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    Summary
    EudraCT Number:2014-000148-14
    Sponsor's Protocol Code Number:PLX108-10
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-03-26
    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 ConcernedUK - MHRA
    A.2EudraCT number2014-000148-14
    A.3Full title of the trial
    A Double-blind, Randomized, Placebo-controlled Phase 3 Study of Orally Administered PLX3397 in Subjects with Pigmented Villonodular Synovitis
    or Giant Cell Tumor of the Tendon Sheath ENLIVEN
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial comparing the effectiveness of PLX3397 against placebo in the treatment of Pigmented Villonodular Synovitis or Giant Cell Tumor of
    the Tendon Sheath
    A.3.2Name or abbreviated title of the trial where available
    PLX108-10
    A.4.1Sponsor's protocol code numberPLX108-10
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02371369
    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 SponsorDaiichi Sankyo , 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 supportDaiichi Sankyo Pharma Development
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportDaiichi Sankyo Company, Limited
    B.4.2CountryJapan
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDaiichi Sankyo , Inc
    B.5.2Functional name of contact pointClinical Trial Information Contact
    B.5.3 Address:
    B.5.3.1Street Address211 Mt. Airy Road
    B.5.3.2Town/ cityBasking Ridge, NJ
    B.5.3.3Post code07920-2311
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 908 9927009
    B.5.5Fax number+1 732 9066652
    B.5.6E-maileu_cta@dsi.com
    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 Yes
    D.2.5.1Orphan drug designation numberEMA/OD/279/14
    D.3 Description of the IMP
    D.3.1Product namePexidartinib
    D.3.2Product code PLX3397
    D.3.4Pharmaceutical form Capsule
    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 INNPEXIDARTINIB
    D.3.9.1CAS number 1029044-16-3
    D.3.9.2Current sponsor codePLX3397
    D.3.9.3Other descriptive namePLX3397 HCL
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    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
    Pigmented villonodular synovitis (PVNS) / giant cell tumour of tendon sheath (GCT-TS)
    E.1.1.1Medical condition in easily understood language
    Tumour of the tendon sheath
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10062856
    E.1.2Term Giant cell tumour of tendon sheath benign
    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
    The primary objective of this study is to compare the response rate of PLX3397 with that of placebo per Response Evaluation Criteria in Solid
    Tumors, version 1.1 (RECIST 1.1) at Week 25 in subjects with symptomatic, locally advanced PVNS or GCT-TS.
    E.2.2Secondary objectives of the trial
    The secondary efficacy objectives are to evaluate: (i) patient-reported
    outcomes (PROs), including the Brief Pain Inventory (BPI) Worst Pain
    Numeric Rating Scale (NRS) item, Patient-reported Outcomes
    Measurement Information System (PROMIS) Physical Function Scale,
    and Worst Stiffness NRS item, at Week 25; (ii) response based on TVS at
    Week 25; (iii) range of motion at Week 25; and (iv) duration of
    response.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥ 18 years.
    2. A diagnosis of PVNS or GCT-TS (i) that has been histologically confirmed either by a pathologist at the treating institution or a central
    pathologist, and (ii) where surgical resection would be associated with potentially worsening functional limitation or severe morbidity (locally
    advanced disease), with morbidity determined consensually by qualified personnel (eg, two surgeons or a multi-disciplinary tumor board).
    3. Measurable disease as defined by RECIST 1.1 (except that a minimal size of 2cm is required) , assessed from MRI scans by a central
    radiologist.
    4. Symptomatic disease because of active PVNS or GCT-TS, defined as one or more of the following:
    a. a worst pain of at least 4 at any time during the week preceding the screening visit (based on scale of 0 to 10, with 10 representing "pain as
    bad as you can imagine").
    b. a worst stiffness of at least 4 at any time during the week preceding the screening visit (based on a scale of 0 to 10, with 10 representing
    "stiffness as bad as you can imagine").
    5. Stable prescription of analgesic regimen during the 2 weeks prior to randomization.
    6. During the 2 weeks prior to randomization, at least 4 of 7 consecutive days of BPI Worst Pain NRS items and Worst Stiffness NRS items
    completed correctly.
    7. Women of childbearing potential must have a negative serum pregnancy test within the 14-day period prior to randomization. (Where
    demanded by local regulations, this test may be required within 72 hours of randomization.)
    8. Male and female subjects of childbearing potential are permitted in the study so long as they consent to avoid getting their partner pregnant
    or becoming pregnant, respectively, by using a highly effective contraception method, as described below, throughout the study and for
    up to 90 days after completion. Highly effective methods of contraception include: hormonal methods associated with inhibition of
    ovulation, intra-uterine device; surgical sterilization (including partner's vasectomy) or sexual abstinence.
    Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year. Women who
    have documentation of at least 12 months of spontaneous amenorrhea and have an FSH level >40 mIU/mL will be considered postmenopausal.
    9. Adequate hematologic, hepatic, and renal function, defined by:
    • Absolute neutrophil count ≥ 1.5 × 109/L • AST/ALT ≤ 1.5 × ULN
    • Hemoglobin > 10 g/dL • Total bilirubin ≤ 1.5 × ULN
    • Platelet count ≥ 100 × 109/L • Serum creatinine ≤ 1.5 × ULN
    10. Willingness and ability to complete the BPI Worst Pain NRS item, Worst Stiffness NRS item, PROMIS Physical Function Scale, and other
    self-assessment instruments throughout the study.
    11. Willingness and ability to use an electronic diary.
    12. Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements.
    E.4Principal exclusion criteria
    1. Investigational drug use within 28 days of randomization.
    2. Previous use of pexidartinib or any biologic treatment targeting CSF-1 or the CSF1R; previous use of oral tyrosine kinase inhibitors, eg, imatinib
    or nilotinib, are allowed.
    3. Active cancer (either concurrent or within the last year of starting study treatment) that requires therapy (eg, surgical chemotherapy or
    radiation therapy), with the exception of adequately treated basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma insitu
    of the cervix or breast or prostrate carcinoma with a prostrate specific antigen value <0.2 ng/mL.
    4. Known metastatic PVNS/GCT-TS.
    5. Active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus or known active or chronic infection with human immunodeficiency
    virus.
    6. Known active tuberculosis.
    7. Significant concomitant arthropathy in the affected joint, serious illness, uncontrolled infection, or a medical or psychiatric history that, in
    the investigator's opinion, would likely interfere with the person's study participation or the interpretation of his or her results.
    8. Women who are breastfeeding.
    9. A screening Fridericia corrected QT interval (QTcF) ≥ 450 ms (men) or ≥ 470 ms (women).
    10. MRI contraindications.
    11. History of hypersensitivity to any excipients in the investigational product
    12. Inability to swallow capsules.
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of subjects who achieve a complete or partial response at the Week 25 visit based on centrally read MRI scans and RECIST 1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 25
    E.5.2Secondary end point(s)
    1. Proportion of responders based on the BPI Worst Pain NRS item and analgesic use by BPI-30 definition (as defined in Section 7.6.2)
    2. Proportion of responders based on centrally evaluated MRI scans and TVS at the Week 25 visit
    3. Mean change from baseline in range of motion of the affected joint, relative to a reference standard for the same joint, at the Week 25 visit
    4. Mean change from baseline score in the PROMIS Physical Function Scale at the Week 25 visit
    5. Mean change from baseline score in the Worst Stiffness NRS item at the Week 25 visit
    6. Duration of response (CR or PR) based on MRI and RECIST 1.1
    7. Duration of response (CR or PR) based on MRI and TVS
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 25
    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 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) 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    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
    Australia
    Canada
    Denmark
    France
    Germany
    Hungary
    Italy
    Netherlands
    Poland
    Spain
    United Kingdom
    United States
    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 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.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 26
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 126
    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)
    Subjects who complete Part 2 will be eligible to enter a separate protocol to continue receiving PLX3397 until disease progression, unacceptable toxicity, or the ocurrence of other termination criteria.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-03-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-10-31
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