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.
Name: Bosulif
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 treatmentDescription: 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 24Description: 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 1-3Allocation: N/A
Single Group Assignment
There are 2 SNPs
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 ---
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 ---