Phase II Study Testing the Tolerability and the Efficacy of Bosutinib in Chronic Phase CML Patients

NCT03205267

Last updated date
Study Location
University Hospital Bonn
Bonn, , 53127, Germany
Contact
+49 228 287 17233

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Chronic Myelogenous Leukaemia
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

- 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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- 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

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Chronic Myelogenous LeukaemiaPhase II Study Testing the Tolerability and the Efficacy of Bosutinib in Chronic Phase CML Patients
NCT03205267
  1. Bonn,
ALL GENDERS
18 Years+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE Phase II Study Testing the Tolerability and the Efficacy of Bosutinib in Chronic Phase CML Patients
Official Title  ICMJE 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
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Chronic Myelogenous Leukaemia
Intervention  ICMJE Drug: Bosulif
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 <G2.
Other Name: Bosutinib
Study Arms  ICMJE Experimental: Bosutinib
Drug: Bosulif 100 mg or 500 mg tablets step in dosing scheme
Intervention: Drug: Bosulif
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: June 28, 2017)
127
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2019
Estimated Primary Completion Date October 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03205267
Other Study ID Numbers  ICMJE MED3-201401-BODO
2014-005531-13 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD:No
Responsible Party Prof. Dr. Dominik Wolf, University of Bonn
Study Sponsor  ICMJE University of Bonn
Collaborators  ICMJE
  • RWTH Aachen University
  • Ludwig-Maximilians - University of Munich
  • University of Jena
  • Heidelberg University
  • Pfizer
Investigators  ICMJE
Principal Investigator:Dominik GF Wolf, Prof. Dr.University of Bonn Medical Faculty
Study Chair:Brümmendorf H Tim, Prof. Dr.University of Aachen Medical Faculty
PRS Account University of Bonn
Verification Date June 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP