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    Summary
    EudraCT Number:2011-001086-41
    Sponsor's Protocol Code Number:UKM10_0014
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2011-09-19
    Trial 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 number2011-001086-41
    A.3Full title of the trial
    A randomized, placebo-controlled, multi-center phase I/II trial to assess the safety and efficacy of nintedanib (BIBF 1120) added to low-dose cytarabine in elderly patients with AML unfit for an intensive induction therapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial to test the effect of nintedanib together with chemotherapy in patients with acute myeloid leukemia
    A.3.2Name or abbreviated title of the trial where available
    BIBF1120 in AML
    A.4.1Sponsor's protocol code numberUKM10_0014
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01488344
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1122-6147
    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 SponsorUniversity Hospital of Muenster
    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 supportBoehringer Ingelheim
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital of Muenster
    B.5.2Functional name of contact pointStudy Office/Study Coordinator
    B.5.3 Address:
    B.5.3.1Street AddressAlbert-Schweitzer-Campus 1, Geb. A1
    B.5.3.2Town/ cityMuenster
    B.5.3.3Post code48149
    B.5.3.4CountryGermany
    B.5.4Telephone number+492518349963
    B.5.5Fax number+492518349964
    B.5.6E-mailkerstin.vehring@ukmuenster.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 Vargatef ® 100 mg Weichkapseln
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim International GmbH
    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 Capsule, soft
    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 INNnot yet assigned
    D.3.9.1CAS number 928326-83-4
    D.3.9.2Current sponsor codeBIBF 1120
    D.3.9.3Other descriptive nameVargatef, Nintedanib
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    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 Vargatef ® 150 mg Weichkapseln
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim
    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 Capsule, soft
    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 INNnot yet assigned
    D.3.9.1CAS number 928326-83-4
    D.3.9.2Current sponsor codeBIBF 1120
    D.3.9.3Other descriptive nameVargatef, Nintedanib
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, soft
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    untreated acute myeloid leukemia patients unfit for an intensive treatment
    E.1.1.1Medical condition in easily understood language
    first diagnosed AML without previous treatment who cannot tolerate an intensive chemotherapy
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10000886
    E.1.2Term Acute myeloid leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    phase I: tolerability of BIBF1120 combined with low-dose cytarabine

    phase II: efficacy of BIBF1120 combined with low-dose cytarabine
    E.2.2Secondary objectives of the trial
    efficacy of BIBF combined with low-dose cytarabine in predefined subgroups for predefined endpoints

    identification of biomarkers correlating with the course of the disease under a therapy with BIBF combined with low-dose cytarabine
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Patients with newly diagnosed, relapsed or refractory AML (except APL) according to the FAB or WHO classification, including AML evolving from MDS or other hematological diseases and AML after previous cytotoxic therapy or radiation (secondary AML), not eligible for a standard induction and consolidation therapy or for an intensive salvage chemotherapy or an allogeneic stem cell transplantation.
    • Bone marrow aspirate or biopsy must contain > 20% blasts of all nucleated cells. In AML FAB M6 ≥ 30% of non-erythroid cells in the bone marrow must be leukemic blasts. In patients with newly diagnosed AML and either 20-30% blasts and/or adverse cytogenetics or myelodysplasia-related changes, the indication for a treatment with 5-azacytidine should be considered prior to inclusion into this trial.
    • Age ≥ 60 years
    • Informed consent, personally signed and dated to participate in the study
    • Male patients enrolled in this trial must use adequate barrier birth control measures during the course of treatment and for at least 6 months after the last administration of study therapy (low-dose cytarabine and/or BIBF 1120).*
    • Patients at risk for hollow organ perforation (i.e., ulcerative colitis, Crohn`s disease, sigma diverticulitis) should only be included if the potential benefit of the study participation outweighs the risk for perforation in the opinion of the investigator.
    E.4Principal exclusion criteria
    • Patients with newly diagnosed AML with either 20-30% bone marrow blasts and/or adverse cytogenetics or myelodysplasia-related changes, which are qualifying for and consenting into a therapy with 5-azacytidine
    • Known central nervous system manifestation of AML
    • Inadequate liver function (ALT or AST ≥ 1.5 x ULN) if not caused by leukemic infiltration. In cases of leukemic liver involvement ALT or AST ≥ 2.5 x ULN.
    • Known chronically active hepatitis C infection or acute Hepatitis
    • History of acute or chronic pancreatitis
    • Chronically impaired renal function (creatinine > 1.5 x ULN or GFR < 45 ml/min)
    • Uncontrolled hypertension with a resting pressure systolic > 160 mmHg or diastolic > 95 mmHg despite adequate treatment
    • Severe trauma or surgery within 4 weeks of study entry
    • Severe, non-healing wounds, ulcer or fracture
    • Uncontrolled active infection
    • Concurrent malignancies other than AML or other severe diseases which in the opinion of the investigator are likely to influence the endpoint assessment
    • Hypersensitivity to cytarabine (not including drug fever or exanthema)
    • Hypersensitivity to nintedanib, peanut, soya, or any of the components of nintedanib capsules according to the Summary of Product Characteristics (SmPC) of nintedanib
    • Phase II only: previous therapy with tyrosine kinase inhibitors or angiogenesis inhibitors
    • Participation in another interventional clinical trial during this trial or within 4 weeks before entry into this trial. There may be exceptions at the discretion of the coordinating investigator.Any severe concomitant condition, which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol
    E.5 End points
    E.5.1Primary end point(s)
    phase I: safety and tolerability of BIBF 1120 combined with low-dose cytarabine

    phase II: overall survival (OS) of patients treated with low-dose cytarabine plus nintedanib as compared to low-dose cytarabine plus placebo
    E.5.1.1Timepoint(s) of evaluation of this end point
    phase I: after one course

    Overall survival (OS) (phase II):
    Time interval from day 1 of study treatment to the day of death. For a patient who is not known to have died by the end of follow-up, observation of OS will be censored on the date the patient was last known to be alive.
    E.5.2Secondary end point(s)
    • response rate (ORR, consisting of: CR, CRp and CRi as defined by IWG criteria1) of the whole study population
    • ORR rate of Flt3-mutated patients versus Flt3-wildtype patients and within different cytogenetic risk groups
    • CR rate of the whole study population
    • CR rate of the Flt3-mutated patients versus the Flt3-wildtype patients and within different cytogenetic risk groups
    • overall survival (OS) of the Flt3-mutated patients versus the Flt3-wildtype patients and within different cytogenetic risk groups
    • relapse-free survival (RFS) of the responding patients
    • the time to response (CR, CRp or CRi) of the responding patients
    • the toxicity in the whole study population
    • the prognostic value of biomarkers indicating the course of disease, including genetic, epigenetic, transcriptional, protein and phosphoprotein markers in leukemic blasts, bone marrow, peripheral blood cells, serum and plasma, and bone marrow microvessel density.
    • development of biomarkers indicating the course of disease
    E.5.2.1Timepoint(s) of evaluation of this end point
    Complete remission rate (CR rate): at any time point during study participation.
    Overall response rate (ORR): at any time point during study participation.
    Overall survival (OS): Time interval from day 1 of study treatment to the day of death. For a patient who is not known to have died by the end of follow-up, observation of OS will be censored on the date the patient was last known to be alive.
    Relapse-free survival (RFS): Time interval from the first day a leukemia-free state is achieved in patients who achieve a CR / CRi / CRp until relapse or death from any course, whatever occurs first. For a patient who is not known to have died or have relapsed by the end of follow-up, observation of RFS will be censored on the date the patient was last known to be alive and in CR.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    first-in-human administration of study drug in combination with cytarabine
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned15
    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
    end of trial is defined as the time point the data bank is locked. Justification for this definition: study-specific documentation has to be completed until this time point.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial 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: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 68
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state113
    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)
    not different from the expected normal treatment of that condition
    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 Decision2012-01-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-02-28
    P. End of Trial
    P.End of Trial StatusOngoing
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