- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03205267
Phase II Study Testing the Tolerability and the Efficacy of Bosutinib in Chronic Phase CML Patients (BODO)
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
Study Overview
Detailed Description
Objectives:
The objective of the BODO trial is to assess the tolerability and efficacy of a step-in dosing concept of the dual SRC-ABL kinase inhibitor Bosutinib in CP-CML patients who either developed intolerance or treatment failure to previous Imatinib, Dasatinib or Nilotinib as 1st line therapy.
Primary endpoint:
• Rate of GI-Toxicity (i.e. incidence and severity of grade 2 to 4 toxicities) within the first 6 months of treatment
Secondary endpoints:
- Tolerability (i.e. all grade, grade 2 to 4 and grade 3 and 4 toxicities) at month 6, 12 and 24
- Efficacy parameters: CCyR, MMR, MR4 and MR4.5 rate at month 3, 6, 12, 18 and 24
- Patient-reported outcome measures (QoL)
- Progression-free survival (PFS)
- Overall survival (OS)
- The rate of emerging mutations during Bosutinib treatment
Exploratory endpoints linked to substudies:
Vascular biology substudy:
- Effects of previous therapy on the baseline vascular risk profile (i.e. Nilotinib- vs. Dasatinib-pre-treatment)
- Biological and clinical surrogates for vascular alterations during Bosutinib therapy at baseline, months 6, 12, and 24
Pharmacokinetic (PK), pharmacodynamic (PD) and immunology sub- study:
- Correlation of PK with response and toxicity
- Correlation of PK with PD (i.e. phosphoproteomic changes) in immune cell populations
- Correlation of PD changes in immune cell populations with response
- Evaluation of the effects of Bosutinib on frequency and phenotype of immune cells
- Evaluation whether Bosutinib-induced changes of immune cells correlate to response
Ultra-deep next-generation sequencing (UD-NGS) and telomere substudy:
- Documentation of subclone evolution or elimination during Bosutinib treatment
- Evaluation of telomere length in leukemic and non-leukemic cells as a prognostic indicator for depth and kinetics of response to and tolerability of Bosutinib
Study Type
Enrollment (Anticipated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Dominik GF Wolf, Prof. Dr.
- Phone Number: +49 228 287 17233
- Email: dominik.wolf@ukb.uni-bonn.de
Study Locations
-
-
-
Bonn, Germany, 53127
- Recruiting
- University Hospital Bonn
-
Contact:
- Dominik Wolf, Prof. Dr.
- Phone Number: +49 228 287 17233
- Email: dominik.wolf@ukb.uni-bonn.de
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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:
- History of or presence of complete left bundle branch block, right bundle branch block plus left anterior hemiblock, bifascicular block in screening ECG
- ST depression of >1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads in screening ECG
- Congenital long QT syndrome
- QTc> 450 msec in the screening ECG
- QT-prolonging concomitant medication
- History of or presence of significant ventricular or atrial tachyarrhythmias in screening ECG
- History of or presence of clinically significant resting bradycardia (< 50 beats per minute)
- Myocardial infarction within 6 months prior to inclusion
- Unstable angina diagnosed or treated during the past 12 months
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Bosutinib
Drug: Bosulif 100 mg or 500 mg tablets step in dosing scheme
|
Patients will start with dose-level 1 (300 mg once daily) Bosutinib.
If patients do not experience any toxicity or only G1 toxicity, they will be dose-increased first to dose-level 2 (400 mg once daily ) and then to dose-level 3 (500 mg once daily).
Dose will not be escalated above 500 mg which is the dose recommended by the summary of product information.
If patients experience G2 toxicity, the study drug will be further continued at the same dose-level.
In patients with G3 or G4 toxicities, therapy will be withheld until toxicity resolved to
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Rate of GI-Toxicity (i.e. incidence and severity of grade 2 to 4 toxicities)
Time Frame: within the first 6 months of treatment
|
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 Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
overall Tolerability (i.e. all grade, grade 2 to 4 and grade 3 and 4 toxicities)
Time Frame: at month 6, 12 and 24
|
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
|
Molecular response mesured by efficacy parametern
Time Frame: at month 3, 6, 12, 18 and 24
|
Rating of CCyR, MMR, MR4 and MR4.5 after bone marrow aspiration and biopsy
|
at month 3, 6, 12, 18 and 24
|
Patient-reported outcome measures (QoL)
Time Frame: at month 3 and 6
|
The EORTC QLQ-CML30 will be scored according to the respective user's guides.
|
at month 3 and 6
|
Progression-free survival (PFS)
Time Frame: at month 3, 6, 9, 12, 15, 18, 21 and 24
|
Progression will be assessed according to the visit schedule at any visit.
|
at month 3, 6, 9, 12, 15, 18, 21 and 24
|
Overall Survival (OS)
Time Frame: at month 3, 6, 9, 12, 15, 18, 21 and 24
|
Survival will be assessed according to the visit schedule at any visit.
|
at month 3, 6, 9, 12, 15, 18, 21 and 24
|
The rate of emerging mutations during Bosutinib treatment
Time Frame: at month 3, 6, 9, 12, 15, 18, 21 and 24
|
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
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Vascular biology substudy: analysis of clinical and laboratory vascular and metabolic risk factors
Time Frame: baseline, at months 6, 12 and 24
|
Ankle Brachial Index (ABI) will be prospectively evaluated followed by analysis of various biomarkers for vascular damage
|
baseline, at months 6, 12 and 24
|
Pharmacokinetic (PK), pharmacodynamic (PD) substudy
Time Frame: at day 1, months 1, 2, 3, 12, 18, 24
|
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
|
Telomere substudy
Time Frame: at months 1, 2, 3, 12 and 24
|
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
|
Ultra-deep next-generation sequencing (UD-NGS)
Time Frame: at months 1, 2, 3, 12 and 24
|
Documentation of subclone evolution or elimination during Bosutinib treatment
|
at months 1, 2, 3, 12 and 24
|
Assessment of patients comorbidities and correlation to individual patient´s adverse side effect profile substudy
Time Frame: through study completion, an average of 2 years
|
Documentation of patient´s comorbidity profile using 3 different comorbidity scales
|
through study completion, an average of 2 years
|
Transport mechanisms of Bosutinib and mechanisms of diarrhea substudy
Time Frame: every 14 days month 1-3
|
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
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Dominik GF Wolf, Prof. Dr., University of Bonn Medical Faculty
- Study Chair: Brümmendorf H Tim, Prof. Dr., University of Aachen Medical Faculty
Study record dates
Study Major Dates
Study Start
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- MED3-201401-BODO
- 2014-005531-13 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Chronic Myelogenous Leukaemia
-
Versailles HospitalRecruitingCHRONIC MYELOGENOUS LEUKAEMIA IN ACCELERATED PHASE | CHRONIC MYELOGENOUS LEUKAEMIA IN MYELOID BLAST CRISISFrance
-
Cell Medica LtdUniversity College, London; Cell Therapy CatapultCompletedAcute Myeloid Leukaemia | Chronic Myeloid LeukaemiaUnited Kingdom
-
Samara State Medical UniversityRecruitingChronic Myeloid LeukaemiaRussian Federation
-
Gruppo Italiano Malattie EMatologiche dell'AdultoCompletedChronic Myeloid LeukaemiaItaly
-
Australasian Leukaemia and Lymphoma GroupMerck Sharp & Dohme LLC; Novartis PharmaceuticalsUnknownChronic Myeloid LeukaemiaAustralia
-
University of LiverpoolImperial College London; Newcastle University; University of GlasgowUnknownChronic Myeloid LeukaemiaUnited Kingdom
-
University Hospital, BordeauxCompleted
-
Novartis PharmaceuticalsTerminatedPhilidelphia Positive Chronic Myeloid LeukaemiaAustralia
-
PETHEMA FoundationCompleted
-
Gruppo Italiano Malattie EMatologiche dell'AdultoActive, not recruitingChronic Phase Philadelphia Positive | BCR-ABL Positive | Chronic Myeloid LeukaemiaItaly
Clinical Trials on Bosulif
-
PfizerCompletedMyeloid LeukemiaUnited Kingdom
-
PfizerpH AssociatesCompletedChronic Myeloid LeukaemiaUnited Kingdom
-
Neurological Associates of West Los AngelesPfizerEnrolling by invitationDementia | Mild Cognitive ImpairmentUnited States
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI); PfizerTerminatedChronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive | Blasts Under 15 Percent of Bone Marrow Nucleated Cells | Blasts Under 15 Percent of Peripheral Blood White Cells | Blasts Under 30 Percent of Bone Marrow Nucleated Cells | Blasts Under 30 Percent of Peripheral Blood White CellsUnited States
-
PfizerDevelopmental Therapeutics ConsortiumTerminatedPreviously Treated PH + CMLSpain, United States, Austria, Sweden, Germany, France, Italy, Norway
-
University of Milano BicoccaIRCCS San RaffaeleCompletedLeukemia | BCR-ABL Positive | Myelogenous | ChronicItaly
-
Georgetown UniversityAlzheimer's AssociationCompletedDementia With Lewy BodiesUnited States
-
Fundacion Espanola para la Curacion de la Leucemia...Pfizer; Roche Farma, S.ATerminatedChronic Phase-Chronic Myeloid LeukemiaSpain
-
PfizerNot yet recruitingChronic Leukemia Myelogenous