Chronic Myelogenous Leukaemia Clinical Trial
— BODOOfficial title:
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.
| Status | Recruiting |
| Enrollment | 127 |
| Est. completion date | October 2019 |
| Est. primary completion date | October 2019 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility |
Inclusion Criteria: - Signed written informed consent - Male or female patients aged =18 years - ECOG performance status of 0 to 2 - CML in 1st or late chronic phase - Intolerant or resistant to pretreatment with one of the approved 1st line TKIs (Imatinib, Nilotinib or Dasatinib). Imatinib therapy prior to 2nd generation TKI therapy for a maximum of 6 weeks is allowed. - Patients must have a serum creatinine of = 2 x ULN, SGOT/SGPT = 3 x ULN, total bilirubin = 2 x ULN (except known Gilbert's syndrome), and Lipase = 1.5 x ULN - Female patients of childbearing potential must have a negative pregnancy test performed during screening period - Male and female patients of reproductive potential must currently use a highly effective contraceptive method and be willing to keep on using it throughout the study and for 6 months following discontinuation of study drug. 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. Uncontrolled hypertension, history of labile hypertension - Known HIV and/or active viral hepatitis (hepatitis B or C). Hepatitis B screening will be performed at screening. Patients with history of hepatitis B with negative HBV DNA may be included when using antiviral prophylaxis - Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinoma of the skin - Treatment with another investigational product during this study or during the last 30 days prior to study start, except treatment with Interferon alpha within the TIGER (CML V) protocol, which must be stopped at least 7 days prior to study entry - Any circumstance at the time of study entry that would preclude completion of the study or the required follow-up prohibits inclusion into this study - Patient must not have any active bacterial, viral or fungal infection at screening - Patient must not have severe cerebral dysfunction and/or legal incapacity - Conditions which interfere with the study treatment at the discretion of the investigator - Women who are pregnant or breast feeding |
| Country | Name | City | State |
|---|---|---|---|
| Germany | University Hospital Bonn | Bonn |
| Lead Sponsor | Collaborator |
|---|---|
| University of Bonn | Heidelberg University, Ludwig-Maximilians - University of Munich, Pfizer, RWTH Aachen University, University of Jena |
Germany,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | Vascular biology substudy: analysis of clinical and laboratory vascular and metabolic risk factors | Ankle Brachial Index (ABI) will be prospectively evaluated followed by analysis of various biomarkers for vascular damage | baseline, at months 6, 12 and 24 | |
| Other | Pharmacokinetic (PK), pharmacodynamic (PD) substudy | 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. | at day 1, months 1, 2, 3, 12, 18, 24 | |
| Other | Telomere substudy | Assessment of telomere length in normal and leukemic cells as potential new biomarker for prognosis, prediction of response under Bosutinib | at months 1, 2, 3, 12 and 24 | |
| Other | Ultra-deep next-generation sequencing (UD-NGS) | Documentation of subclone evolution or elimination during Bosutinib treatment | at months 1, 2, 3, 12 and 24 | |
| Other | Assessment of patients comorbidities and correlation to individual patient´s adverse side effect profile substudy | Documentation of patient´s comorbidity profile using 3 different comorbidity scales | through study completion, an average of 2 years | |
| Other | Transport mechanisms of Bosutinib and mechanisms of diarrhea substudy | 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 | every 14 days month 1-3 | |
| Primary | Rate of GI-Toxicity (i.e. incidence and severity of grade 2 to 4 toxicities) | calculation of the incidence rate of grade 2 to 4 GI toxicity with and without regard to causality | within the first 6 months of treatment | |
| Secondary | overall Tolerability (i.e. all grade, grade 2 to 4 and grade 3 and 4 toxicities) | 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). | at month 6, 12 and 24 | |
| Secondary | Molecular response mesured by efficacy parametern | Rating of CCyR, MMR, MR4 and MR4.5 after bone marrow aspiration and biopsy | at month 3, 6, 12, 18 and 24 | |
| Secondary | Patient-reported outcome measures (QoL) | The EORTC QLQ-CML30 will be scored according to the respective user's guides. | at month 3 and 6 | |
| Secondary | Progression-free survival (PFS) | Progression will be assessed according to the visit schedule at any visit. | at month 3, 6, 9, 12, 15, 18, 21 and 24 | |
| Secondary | Overall Survival (OS) | Survival will be assessed according to the visit schedule at any visit. | at month 3, 6, 9, 12, 15, 18, 21 and 24 | |
| Secondary | The rate of emerging mutations during Bosutinib treatment | The rate and type of mutations will be described. The rate will be given as percentage of patients developing mutations. | at month 3, 6, 9, 12, 15, 18, 21 and 24 |