (PS) score 0-2 - Patients for major molecular response (MMR) with no CMR - Adequate organ function (hepatic, renal and lung) - Signed written informed consent Exclusion Criteria: - A case with the double cancer of the activity - Women who are pregnant or breastfeeding - The case of Pleural effusion clearly - Patients with complications or a history of severe or uncontrolled cardiovascular failure following - have a Myocardial infarction within 6 months - have an Angina within 3 months - have a Congestive heart failure within 3 months - have a suspected congenital QT syndrome - have a QTc interval of more than 450msec at baseline - A serious uncontrolled medical disorder that would impair the ability of the subjects to receive protocol therapy - Prior treatment with dasatinib - Subjects with T315I, F317L and V299L BCR-ABL point mutations Chronic Myeloid Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive null --- T315I --- --- F317L --- --- V299L ---
Inclusion Criteria: - Chronic Myeloid Leukemia in the Chronic Phase - 20 years old over - ECOG performance status (PS) score 0-2 - Patients for major molecular response (MMR) with no CMR - Adequate organ function (hepatic, renal and lung) - Signed written informed consent Exclusion Criteria: - A case with the double cancer of the activity - Women who are pregnant or breastfeeding - The case of Pleural effusion clearly - Patients with complications or a history of severe or uncontrolled cardiovascular failure following - have a Myocardial infarction within 6 months - have an Angina within 3 months - have a Congestive heart failure within 3 months - have a suspected congenital QT syndrome - have a QTc interval of more than 450msec at baseline - A serious uncontrolled medical disorder that would impair the ability of the subjects to receive protocol therapy - Prior treatment with dasatinib - Subjects with T315I, F317L and V299L BCR-ABL point mutations Inclusion Criteria: - Chronic Myeloid Leukemia in the Chronic Phase - 20 years old over - ECOG performance status (PS) score 0-2 - Patients for major molecular response (MMR) with no CMR - Adequate organ function (hepatic, renal and lung) - Signed written informed consent Exclusion Criteria: - A case with the double cancer of the activity - Women who are pregnant or breastfeeding - The case of Pleural effusion clearly - Patients with complications or a history of severe or uncontrolled cardiovascular failure following - have a Myocardial infarction within 6 months - have an Angina within 3 months - have a Congestive heart failure within 3 months - have a suspected congenital QT syndrome - have a QTc interval of more than 450msec at baseline - A serious uncontrolled medical disorder that would impair the ability of the subjects to receive protocol therapy - Prior treatment with dasatinib - Subjects with T315I, F317L and V299L BCR-ABL point mutations Chronic Myeloid Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive null --- T315I --- --- F317L --- --- V299L --- --- T315I --- --- F317L --- --- V299L ---
Primary Outcomes
Measure: Rate of complete molecular response (CMR) after treatment with dasatinib Time: at 12 monthsSecondary Outcomes
Measure: Dasatinib of dose intensity Time: at 12 monthsMeasure: Expansions rate of large granular lymphocyte Time: at 12 months
Measure: Progression free survival Time: at 12 months
Measure: Number of Participants with Adverse Events Time: at 12 months
2 Dynamics of ABL Mutations in Imatinib Failed Ph Positive or Bcr-Abl Positive CML CP or AP Patients Who Treated With Nilotinib as Second-line TKI Therapy (AMICAN-Prospective)in Asia
The purposes of this study are to investigate expression and frequency of ABL point mutations, a major cause of resistance in imatinib failed CML Asian patients and to find causes of Asian-specific resistance to cancer-targeting therapies through a prospective investigation of dynamics of point mutations and expression of new point mutations during nilotinib treatment.
NCT01562847 Chronic Myeloid Leukemia Drug: Nilotinib MeSH:Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia
With regard to peculiar point mutations, V299L, F317L, and E25K/V show relative resistance to dasatinib, and p-loop mutations including G250E, Q252H, Y253F/H and E255K/V and F359C/V show relative resistance to nilotinib. --- V299L ---
Primary Outcomes
Measure: To confirm the patterns of resistance including point mutations which are newly expressed during the nilotinib treatment Time: 5 yearsSecondary Outcomes
Measure: To analyze and evaluate the overall survival and disease free survival in the nilotinib treatment according to progression of the disease and types of point mutations Time: 5 years3 An Open Label, Randomized (2:1) Phase IIb Study of Dasatinib Versus Imatinib in Patients With Chronic Phase Chronic Myeloid Leukemia Who Have Not Achieved an Optimal Response to 3 Months of Therapy With 400 mg Imatinib
The purpose of this study is to test the hypothesis that patients with CML who have not achieved optimal response after 3 months of treatment with imatinib will have a better response by switching to dasatinib compared to staying on their original imatinib regimen.
NCT01593254 Chronic Phase Chronic Myeloid Leukemia Drug: Imatinib Drug: Dasatinib MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia
Patients with no evidence of clonal evolution, including those patients whose cytogenetic testing fails or bone marrow aspiration is a dry tap at 3 months, are eligible for the study - Subjects with less than CHR after 3 months of imatinib treatment or lost CHR after initial achievement - Documented T315I/A, F317L, or V299L mutations (if already available - not required for screening) - A serious uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com. --- T315I --- --- F317L --- --- V299L ---
Patients with no evidence of clonal evolution, including those patients whose cytogenetic testing fails or bone marrow aspiration is a dry tap at 3 months, are eligible for the study - Subjects with less than CHR after 3 months of imatinib treatment or lost CHR after initial achievement - Documented T315I/A, F317L, or V299L mutations (if already available - not required for screening) - A serious uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy Chronic Phase Chronic Myeloid Leukemia Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase null --- T315I --- --- F317L --- --- V299L ---
Primary Outcomes
Description: Major Molecular Response, is defined as a 3-log reduction in BCR-ABL transcripts from the standardized baseline, which represents 100% on the international scale, so a 3-log reduction is fixed at 0.1% for MMR; N/A = not applicable. 95% CI is Clopper-Pearson(Exact) two-sided 95% confidence intervals. P-value is based on Cochran-Mantel-Haenszel (CMH) test stratified by Sokal score(high, intermediate, low, and unknown) and time between 3 month molecular analysis and randomization (<=4 weeks vs >4 weeks). Month 12 is calculated fro
Measure: Percentage of Patients Achieving Major Molecular Response (MMR) After 12 Months of CML Treatment Time: At 12 months after Day 1 initiation of 1st line treatment with imatinib or imatinib at any dose, after less than optimal response to first-line imatinib.Secondary Outcomes
Description: Time to MMR is how fast patients achieve optimal response. It is the time between randomization date and first date that MMR criteria are satisfied.
Measure: Median Time to Major Molecular Response (MMR) Time: Up to 10 yearsDescription: Time to MR^4.5 is how fast patients achieve a deeper response. It is the time between randomization date and first date that MR^4.5 criteria are satisfied.
Measure: Time to Molecular Response (MR)^4.5 Time: Up to 10 yearsDescription: PFS is how long patients are likely to live without progression of their disease. It is the time from randomization date to progression date or death date, whichever occurs first.
Measure: Progression Free Survival (PFS) Time: Up to 10 yearsDescription: OS is how long patients are likely to remain alive. It is the time from randomization date to death date.
Measure: Overall Survival (OS) Time: Up to 10 years4 Discontinuation of Dasatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase Who Have Maintained Complete Molecular Remission for Two Years; Dasatinib Stop Trial
The purpose of this study is to assess whether dasatinib can be discontinued without occurrence of molecular relapse in patients with chronic myeloid leukemia in chronic phase in complete molecular remission (CMR) while on dasatinib.
NCT01627132 Chronic Myeloid Leukemia Drug: Dasatinib MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia
- Patients with mutation of T315I, F317L, V299L. --- T315I --- --- F317L --- --- V299L ---
Primary Outcomes
Measure: The overall probability of maintenance of complete molecular remission at 12 months after stopping dasatinib. Time: at 12 monthsSecondary Outcomes
Measure: Rate of complete molecular remission that will be sustained after dasatinib rechallenge. Time: at 12 months5 A PHASE 4 SAFETY AND EFFICACY STUDY OF BOSUTINIB (BOSULIF (REGISTERED)) IN PATIENTS WITH PHILADELPHIA CHROMOSOME POSITIVE CHRONIC MYELOID LEUKEMIA PREVIOUSLY TREATED WITH ONE OR MORE TYROSINE KINASE INHIBITORS
The purpose of this study is to fulfill the post-authorization commitment made by Pfizer to the European Medicines Agency in providing additional safety and efficacy data in approximately 150 Philadelphia Chromosome Positive Chronic Myeloid Leukemia patients with high unmet medical need, including 75 Chronic Phase, Accelerated Phase or Blast Phase patients in the fourth or later line treatment setting (i.e., after treatment with at least 3 other Tyrosine Kinase Inhibitors).
NCT02228382 Previously Treated PH + CML Drug: Bosutinib MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia
- Known T315I or V299L mutation. --- T315I --- --- V299L ---
Primary Outcomes
Description: Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive cells in metaphase from Bone Marrow sample.
Measure: Percentage of Participants with Major Cytogenetic Response (MCyR) by Week 52 in Chronic Phase Second-line Population and Chronic Phase Third-line Population of Philadelphia Chromosome Positive Chronic Myeloid Leukemia patients. Time: Week 52Description: Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive cells in metaphase from Bone Marrow sample.
Measure: Percentage of Participants with Major Cytogenetic Response (MCyR) by Week 52 in Chronic Phase Fourth-line and later-line Population of Philadelphia Chromosome Positive Chronic Myeloid Leukemia patients. Time: Week 52Description: OHR includes Complete Hematological Response (CHR) or return to chronic phase (RCP).
Measure: Percentage of Participants with Overall Hematologic Response (OHR) by Week 52 in Advanced Leukemia Population patients. Time: Week 52Secondary Outcomes
Description: Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive cells in metaphase from Bone Marrow sample.
Measure: Estimate cumulative probability of Percentage of Participants with Major Cytogenetic Response in Chronic Phase and Advanced Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations. Time: Week 52Description: OHR includes Complete Hematological Response (CHR) or return to chronic phase (RCP).
Measure: Estimate cumulative probability of Percentage of Participants with Overall Hematologic Response in the Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient population by number of lines of prior therapy. Time: Week 52Measure: Characterize distribution of best response (molecular, cytogenetic, or hematologic) in the Chronic Phase, Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations. Time: Week 52
Measure: Estimating probability of Percentage of Participants with Major Cytogenetic Response at 3, 6, 12, 18, and 24 months in the Chronic Phase, Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations. Time: Month 3, 6, 12, 18, and 24
Measure: Estimating the probability of confirmed Overall Hematologic Response at 3, 6, 9, 12, 18, and 24 months in the Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations. Time: Month 3, 6, 9, 12, 18, and 24
Measure: Estimating the probability of cumulative confirmed Complete Hematologic Response in the Chronic Phase, Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations. Time: Week 52
Measure: Estimating the probability of cumulative major molecular response in the Chronic Phase, Accelerated Phase and Blast Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia patient populations. Time: Week 52
6 Phase I Trial Adding Ruxolitinib to a Combination of Dasatinib Plus Dexamethasone in Remission Induction Therapy in Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Patients Aged 40 Years or Older.
The purpose of this study is to test the safety of a new combination of three oral drugs in Ph+ ALL. These drugs are dexamethasone, dasatinib, and ruxolitinib. All three drugs have been studied before in humans. This is a phase I study in which ruxolitinib dose will start low for the first patient together with dexamethasone plus dasatinib. If this dose does not cause a bad side effect, the ruxolitinib dose will slowly be made higher as new patients take part in the study. This will help the investigators find the right dose of ruxolitinib to give together with dexamethasone and dasatinib that will be used in future studies
NCT02494882 Acute Lymphoblastic Leukemia Drug: Ruxolitinib Drug: Dasatinib Drug: Dexamethasone MeSH:Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Philadelphia Chromosome
HPO:Leukemia Lymphoid leukemia
L248R, L248V, Q252H, E255K, V299L, T315A, T315I, F317C, F317L, F317S, F317V) - Relapsed or refractory Ph-like ALL without prior exposure to dasatibin and with mutations or rearrangements of genes conferring sensitivity to dasatibin (ABL, CSF1R, PDGFRB) or ruxolitinib (CRLF2, JAK3, EPOR, TSLP) - Newly diagnosed or relapsed CML in lymphoid blast crisis - Confirmation of Philadelphia chromosome positivity by cytogenetics (karyotype/FISH) and/or molecular tests (BCR-ABL1 transcripts) - Acceptable end-organ function, except for documented exclusions for organ function compromise due to ALL itself - ECOG performance status ≤ 2 - Men and women of childbearing potential must be willing to practice an effective method of birth control during treatment and for at least 4 months following treatment on study Exclusion Criteria: - Ph-negative ALL - Patients with dominant leukemic clone bearing documented bcr-abl mutations enabling bcr-abl TKI resistance at diagnosis - Mature B-cell (Burkitt's) ALL - Serum creatinine > 1.5x ULN and calculated creatinine clearance, based on a 24-hour urine collection, < 30 mL/min--unless related to ALL/tumor lysis syndrome and able to be corrected - Direct Bilirubin > 2x ULN; AST/ALT > 10x ULN, unless related to ALL liver infiltration. --- L248R --- --- L248V --- --- Q252H --- --- E255K --- --- V299L ---
Primary Outcomes
Description: is to be evaluated by using a combination of criteria. Molecular remissions will be defined by standard criteria for BCR-ABL1 and IGH qRT-PCR. Flow cytometric assessment of MRD will be defined by standard flow cytometry criteria
Measure: Clinical response Time: 2 yearsSecondary Outcomes
Description: Molecular remission status will be defined by undetectable BCR-ABL1 transcripts and/or IGH clonal gene rearrangement in bone marrow aspirate (BMA) examination as determined by qRT-PCR in CLIA laboratory.
Measure: Complete Molecular Remission (CMR) rate Time: 2 years7 Bosutinib Efficacy, Safety, Tolerability (BEST) Study in Elderly Chronic Myeloid Leukemia Patients Failing Front-line Treatment With Other Tyrosine Kinase Inhibitors
The objective of the present study is to evaluate a new drug called bosutinib as it is believed that this agent may be able to predict an excellent prognosis in patients that did not obtain any benefit with other drugs before. Still, this needs to be proved and we hope this study is able to do so.
NCT02810990 Chronic Myeloid Leukemia Drug: Bosutinib MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia
Exclusion Criteria: 1. Accelerated or blastic phase CML (according to ELN 2013 criteria) 2. Patients with the T315I or the V299L mutation 3. Patients previously treated with 2 TKIs or more 4. Compelled to take medications that are known to be associated with Torsades de Pointes and/or with significant QTc prolongation 5. Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug 6. --- T315I --- --- V299L ---
Primary Outcomes
Measure: Number of patients who are in major molecular response (MMR) Time: One year treatmentSecondary Outcomes
Measure: Number of patients who obtain molecular response Time: At 6 and 12 months from treatment startMeasure: Number of patients discontinuing treatment for failure, adverse events or other reasons Time: At 12 and 36 months
Measure: Number of Adverse Events (AEs) Time: At 36 months
Measure: Number of patients alive Time: At 36 months
Measure: Number of patients on treatment at 200, 300 and 400 mg or more daily Time: At 6, 12 and 36 months
Measure: Number and type of BCR-ABL1 mutations Time: At 36 months
Measure: Patient reported quality of life Time: At 3, 6, and 12 months
8 A Phase 3, Multi-center, Open-label, Randomized Study of Oral ABL001 Versus Bosutinib in Patients With Chronic Myelogenous Leukemia in Chronic Phase (CML-CP), Previously Treated With 2 or More Tyrosine Kinase Inhibitors
The purpose of this pivotal study is to compare the efficacy of ABL001 with that of bosutinib in the treatment of patients with CML-CP having previously been treated with a minimum of two prior ATP-binding site TKIs. Patients intolerant to the most recent TKI therapy must have BCR-ABL1 ratio > 0.1% IS at screening and patients failing their most recent TKI therapy must meet the definition of treatment failure as per the 2013 ELN guidelines. Patients with documented treatment failure while on bosutinib treatment will have the option to switch to asciminib treatment within 96 weeks after the last patient has been randomized on study.
NCT03106779 Chronic Myelogenous Leukemia Drug: ABL001 Drug: Bosutinib MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia
- Three months after the initiation of therapy: No CHR or > 95% Ph+ metaphases - Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 65% Ph+ metaphases - Twelve months after initiation of therapy: BCR-ABL1 ratio > 10% IS and/or > 35% Ph+ metaphases - At any time after the initiation of therapy, loss of CHR, CCyR or PCyR - At any time after the initiation of therapy, the development of new BCR-ABL1 mutations which potentially cause resistance to study treatment - At any time after the initiation of therapy, confirmed loss of MMR in 2 consecutive tests, of which one must have a BCR-ABL1 ratio ≥ 1% IS - At any time after the initiation of therapy, new clonal chromosome abnormalities in Ph+ cells: CCA/Ph+ - Intolerance is defined as: - Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or with persistent grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the patient if response is already suboptimal) - Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil count [ANC] or platelets) while on therapy that is recurrent after dose reduction to the lowest doses recommended by manufacturer Exclusion Criteria: Known presence of the T315I or V299L mutation at any time prior to study entry Known second chronic phase of CML after previous progression to AP/BC Previous treatment with a hematopoietic stem-cell transplantation Patient planning to undergo allogeneic hematopoietic stem cell transplantation Cardiac or cardiac repolarization abnormality, including any of the following: - History within 6 months prior to starting study treatment of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) - Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block) - QTcF at screening ≥450 msec (male patients), ≥460 msec (female patients) - Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: - Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia - Concomitant medication(s) with a known risk of Torsades de Pointes per www.crediblemeds.org that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication. --- T315I --- --- V299L ---
Primary Outcomes
Description: To compare the MMR rate of ABL001 versus bosutinib
Measure: Major Molecular Response (MMR) rate Time: at 24 weeksSecondary Outcomes
Description: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Major Molecular Response (MMR) rate Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib. Cytogenic response will include Complete, Partial, Major, Minor, Minimal and no response.
Measure: Complete Cytogenetic response rate Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Time to MMR Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Duration of MMR Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Time to CCyR Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Duration of CCyR Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Time to treatment failure Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Progression free survival Time: 96 weeks after the last patient received the first study doseDescription: To compare additional parameters of the efficacy of ABL001 versus bosutinib
Measure: Overall survival Time: 96 weeks after the last patient received the first study doseDescription: To characterize the PK of ABL001 in the CML-CP population
Measure: Trough plasma concentrations Time: 96 weeks after the last patient received the first study doseDescription: To characterize the PK of ABL001 in the CML-CP population
Measure: PK parameter: Cmax, Time: 96 weeks after the last patient received the first study doseDescription: To characterize the PK of ABL001 in the CML-CP population
Measure: PK parameter: Tmax Time: 96 weeks after the last patient received the first study doseDescription: To characterize the PK of ABL001 in the CML-CP population
Measure: PK parameter: AUC0-12h Time: 96 weeks after the last patient received the first study doseDescription: To characterize the PK of ABL001 in the CML-CP population
Measure: PK parameter: CL/F Time: 96 weeks after the last patient received the first study dose9 Multicenter, Open-label Single Arm Phase II Study Testing the Tolerability and the Efficacy of Bosutinib step-in Dosing in Chronic Phase CML Patients Intolerant or Refractory to Previous Imatinib, Nilotinib or Dasatinib Therapy
Bosutinib is a 2nd generation tyrosine kinase inhibitor that has shown promising results from first up to fourth line treatment in patients with in chronic phase of chronic myelogenous leukaemia. Most patients discontinuing the treatment with Bosutinib do so because of side effects occuring early after starting the treatment. A step in dosing scheme could improve these early toxicities. The aim of this study therefore is to demonstrate that temporary lowering of the Bosutinib dose during early treatment may help to reduce or prevent side effects while preserving efficacy.
NCT03205267 Chronic Myelogenous Leukaemia Drug: Bosulif MeSH:Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase
HPO:Chronic myelogenous leukemia Myeloid leukemia
Exclusion Criteria: - Hypersensitivity against Bosutinib or other ingredients of the medicinal product - Evidence of features of accelerated (AP) or blast phase (BC) at any time before inclusion - Patients with BCR-ABL negative CML - Patients having received Imatinib for more than 6 weeks prior to initiation of 2nd generation TKI (either Nilotinib or Dasatinib) - Patients with known T315I or V299L mutation - Concomitant medications known to be strong inducers or inhibitors of P450 isoenzyme CYP3A4 - History of pancreatitis, inflammatory bowel disease requiring systemic or topical immunosuppressive therapy within the last 12 months - Impaired cardiac function, including any of the following: 1. History of or presence of complete left bundle branch block, right bundle branch block plus left anterior hemiblock, bifascicular block in screening ECG 2. ST depression of >1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads in screening ECG 3. Congenital long QT syndrome 4. QTc> 450 msec in the screening ECG 5. QT-prolonging concomitant medication 6. History of or presence of significant ventricular or atrial tachyarrhythmias in screening ECG 7. History of or presence of clinically significant resting bradycardia (< 50 beats per minute) 8. Myocardial infarction within 6 months prior to inclusion 9. Unstable angina diagnosed or treated during the past 12 months 10. --- T315I --- --- V299L ---
Primary Outcomes
Description: calculation of the incidence rate of grade 2 to 4 GI toxicity with and without regard to causality
Measure: Rate of GI-Toxicity (i.e. incidence and severity of grade 2 to 4 toxicities) Time: within the first 6 months of treatmentSecondary Outcomes
Description: Apart from grade 2 to 4 GI toxicity, the occurrence of toxicity will be analyzed in general. This regards all grade toxicity, 2 to 4 grade and 3 to 4 grade toxicity (NCI CTCAE v4.0).
Measure: overall Tolerability (i.e. all grade, grade 2 to 4 and grade 3 and 4 toxicities) Time: at month 6, 12 and 24Description: Rating of CCyR, MMR, MR4 and MR4.5 after bone marrow aspiration and biopsy
Measure: Molecular response mesured by efficacy parametern Time: at month 3, 6, 12, 18 and 24Description: The EORTC QLQ-CML30 will be scored according to the respective user's guides.
Measure: Patient-reported outcome measures (QoL) Time: at month 3 and 6Description: Progression will be assessed according to the visit schedule at any visit.
Measure: Progression-free survival (PFS) Time: at month 3, 6, 9, 12, 15, 18, 21 and 24Description: Survival will be assessed according to the visit schedule at any visit.
Measure: Overall Survival (OS) Time: at month 3, 6, 9, 12, 15, 18, 21 and 24Description: The rate and type of mutations will be described. The rate will be given as percentage of patients developing mutations.
Measure: The rate of emerging mutations during Bosutinib treatment Time: at month 3, 6, 9, 12, 15, 18, 21 and 24Other Outcomes
Description: Ankle Brachial Index (ABI) will be prospectively evaluated followed by analysis of various biomarkers for vascular damage
Measure: Vascular biology substudy: analysis of clinical and laboratory vascular and metabolic risk factors Time: baseline, at months 6, 12 and 24Description: It is planned to analyze PK parameters sequentially by taking serum from PB and subsequent HPLC-MS/MS technology. Pharmacodynamics in different compartments will be analyzed by means of flow-cytometry of PB and BM samples.
Measure: Pharmacokinetic (PK), pharmacodynamic (PD) substudy Time: at day 1, months 1, 2, 3, 12, 18, 24Description: Assessment of telomere length in normal and leukemic cells as potential new biomarker for prognosis, prediction of response under Bosutinib
Measure: Telomere substudy Time: at months 1, 2, 3, 12 and 24Description: Documentation of subclone evolution or elimination during Bosutinib treatment
Measure: Ultra-deep next-generation sequencing (UD-NGS) Time: at months 1, 2, 3, 12 and 24Description: Documentation of patient´s comorbidity profile using 3 different comorbidity scales
Measure: Assessment of patients comorbidities and correlation to individual patient´s adverse side effect profile substudy Time: through study completion, an average of 2 yearsDescription: Investigation the role of the 5-HT pathway in directing bosutinib induced diarrhea by assessment of 5-HT and certain cytokine levels and genetic analysis including SNP and GWAS
Measure: Transport mechanisms of Bosutinib and mechanisms of diarrhea substudy Time: every 14 days month 1-310 A Phase I/II Study of Bosutinib in Pediatric Patients With Newly Diagnosed Chronic Phase or Resistant/Intolerant Ph + Chronic Myeloid Leukemia", Study ITCC-054/COG-AAML1921
This is a Phase 1-2, multicenter, international, single-arm, open-label study designed to identify a recommended dose of bosutinib administered orally once daily in pediatric patients with newly diagnosed chronic phase Ph+ CML (ND CML) and pediatric patients with Ph+CML who have received at least one prior TKI therapy (R/I CML), to preliminary estimate the safety and tolerability and efficacy, and to evaluate the PK of bosutinib in this patient population.
NCT04258943 Philadelphia Chromosome Positive CML Accelerated Phase Chronic Myelogenous Leukemia Blastic Phase Chronic Myelogenous Leukemia Chronic Phase Chronic Myelogenous Leukemia Drug: Bosutinib MeSH:Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase Blast Crisis Leukemia, Myeloid, Accelerated Phase Philadelphia Chromosome
HPO:Chronic myelogenous leukemia Leukemia Myeloid leukemia
4. Documented prior history of T315I or V299L BCR-ABL1 mutations (Note: BCR-ABL1 mutation testing will be performed at screening for a baseline assessment, but results are not used to determine eligibility. --- T315I --- --- V299L ---
3. Documented prior history of T315I or V299L BCR-ABL1 mutations (Note: BCR-ABL1 mutation testing will be performed at screening for a baseline assessment, but results are not used to determine eligibility. --- T315I --- --- V299L ---
Primary Outcomes
Description: Data from Phase 1; Dose-limiting toxicities determined as adverse events occurring in the first cycle (28 days) of treatment, which are attributable to bosutinib. Assessment will be done according the following DLT definition: Non-hematologic AEs: grade ≥3 toxicities, except those that have not been optimally treated; any grade ≥2 toxicity requiring discontinuation/interruption for ≥7 days during the first 28 days of treatment; clinically significant laboratory abnormalities grade ≥3 or lasting ≥7 days despite optimal treatment Hematologic AEs: grade 4 neutropenia or thrombocytopenia lasting ≥7 days (not explained by persistent leukemia).
Measure: 1. Incidence (and severity) of Dose-Limiting Toxicities (DLTs) assessed during the first 28 days of treatment. Time: First 28 days of treatment (first cycle)Description: Data from Phase 1; Maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time postdose and actual dose will be used for all calculations.
Measure: PK parameters of bosutinib: Maximum observed plasma concentration (Cmax) Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose and before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days); unexpected and/or serious bosutinib-related AEs: when AE is detectedDescription: Data from Phase 1; Time to maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post dose and actual dose will be used for all calculations.
Measure: PK parameters of bosutinib:Time to Cmax (Tmax) Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detectedDescription: Data from Phase 1; Area under the plasma concentration versus time curve from time zero to the dosing interval calculated from the plasma concentration-time data by linear trapezoidal rule during the ascending phase and log trapezoidal rule during the descending phase.
Measure: PK parameters of bosutinib: Area under the plasma concentration versus time curve from time zero to the dosing interval (AUCτ) Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detectedDescription: Data from Phase 1; Pre-dose concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post dose and actual dose will be used for all calculations.
Measure: PK parameters of bosutinib: Pre-dose concentration (Ctrough) Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detectedDescription: Data from Phase 1; Apparent clearance of the drug from plasma after oral administration, calculated as Dose/AUCt.
Measure: PK parameters of bosutinib: Apparent clearance (CL/F). Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detectedDescription: Data from Phase 2; AEs will be graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and coded using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment emergent AEs (TEAEs) are defined as those with initial onset or increasing in severity after the first dose of study medication. Endpoints include maximum toxicity, time to first event (time from first dose to date of first event including only non-partial dates), duration of any stage/grade event (time from start date to stop date including only non-partial dates).
Measure: AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy (pooled across ND and R/I CML patients and by line of therapy). Time: AE's will be collected from signing informed consent continuously during the study until 28 days after last dose (on average, 2 years).Description: Data from Phase 2; subset of newly diagnosed patients. Maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.
Measure: PK parameters of bosutinib: Maximum observed plasma concentration (Cmax) Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose and before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 & and before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detectedDescription: Data from Phase 2; subset of newly diagnosed patients. Time to maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.]
Measure: PK parameters of bosutinib:Time to Cmax (Tmax) Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detectedDescription: Data from Phase 2; subset of newly diagnosed patients. Area under the plasma concentration versus time curve from time zero to the dosing interval calculated from the plasma concentration-time data by linear trapezoidal rule during the ascending phase and log trapezoidal rule during the descending phase.
Measure: PK parameters of bosutinib: Area under the plasma concentration versus time curve from time zero to the dosing interval (AUCτ) Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detectedDescription: Data from Phase 2; subset of newly diagnosed patients. Pre-dose concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.
Measure: PK parameters of bosutinib: Pre-dose concentration (Ctrough) Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detectedDescription: Data from Phase 2; subset of newly diagnosed patients. Apparent clearance of the drug from plasma after oral administration, calculated as Dose/AUCt.
Measure: PK parameters of bosutinib: Apparent clearance (CL/F). Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detectedDescription: Data from Phase1 and Phase 2. Population PK parameters of bosutinib including volume of distribution based on combined PK data from Phase 1 and Data from Phase1 and Phase 2. Volume of distribution are calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.
Measure: Population PK parameters of bosutinib including volume of distribution based on combined PK data from Phase 1 and Phase 2 Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing(each cycle is 28 days); for unexpected and/or serious bosutinib-related AEs: when AE is detectedDescription: Data from Phase1 and Phase 2. Clearance is calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations
Measure: Population PK parameters of bosutinib including clearance based on combined PK data from Phase 1 and Phase 2 Time: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose and before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing(each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detectedSecondary Outcomes
Description: Data from Phase 1. AEs will be graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and coded using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment emergent AEs (TEAEs) are defined as those with initial onset or increasing in severity after the first dose of study medication. Endpoints include maximum toxicity, time to first event (time from first dose to date of first event including only non-partial dates), duration of any stage/grade event (time from start date to stop date including only non-partial dates).]
Measure: AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy; Time: From signing informed consent, continuously during the study until 28 days after last dose (on average 2 years).Description: Data from Phase 1. Test abnormalities in hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy test will be recorded. Severity of laboratory test abnormalities will be graded using NCI CTCAE version, v4.03. For those laboratory abnormalities without CTCAE grade definitions, results will be categorized as normal, abnormal or not done. Coagulation and HBsAG only tested at screening. Urinalysis and pregnancy test and contraception check not tested at days 8, 14, 15 and 22 of cycle 1. Urinalysis not performed at beginning of cycles 2, 3, 5 and 6
Measure: Occurrence of laboratory abnormalities of hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy tests values, as characterized by type, frequency, severity and timing summarized in an overview table Time: Screening; cycle 1 days 1, 8, 14, 22; cycles 2 to 7: at start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days)Description: Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points. Kamofsky or Lansky performance score is collected to evaluate performance status.
Measure: ECG abnormalities: QT interval Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)Description: Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points.
Measure: ECG abnormalities: RR interval Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)Description: Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points.
Measure: ECG abnormalities: PR interval Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)Description: Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points.
Measure: ECG abnormalities: QRS duration Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)Description: Data from Phase 1. Kamofsky or Lansky (depending on age) performance score as assessed by physician is collected to evaluate performance status
Measure: Performance status abnormalities Time: Screening; on day 1 of every subsequent cycle end of treatment (each cycle is 28 days)Description: Data from Phase 1. MCyR is defined as complete cytogenetic response [CCyR] plus partial cytogenetic response [PCyR]. (definitions in appendix 2).]
Measure: Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR), major molecular response (MMR) and deep molecular response Time: Hematologic response:Screening; Cycles 2 to 7: start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days).Description: Data from Phase 2. MCyR is defined as complete cytogenetic response [CCyR] plus partial cytogenetic response [PCyR]. (definitions in appendix 2).
Measure: Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR), major molecular response (MMR) and deep molecular response Time: Screening; Cycles 2 to 7: start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days).]Description: Time to response is defined as the time period from start of treatment with bosutinib to first response, unconfirmed for molecular and cytogenetic and confirmed for hematologic. Patients without events are censored at the last molecular, cytogenetic, or hematologic assessment where response could be assessed for the respective endpoint
Measure: Time to the respective responses by line of therapy Time: Through study completion, a maximum of around 10 yearsDescription: Data from Phase 2. Duration of response is defined is defined as the time period from the date of the earliest demonstration of a response until the earliest date of confirmed loss of that response.
Measure: Duration of the respective responses by line of therapy Time: Through study completion, a maximum of around 10 yearsDescription: Data from Phase 2. EFS is defined as the interval from the date of first dose of bosutinib until the earlier date of EFS events. Patients without the event will be censored at the last evaluation date.
Measure: Event-free survival (EFS; including time to transformation to AP and BP CML) by line of therapy (definition in appendix 2). Time: Through study completion, a maximum of around 10 yearsDescription: Data from Phase 2. OS or survival time is defined as the interval from the date of first dose of bosutinib until the date of death due to any cause. Patients without the event will be censored at the last evaluation date
Measure: Overall survival (OS) in pediatric patients with Ph+ CML by line of therapy Time: Through study completion, a maximum of around 10 yearsDescription: Data from Phase 2. Pooled across ND and R/I CML and by line of therapy. Test abnormalities in hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy test and contraception will be recorded. Severity of laboratory test abnormalities will be graded using NCI CTCAE version, v4.03. For those laboratory abnormalities without CTCAE grade definitions, results will be categorized as normal, abnormal or not done. Coagulation and HBsAG only tested at screening. Urinalysis and pregnancy test and contraception check not tested at days 8, 14, 15 and 22 of cycle 1. Urinalysis not performed at beginning of cycles 2, 3, 5 and 6
Measure: Occurrence of laboratory abnormalities of hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy tests values, as characterized by type, frequency, severity and timing summarized in an overview table Time: Screening; cycle 1 days 1, 8, 14, 22; cycles 2 to 7: at start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days)Description: Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points
Measure: ECG abnormalities: QT interval Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)Description: Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points
Measure: ECG abnormalities: RR interval Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)Description: Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points
Measure: ECG abnormalities: PR interval Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)Description: Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points
Measure: ECG abnormalities: QRS duration Time: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)Description: Data from Phase 2. Kamofsky or Lansky (depending on age) performance score as assessed by physician is collected to evaluate performance status.
Measure: Performance status abnormalities Time: Screening; on day 1 of every subsequent cycle end of treatment (each cycle is 28 days)Other Outcomes
Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX). The analysis of bone age, pubertal status and results of serum chemistry tests will be descriptive. Height (cm), weight (kg), bone age (yr), Tanner stage, serum chemistry and bone densitometry scan results [Lumbar Spine (L1-L4) (g/cm2)] will be provided in listings and summarized by study visit (including change from baseline).
Measure: Parameters of bone metabolism and growth: linear growth Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).
Measure: Parameters of bone metabolism and growth: bone age Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).
Measure: Parameters of bone metabolism and growth: bone mineral density of lumbar spine Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).
Measure: Parameters of bone metabolism and growth: physical signs of pubertal maturation (Tanner stage and testicular volume of boys), Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).
Measure: Parameters of bone metabolism and growth: hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) Time: [Time Frame: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).Description: Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).
Measure: Parameters of bone metabolism and growth: markers of bone formation and bone resorption (bone alkaline phosphatase and CTX). Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).Description: Data from Phase 1. Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale questionnaires will be used to assess gastrointestinal symptoms. ON a scale of 0 to 4, with 0 being: 'never' and 4 being: 'almost always'
Measure: Patient and/or caregiver-reported assessments of gastrointestinal symptoms, as measured by selected domains from the Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale Time: Through study completion, a maximum of around 10 yearsDescription: Data from Phase 1. A questionnaire with different kind of questions, using a 1 to 3 score on difficulty to swallow, with 1 being' difficult to swallow' and 3 being:' no trouble, easy to swallow' and a 1 to 5 score on assessment of taste and overall ease, with 1 being: 'dislike very much' and 5 being: ' like very much'.
Measure: Patient and/or caregiver-reported assessment of the taste and ability to swallow the medicine, as measured by the Palatability Questionnaire for Bosutinib in patients aged 4-18 years of age. Time: Through study completion, a maximum of around 10 yearsDescription: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX). The analysis of bone age, pubertal status and results of serum chemistry tests will be descriptive. Height (cm), weight (kg), bone age (yr), Tanner stage, serum chemistry and bone densitometry scan results [Lumbar Spine (L1-L4) (g/cm2)] will be provided in listings and summarized by study visit (including change from baseline).
Measure: Parameters of bone metabolism and growth: linear growth Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).
Measure: Parameters of bone metabolism and growth: bone age Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).
Measure: Parameters of bone metabolism and growth: bone mineral density of lumbar spine Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).
Measure: Parameters of bone metabolism and growth: physical signs of pubertal maturation (Tanner stage and testicular volume of boys Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).
Measure: Parameters of bone metabolism and growth: hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).Description: Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX).
Measure: Parameters of bone metabolism and growth: markers of bone formation and bone resorption (bone alkaline phosphatase and CTX). Time: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).Description: Data from Phase 2. Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale questionnaires will be used to assess gastrointestinal symptoms. On a scale of 0 to 4, with 0 being: 'never' and 4 being: 'almost always'
Measure: Patient and/or caregiver-reported assessments of gastrointestinal symptoms, as measured by selected domains from the Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale. Time: Through study completion, a maximum of around 10 yearsDescription: Data from Phase 2 A questionnaire with different kind of questions, using a 1 to 3 score on difficulty to swallow, with 1 being' difficult to swallow' and 3 being:' no trouble, easy to swallow' and a 1 to 5 score on assessment of taste and overall ease, with 1 being: 'dislike very much' and 5 being: ' like very much'.
Measure: Patient and/or caregiver-reported assessment of the taste and ability to swallow the medicine, as measured by the Palatability Questionnaire for Bosutinib in patients aged 4-18 years of age. Time: Through study completion, a maximum of around 10 years