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    Summary
    EudraCT Number:2011-003399-36
    Sponsor's Protocol Code Number:MK-4214-008
    National Competent Authority:Latvia - SAM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2011-08-25
    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 ConcernedLatvia - SAM
    A.2EudraCT number2011-003399-36
    A.3Full title of the trial
    A Phase III Randomized, Double-Blind, Active-Controlled Clinical Trial to Study the Efficacy and Safety of MK-4214 (filgrastim) and Neupogen™ as an Adjunct to Combination Chemotherapy with Doxorubicin and Docetaxel in Breast Cancer Patients
    A.4.1Sponsor's protocol code numberMK-4214-008
    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 SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.1.3.4CountryUnited States
    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 supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMSD Regional Business Support Center GmbH
    B.5.2Functional name of contact pointSteven Hildemann
    B.5.3 Address:
    B.5.3.1Street AddressRichard-Reitzner-Allee 1
    B.5.3.2Town/ cityHaar
    B.5.3.3Post code85540
    B.5.3.4CountryGermany
    B.5.4Telephone number+498962731350
    B.5.5Fax number+4989456655222
    B.5.6E-mailsteven.hildemann@essex.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 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.3.1Product nameFilgrastim
    D.3.2Product code MK-4214
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFilgrastim
    D.3.9.2Current sponsor codeMK-4214
    D.3.9.3Other descriptive nameRecombinant human granulocyte colony-stimulating factor
    D.3.10 Strength
    D.3.10.1Concentration unit µg/kg microgram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 RoleComparator
    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 Neupogen™
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen Inc.
    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.3.1Product nameNeupogen™
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFilgrastim
    D.3.9.1CAS number 143011-72-7
    D.3.9.3Other descriptive nameNeupogen™
    D.3.9.4EV Substance CodeSUB14018MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg/kg microgram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    Breast Cancer
    E.1.1.1Medical condition in easily understood language
    Breast Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10006201
    E.1.2Term Breast cancer stage III
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10006202
    E.1.2Term Breast cancer stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10006200
    E.1.2Term Breast cancer stage II
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1) To compare DSN, defined as the number of days with ANC < 0.5 x 109/L, during Cycle 1, in patients with breast cancer receiving MK-4214 or Neupogen™ as adjunct to chemotherapy with doxorubicin in combination with docetaxel.
    E.2.2Secondary objectives of the trial
    1. To evaluate the incidence of FN, defined as an oral temperature of ≥ 38.3ºC, persisting for at least one hour, concurrent with an ANC < 0.5 x 109/L within 24 hours of the fever, by cycle and across all cycles of chemotherapy in patients treated
    with MK-4214 or Neupogen™ .
    2. To evaluate the incidence of hospitalization due to infection by cycle and across all cycles of chemotherapy in patients treated with MK-4214 or Neupogen™
    3. To evaluate the usage (incidence) of IV anti-infective agents by cycle and across all
    cycles of chemotherapy in patients treated with MK-4214 or Neupogen™
    4. To assess the safety and tolerability of MK-4214 and Neupogen™
    5. To evaluate the incidence of anti-rG-CSF antibodies in patients treated with
    MK-4214 or Neupogen™
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient understands the study procedures, alternative treatments available, the risks involved with the study, and agrees to participate by giving written informed consent.
    2. Female who is ≥ 18 years of age on the day of signing informed consent.
    3. Female who is not free from menses for > 1 year, or posthysterectomy/oophorectomy, or surgically sterilized, is willing to use 2 adequate barrier methods of contraception to prevent pregnancy or agrees to abstain from heterosexual activity throughout the study, starting with Visit 1 through 6 Months after the last dose of chemotherapy in the Randomized Blinded Trial or Open-Label Extension. Adequate contraceptive methods include for example, intrauterine device, diaphragm with spermicide, cervical cap with spermicide, or female condom with spermicide. Spermicides alone are not an acceptable method of contraception.
    4. Patient has been diagnosed with Stage II, III, or IV breast cancer, classification according to American Joint Committee on Cancer, 7th Edition (See Appendix 6.6), and based on clinical disease characteristics is considered by the investigator to be an appropriate candidate for treatment with the combination of doxorubicin and docetaxel at the protocol-specified full doses. NOTE: Patient must receive full dose of chemotherapy in Cycle 1 in order to be eligible for randomization.
    5. Patients with Stage II or III disease who have not received prior chemotherapy. Patients with Stage IV disease who have not received prior chemotherapy for metastatic disease (prior neo-adjuvant and/or adjuvant chemotherapy for early stage breast cancer is allowed, provided time since last dose of chemotherapy is > 1 year).
    Prior or concomitant hormonal breast cancer therapy is allowed.
    6. Patient satisfies the Eastern Cooperative Oncology Group performance status (ECOG) of ≤ 2 (Appendix 6.4).
    7. In those cases of prior neo-adjuvant or adjuvant use of an anthracycline, patient will be able to receive a full course of doxorubicin-docetaxel chemotherapy at the protocol-specified doses for 4-6 cycles (duration of therapy in accordance with institutional standards of care) without exceeding a total cumulative anthracycline dose of 550 mg/m2. The calculation should include doxorubicin received on the current study as well as anthracyclines and/or anthracenediones received in prior adjuvant chemotherapy.
    8. Patient has adequate cardiac, bone marrow, liver, kidney and other organ function for chemotherapy with doxorubicin in combination with docetaxel at the protocolspecified dosing, according to general treatment guidelines and institutional standards of care.
    E.4Principal exclusion criteria
    1. Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of receiving study therapy.
    2. Patient is pregnant or breastfeeding, or expecting to conceive within the projected duration of the study or within 6 months after the last dose of chemotherapy.
    3. Patient has known sickle cell disorder.
    4. Patient has received a systemic anti-infective agent within 72 hours of randomization.
    5. Patient has received filgrastim, pegfilgrastim or any granulocyte-colony-stimulating factors (G-CSF) or recombinant granulocyte–macrophage colony-stimulating factors (GM-CSF) or is expected to receive erythropoietin, darbepoetin, or another colonystimulating
    factor other than study drug for the duration of the study. NOTE: Prior
    erythropoietin or darbepoetin use > 6 weeks prior to randomization is permissible.
    6. Patient is expected to take lithium during the course of the trial (lithium may potentiate the release of neutrophils).
    7. Patient has a hypersensitivity to filgrastim or pegfilgrastim or any of the excipients of MK-4214 or Neupogen.
    8. Patient has received biologics as targeted therapy (e.g. Herceptin within 4 weeks of randomization into the study.
    9. Patient has undergone radiation therapy within 4 weeks of randomization with the exception of spot radiation (irradiation to ≤ 25% of total marrow) for the treatment of bone metastases.
    10. Patient has had prior bone marrow or stem cell transplant.
    11. Patient has hypersensitivity or intolerance to filgrastim or any of the excipients of MK-4214.
    12. Patient is allergic or intolerant to latex (latex is a component of the pre-filled syringes of MK-4214 and Neupogen
    13. Patient has known central nervous system (CNS) metastases and/or carcinomatous meningitis.
    14. Patient has undergone a major surgical procedure within 4 weeks prior to study start.
    15. Patient with a history of a prior malignancy, other than breast cancer, with the exception of cervical intraepithelial neoplasia; basal cell carcinoma of the skin; or
    who has undergone potentially curative therapy with no evidence of that disease for five years, or who is deemed at low risk for recurrence by her treating physician.
    16. Patient is taking anticoagulation therapy (with exception of low dose aspirin), or has a known bleeding disorder, or a history of increased bleeding tendencies, spontaneously or subsequent to minor traumas.
    17. 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
    E.5 End points
    E.5.1Primary end point(s)
    Duration of severe neutropenia in Cycle 1 as defined as the number of days with ANC < 0.5 x 109/L, during Cycle 1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Planned analysis is after the last patient has their last visit
    E.5.2Secondary end point(s)
    - Febrile Neutropenia, defined as an oral temperature of ≥ 38.3°C persisting for at least an hour, concurrent with an ANC < 0.5 109/L within 24 hours of the fever, by cycle, and across all cycles of chemotherapy

    - Hospitalization for infection by cycle and across all cycles of chemotherapy

    - Hospitalization for IV anti-infectives by cycle and across all cycles of chemotherapy

    - Depth of ANC nadir in Cycle 1

    -Time to ANC recovery in Cycle 1. This time begins at the start of chemotherapy and is defined as the number of days required for the ANC to reach ANC ≥ 2 x 109/L.

    - Immunogenicity testing to assess the potential development of antibodies directed against G-CSF
    E.5.2.1Timepoint(s) of evaluation of this end point
    Planned analysis is after the last patient has her last visit, with the exception of immunogenicity testing, which will be completed after patients have their 6-month follow up visit (about 2 years after last patient enrolls).
    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) 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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 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) Yes
    E.8.2.2Placebo No
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA14
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Belarus
    Brazil
    Chile
    Croatia
    Georgia
    Germany
    India
    Italy
    Latvia
    Lithuania
    Macedonia, the former Yugoslav Republic of
    Mexico
    Peru
    Philippines
    Romania
    Russian Federation
    Serbia
    South Africa
    Ukraine
    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
    Last patient, Last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    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 years2
    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: 175
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 175
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 state32
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 350
    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 Decision2011-10-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-08-31
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2012-01-26
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