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    Summary
    EudraCT Number:2014-005531-13
    Sponsor's Protocol Code Number:MED3-201401
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-09-21
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2014-005531-13
    A.3Full title of the trial
    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 Dose Optimization Study - BODO-Study"
    Multizentrische, offene einarmige Phase II Studie, welche die Verträglichkeit und Wirksamkeit von Bosutinib mit initialer langsamer Dosisteigerung testet bei CML-Patienten, die sich refraktär oder intolerant auf eine Therapie mit Imatinib, Nilotinib oder Dasatinib gezeigt haben.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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 Dose Optimization Study - BODO-Study"
    Multizentrische, offene einarmige Phase II Studie, welche die Verträglichkeit und Wirksamkeit von Bosutinib mit initialer langsamer Dosisteigerung testet bei CML-Patienten, die sich refraktär oder intolerant auf eine Therapie mit Imatinib, Nilotinib oder Dasatinib gezeigt haben.
    A.3.2Name or abbreviated title of the trial where available
    BODO-Study
    BODO-Studie
    A.4.1Sponsor's protocol code numberMED3-201401
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniverity of Bonn
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPfizer Pharma GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationStudienzentrale Studienzentrum Bonn (SZB)
    B.5.2Functional name of contact pointDr. Mareille Warnken-Uhlich
    B.5.3 Address:
    B.5.3.1Street AddressSigmund-Freud-Str. 25
    B.5.3.2Town/ cityBonn
    B.5.3.3Post code53127
    B.5.3.4CountryGermany
    B.5.4Telephone number4922828716040
    B.5.5Fax number4922828716039
    B.5.6E-mailstudienzentrale-szb@ukbonn.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Bosulif
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Ltd. Great Britian
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBosutinib
    D.3.9.2Current sponsor codeMED3-201401-BODO
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Bosulif
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Ltd. Great Britian
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBosutinib
    D.3.9.2Current sponsor codeMED3-201401-BODO
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic Phase Chronic myelogenous leukaemia( CP-CML) patients who either developed intolerance or treatment failure to previous Imatinib, Dasatinib or Nilotinib as 1st or 2nd line therapy.
    E.1.1.1Medical condition in easily understood language
    Chronic Phase Chronic myelogenous leukaemia( CP-CML) patients who either developed intolerance or treatment failure to previous Imatinib, Dasatinib or Nilotinib as 1st or 2nd line therapy.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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 or 2nd line therapy
    E.2.2Secondary objectives of the trial
    To assess:
    • Tolerability (i.e. all grade, grade 2 to 4 and grade 3 and 4 toxicities) at month 6, 12 and 24
    • Efficacy parameters: MMR (Major Molecular Response), MR4 (Molecular Response with a sensitivity of 1:10000), MR4.5 (Molecular Response with a sensitivity of 1:50000) and CCyR (Complete Cytogenetic Response) 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
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Version of all substudies is V2.0, release date 15th of August 2015:
    Substudy 1: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
    Substudy 2:Pharmacokinetic (PK), pharmacodynamic (PD) 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
    Substudy 3:Ultra-deep next-generation sequencing (UD-NGS)
    • Documentation of subclone evolution or elimination during Bosutinib treatment
    Substudy 4:telomere substudy:
    • Assessment of telomere length in normal and leukemic cells as potential new biomarker for prognosis, prediction of response and of (haematological and nonhematological) toxicity experienced under Bosutinib
    Substudy 5: 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
    • Assessment of adverse side effects throughout study
    • Correlation between both profiles
    Substudy 6: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 Single Nucleotide Polymorphism and genome-wide association study.
    E.3Principal inclusion criteria
    1. Signed written informed consent
    2. Male or female patients aged ≥18 years
    3. ECOG performance status of 0 to 2
    4. CML in 1st or late chronic phase
    5. Intolerant* or resistant** to pretreatment with one or two of the approved first line TKI (Imatinib, Nilotinib or Dasatinib). Imatinib therapy prior to 2nd generation TKI therapy for a maximum of 6 weeks is allowed.
    6. 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
    7. Female patients of childbearing potential must have a negative pregnancy test performed during screening period
    8. Male and female patients of reproductive potential must agree to employ a highly effective contraceptive method*** throughout the study and for 6 months following discontinuation of study drug.

    * Intolerance is defined as discontinuation of Imatinib OR Nilotinib OR Dasatinib due to grade 3 or 4-related adverse event (AE), despite optimal supportive care, or because of a persistent grade 2-related AE, despite optimal supportive care, which persists ≥1 month or recurs >2 times with TKI dose reduction or which is medically significant (independent of grade) and according to investigator´s opinion should lead to change of TKI.

    ** Resistance is defined as not achieving optimal response to Imatinib OR Nilotinib OR Dasatinib according to ELN2013-defined recommendations (Baccarani, Blood 2013).
    Optimal response is defined as:
    - BCR-ABL1 ≤ 10% and/or Ph+ ≤ 35% at 3 months
    - BCR-ABL1 < 1%, and/or Ph + 0% at 6 months
    - BCR-ABL1 ≤ 0,1% (MMR) at 12 months
    - BCR-ABL1 ≤ 0.1% (MMR) after 12 months
    - no loss of MMR (Major Molecular Response)
    - no loss of CCyR (Complete Cytogenetic Response)
    - no loss of complete hematologic response (CHR)

    *** Highly effective contraceptive methods (Pearl Index <1) are surgical sterilization, hormonal contraceptives, intrauterine devices and sexual abstinence. Oral contraceptives shall be used in conjunction with barrier methods (i.e. condoms) during study treatment.
    E.4Principal exclusion criteria
    1. Hypersensitivity against Bosutinib or other ingredients of the medicinal product
    2. Evidence of features of accelerated (AP) or blast phase (BC) at any time before inclusion
    3. Patients with BCR-ABL negative CML
    4. Patients having received Imatinib for more than 6 weeks prior to initiation of 2nd generation TKI (either Nilotinib or Dasatinib)
    5. Patients with known T315I or V299L mutation
    6. Concomitant medications known to be strong inducers or inhibitors of P450 isoenzyme CYP3A4 (see www.drug-interactions.com)
    7. History of pancreatitis, inflammatory bowel disease requiring systemic or topical immunosuppressive therapy within the last 12 months
    8. Impaired cardiac function, including any of the following:
    a. History of or presence of complete left bundle branch block, right bundle branch block plus left anterior hemiblock, bifascicular block in screening ECG
    b. ST depression of >1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads in screening ECG
    c. Congenital long QT syndrome
    d. QTc> 450 msec in the screening ECG
    e. QT-prolonging concomitant medication
    f. History of or presence of significant ventricular or atrial tachyarrhythmias in screening ECG
    g. History of or presence of clinically significant resting bradycardia (< 50 beats per minute)
    h. Myocardial infarction within 6 months prior to inclusion
    i. Unstable angina diagnosed or treated during the past 12 months
    j. Uncontrolled hypertension, history of labile hypertension

    9. Known HIV and/or active viral hepatitis (hepatitis B or C). Hepatitis B screening will be performed at screening. Patients with a history of hepatitis B with negative HBV DNA may be included when using antiviral prophylaxis.
    10. Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinoma of the skin
    11. 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 start
    12. 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
    13. Patient must not have any active bacterial, viral or fungal infection at screening
    14. Patient must not have severe cerebral dysfunction and/or legal incapacity
    15. Conditions which interfere with the study treatment at the discretion of the investigator
    16. Women who are pregnant or breast feeding
    E.5 End points
    E.5.1Primary end point(s)
    Rate of GI-Toxicity (i.e. incidence and severity of grade 2 to 4 toxicities) within the first 6 months of treatment
    E.5.1.1Timepoint(s) of evaluation of this end point
    at Screening (visit 1), first application of IMP = Day 1 (visit 2), during dose escalation every 14 days until end of month 3 (visit 3 to 7), end of month 3 (visit 8) and end of month 6 (visit 9)
    E.5.2Secondary end point(s)
    • Tolerability (i.e. all grade, grade 2 to 4 as well as grade 3 and 4 toxicities)
    • Efficacy parameters: MMR (Major Molecular Response), MR4 (Molecular Response with a sensitivity of 1:10000), MR4.5 (Molecular Response with a sensitivity of 1:50000) and CCyR (Complete Cytogenetic Response) rate
    • Patient-reported outcome measures (QoL)
    • Progression-free survival (PFS)
    • Overall survival (OS)
    • The rate of emerging mutations during Bosutinib treatment
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Tolerability (i.e. all grade, grade 2 to 4 as well as grade 3 and 4 toxicities) at 6, 12 and 24 months (visit 9, 11 and 15)
    • Efficacy parameters: MMR, MR4, MR4.5 and CCyR rate at month 3, 6, 12, 18 and 24 (visit 8, 9, 11, 13 and 15)
    • Patient-reported outcome measures (QoL) at Screening (visit 1), first application of IMP = Day 1 (visit 2), during dose escalation every 14 days until end of month 3 (visit 3 to 7), every 3 month until end of study (visit 8 to 15)
    • Progression-free survival (PFS), Overall survival (OS) and the rate of emerging mutations during Bosutinib treatment during dose escalation every 14 days until end of month 3 (visit 3 to 7), every 3 month until end of study (visit 8 to 15)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Substudy 4: Assessment of telomere length in normal and leukemic cells as potential new biomarker for prognosis, prediction of response and of (haematological and nonhematological) toxicity experienced under Bosutinib
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned17
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 64
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 63
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state127
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients will continue to be followed up for survival and disease status until the end of the BODO trial. Following the administration of the last dose of study medication, responding patients will then be treated “in-label” after study termination. Subsequent treatment of patients that did not respond to the study medication will be performed at the discretion of the treating physician.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-10-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-26
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2019-06-19
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