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    Summary
    EudraCT Number:2019-004854-27
    Sponsor's Protocol Code Number:PROTAM
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-01-07
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2019-004854-27
    A.3Full title of the trial
    The influence of UGT inhibition on endoxifen exposure in cancer patients treated with tamoxifen: A proof of concept study. “The PROTAM study”
    De invloed van UGT remming op endoxifen blootstelling bij kankerpatiënten behandeld met tamoxifen: een proof of concept studie. ''De PROTAM studie''
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The influence of UGT inhibition on endoxifen exposure in cancer patients treated with tamoxifen: A proof of concept study. “The PROTAM study”
    De invloed van UGT remming op endoxifen blootstelling bij kankerpatiënten behandeld met tamoxifen: een proof of concept studie. ''De PROTAM studie''
    A.4.1Sponsor's protocol code numberPROTAM
    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 SponsorErasmus MC Cancer Institute
    B.1.3.4CountryNetherlands
    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 supportErasmus MC Cancer Institute
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus MC Cancer Institute
    B.5.2Functional name of contact pointR.H.J. Mathijssen
    B.5.3 Address:
    B.5.3.1Street AddressDr. Molewaterplein 40
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3015 GD
    B.5.3.4CountryNetherlands
    B.5.6E-maila.mathijssen@erasmusmc.nl
    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 tamoxifen
    D.2.1.1.2Name of the Marketing Authorisation holderMylan B.V
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 No
    D.3.7Routes of administration for this IMPOral use
    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 Probenecid
    D.2.1.1.2Name of the Marketing Authorisation holderBiokanol Pharma GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 No
    D.3.7Routes of administration for this IMPOral use
    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
    Hormone positive breast cancer
    Hormoongevoelige borstkanker
    E.1.1.1Medical condition in easily understood language
    Hormone positive breast cancer
    Hormoongevoelige borstkanker
    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
    To compare the Area under the curve (AUC) of endoxifen in patients with breast cancer treated with tamoxifen with and without probenecid.
    Vergelijken van de farmacokinetische parameter oppervlakte onder de curve (AUC) van endoxifen in patiënten met borstkanker die behandeld worden met tamoxifen in aan- en afwezigheid van probenecide.
    E.2.2Secondary objectives of the trial
    1. To compare the Area under the Curve (AUC) of tamoxifen and endoxifen-glucuronide in patients with breast cancer treated with tamoxifen with and without probenecid.
    2. To compare other tamoxifen, endoxifen-glucuronide and endoxifen pharmacokinetic outcomes (i.e. clearance, maximum concentration (Cmax), minimal concentration (Ctrough) and time until maximum concentration (tmax) and elimination half-life (t½)). Furthermore the endoxifen/endoxifen-glucuronide ratio will be determined in patients with breast cancer treated with tamoxifen with and without probenecid.
    3. To evaluate the incidence and severity of side-effects of treatment with tamoxifen in absence and presence of probenecid.
    1. Vergelijken van de oppervlakte onder de curve (AUC) van tamoxifen en endoxifen-glucuronide van patiënten met borstkanker die behandeld worden met tamoxifen in aan- en afwezigheid van probenecide.

    2. Vergelijken van andere farmacokinetische parameters van tamoxifen, endoxifen-glucuronide en endoxifen (d.w.z. klaring, maximale concentratie (Cmax), minimale concentratie (Cmin), de tijdsduur tot de maximale waarde van de plasmaconcentratie (Tmax) en de eliminatiehalfwaardetijd (t1/2). Daarnaast zal de endoxifen/endoxifen-glucuronide ratio worden bepaald in patiënten met borstkanker die behandeld worden met tamoxifen in aan- en afwezigheid van probenecide.

    3. Evalueren van de incidentie en mate van ernst van bijwerkingen van behandeling met tamoxifen in aan- en afwezigheid van probenecide.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥ 18 years
    2. Patients with a confirmed diagnosis of primary or advanced breast cancer, who are on tamoxifen treatment for at least three months (steady state concentration).
    3. A CYP2D6 poor metabolizer or intermediate metabolizer phenotype
    4. WHO performance ≤ 1
    5. Able and willing to sign the informed consent form prior to screening evaluations
    6. Willing to abstain from strong CYP3A4, CYP2D6, CYP2C9/2C19, UGT and P-gp inhibitors or inducers, herbal or dietary supplements or other over-the-counter medication besides paracetamol. ( Appendix C)
    7. Adequate kidney function defined as: GFR > 50 ml/min/1.73 m2
    1. Leeftijd ≥ 18 jaar
    2. Patiënten met een officiële diagnose voor borstkanker die tevens minimaal 3 maanden achtereenvolgend behandeld worden met tamoxifen (steady-state concentratie)
    3. Een CYP2D6 poor of intermediair metaboliseerder fenotype.
    4. WHO performance ≤ 1
    5. Studiepatiënten moeten bereid zijn om het informed consent formulier te ondertekenen voorafgaand aan de screening evaluaties
    6. Onthouding van sterke CYP3A4, CYP2D6, CYP2C9/2C19, UGT en P-gp remmers of inductoren, kruidengeneesmiddelen of andere (voedings)supplementen die zonder recept verkrijgbaar zijn, anders dan paracetamol.
    7. Adequate nierfunctie, gedefinieerd als: GFR > 50 ml/min/1.73 m2
    E.4Principal exclusion criteria
    1. Pregnant or lactating patients
    2. Patients with known impaired drug absorption (e.g. gastrectomy and achlorhydria)
    3. Use of drugs which may show an increased systemic exposure when taken concomitantly with probenecid e.g. methotrexate, penicillin, cephalosporin or chinolon antibiotics or NSAIDs.
    4. Patients with known blood dyscrasias, porphyria, uric acid kidney stones or until an acute gouty attack has subsided.
    5. Known serious illness or medical unstable conditions that could interfere with this study requiring treatment (e.g. HIV, hepatitis, Varicella zoster or herpes zoster, organ transplants, kidney failure (GFR<30 ml/min/1.73 m2), serious liver disease (e.g. severe cirrhosis), cardiac and respiratory diseases)
    1. Vrouwen die zwanger zijn of borstvoeding geven
    2. Patiënten met een bekend probleem van geneesmiddel absorptie (o.a. gastrectomie en achloorhydrie)
    3. Gebruik van medicijnen waarvan de systemische blootstelling verhoogd kan worden, wanneer deze tegelijk met probenecide gebruikt wordt, b.v. methotrexaat, penicilline, cefalosporines, quinolonen of NSAID's.
    4. Patiënten bekend met een bloeddyscrasie, porfyrie, urinezuur nierstenen of totdat een acute galaanval verdwenen is.
    5. Patiënten met een onderliggend ziektebeeld of medisch instabiele conditie, hetgeen kan interfereren met de interventie in deze studie (bijvoorbeeld HIV, hepatitis, Varicella Zoster of herpes zoster, orgaan transplantaties, nierfalen (GFR<30 ml/min/1.73 m2), een serieuze leverziekte (o.a. ernstige levercirrose), cardiale en respiratoire ziekten)
    E.5 End points
    E.5.1Primary end point(s)
    Main pharmacokinetic parameter to be determined will be Area Under the plasma-concentration time Curve (AUC) of endoxifen.
    De farmacokinetische parameter oppervlakte onder de curve (AUC) van endoxifen.
    E.5.1.1Timepoint(s) of evaluation of this end point
    after 35 days
    Na 35 dagen
    E.5.2Secondary end point(s)
    1. To compare the Area Under the Curve (AUC) of tamoxifen and endoxifen-glucuronide in patients with breast cancer treated with tamoxifen with and without probenecid.

    2. To compare other tamoxifen, endoxifen-glucuronide and endoxifen pharmacokinetic outcomes (i.e. clearance, maximum concentration (Cmax), minimal concentration (Ctrough) and time until maximum concentration (Tmax) and elimination half-life (T½)). in patients with breast cancer treated with tamoxifen with and without probenecid.

    3. To evaluate the incidence and severity of side-effects of treatment with tamoxifen in absence and presence of probenecid.
    1. Vergelijken van de farmacokinetische parameter oppervlakte onder de curve (AUC) van endoxifen in patiënten met borstkanker die behandeld worden met tamoxifen in aan- en afwezigheid van probenecide.


    2. Vergelijken van andere farmacokinetische parameters van tamoxifen, endoxifen-glucuronide in patiënten met borstkanker die behandeld worden met tamoxifen in aan- en afwezigheid van probenecide.


    3. Evalueren van de incidentie en mate van ernst van bijwerkingen van behandeling met tamoxifen in aan- en afwezigheid van probenecide.
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of the study
    Einde van de studie
    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 No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 No
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    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 Yes
    E.8.2.3.1Comparator description
    tamoxifen monotherapie vs tamoxifen met probenecide
    tamoxifen monotherapy vs tamoxifen with probenecid
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 No
    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
    Laatste visite van de laatste patiënt
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months24
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months24
    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: 7
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 7
    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 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 state14
    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 may continue the use of tamoxifen post trial according to regular treatment
    Patiënten kunnen het gebruik van tamoxifen continueren na de studie volgens het reguliere behandelprotocol
    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 Decision2020-01-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-10-24
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