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    Summary
    EudraCT Number:2007-003674-26
    Sponsor's Protocol Code Number:MK0457-009
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2007-07-30
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2007-003674-26
    A.3Full title of the trial
    A Phase I Dose Escalation of MK-0457 in Combination With Dasatinib in Patients With Refractory Chronic Myelogenous Leukemia and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.
    A.3.2Name or abbreviated title of the trial where available
    ND
    A.4.1Sponsor's protocol code numberMK0457-009
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberND
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMERCK SHARP DOHME
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 No
    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.3.2Product code MK0457
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeMK0457
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    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 dasatinib
    D.2.1.1.2Name of the Marketing Authorisation holderBristol Mayer Squibb
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNdasatinib
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number70
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    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
    Patients with Refractory Chronic Myelogenous Leukemia and Philadelphia Chromosome-Positive Acute Lymphoblastic.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10009013
    E.1.2Term Chronic myeloid leukaemia
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary

    (1) To determine dose-limiting toxicities (DLT), the maximum tolerated dose (MTD), and the recommended Phase II dose (RP2D) of MK-0457 administered in combination with dasatinib in patients with treatment-refractory CML or Ph+ ALL.

    Hypothesis: Administration of MK-0457 in combination with dasatinib will be sufficiently safe and tolerated to permit further study in CML and Ph+ ALL.

    (2) To determine pharmacokinetics of MK-0457 given in combination with dasatinib.
    E.2.2Secondary objectives of the trial
    Secondary

    To evaluate the efficacy of MK-0457 in combination with dasatinib as measured by the induction or durability of hematologic response, cytogenetic response, or molecular response.

    Hypothesis: MK-0457 administered in combination with dasatinib will either induce response in patients not responding to dasatinib after 3 months of dasatinib monotherapy, or will prolong the duration of response in patients responding to dasatinib after 3 months of dasatinib monotherapy.

    2.1.3 Exploratory

    To assess the pharmacodynamics (inhibition of Aurora kinases and BCR-ABL) of MK¬0457 in combination with dasatinib in patients with treatment-refractory CML or Ph+ ALL.
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    1 Patients must have chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

    2 Patients must be at least 3 months from the start of dasatinib therapy and are currently receiving dasatinib therapy for CML or Ph+ ALL and be evaluable for hematologic response prior to entering the study.

    3 Patient is able to be treated with a 70 mg bid dose of dasatinib without significant toxicity at the time of study entry.

    4 Patient is male or female of any race, and &#8805;18 years of age on day of signing informed consent.

    1 Patient must have performance status &#8804; 2 on the ECOG Performance Scale (Appendix 6.1).

    6. Patients must have the following laboratory values unless considered due to leukemia: i) ALT and AST &#8804; 2.5 x upper limit of normal (ULN) ii) Serum total bilirubin &#8804; 2.0 x ULN OR Direct bilirubin &#8804; ULN for patients with total bilirubin levels > 2.0 ULN

    iii) Serum creatinine &#8804; 1.5 x ULN OR

    &#8805; 60ml/min for patients with creatinine levels >1.5 X institutional ULN



    2 Female patient of childbearing potential has a negative serum or urine pregnancy test within 14 days of study enrollment.

    3 Patient, or the patient’s legal representative, has voluntarily agreed to participate by giving written informed consent.

    4 Patients with active CNS disease are included and may be treated concurrently with intrathecal therapy as per institutional standards.
    E.4Principal exclusion criteria
    1 Patient has had treatment with any anti-leukemia therapy (investigational or approved) other than dasatinib during the preceding 3 months. Pheresis or hydroxyurea treatment in the preceding 3 months will not exclude patients from eligibility.

    2 Patient has unresolved &#8805; grade 2 clinically significant toxicity attributed to dasatinib at the time of study entry.

    3 Patient has known hypersensitivity to the components of study drug or its analogs.

    4 Patient has a history or current evidence of any condition, therapy, or lab abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate.

    5 Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

    1 Patient is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or had a recent history (within the last year) of drug or alcohol abuse.

    2 Patient is pregnant or breastfeeding, or expecting to conceive within the projected duration of the study.

    3 Patient has symptomatic ascites, pericardial or pleural effusion. A patient who is clinically stable following treatment for these conditions is eligible.

    4 Patient has had prior radiation therapy to more than 10% of the bone marrow; patients must have recovered for at least 3 weeks from the hematologic toxicity of prior radiotherapy.

    5 Patient has a LVEF <40% by multigated radionucleotide angiography (MUGA) or echocardiography.
    E.5 End points
    E.5.1Primary end point(s)
    Primary

    (1) To determine dose-limiting toxicities (DLT), the maximum tolerated dose (MTD), and the recommended Phase II dose (RP2D) of MK-0457 administered in combination with dasatinib in patients with treatment-refractory CML or Ph+ ALL.

    Hypothesis: Administration of MK-0457 in combination with dasatinib will be sufficiently safe and tolerated to permit further study in CML and Ph+ ALL.

    (2) To determine pharmacokinetics of MK-0457 given in combination with dasatinib.



    Hypothesis: Administration of dasatinib with MK-0457 will not significantly alter the pharmacokinetics of MK-0457.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Information not present in EudraCT
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Information not present in EudraCT
    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
    phase I/II study
    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 No
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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.8.5The 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 Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Information not present in EudraCT
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months0
    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.1.3Elderly (>=65 years) Yes
    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 Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2007-07-30. Yes
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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 state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 7
    F.4.2.2In the whole clinical trial 48
    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 Decision2007-09-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-07-17
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2008-07-30
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