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    Summary
    EudraCT Number:2013-001731-40
    Sponsor's Protocol Code Number:UMCN-ONCO-201301
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-08-15
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2013-001731-40
    A.3Full title of the trial
    Influence of exceptional patient characteristics on everolimus exposure
    De invloed van bijzondere patientkarakteristieken op everolimus blootstelling
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Influence of obesity and old age on the concentration of everolimus in blood
    De invloed van overgewicht en ouderdom op de concentratie everolimus in het bloed
    A.3.2Name or abbreviated title of the trial where available
    INPRES
    A.4.1Sponsor's protocol code numberUMCN-ONCO-201301
    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 SponsorRadboud University Nijmegen Medical Centre
    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 supportNovartis
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRadboud University Nijmegen Medical Centre
    B.5.2Functional name of contact pointResearch verpleegkundigen oncologie
    B.5.3 Address:
    B.5.3.1Street AddressGeert Grooteplein 10
    B.5.3.2Town/ cityNijmegen
    B.5.3.3Post code6525 GA
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031243610353
    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 Afinitor
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Ltd.
    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 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
    breast cancer
    borstkanker
    E.1.1.1Medical condition in easily understood language
    breast cancer
    borstkanker
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10072737
    E.1.2Term Advanced breast cancer
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To evaluate the effect of old age (≥ 70 years) on everolimus pharmacokinetics (AUC0-24hr)
    - To evaluate the effect of obesity (BMI ≥ 30 kg/m2) on everolimus pharmacokinetics (AUC0-24hr)
    - Vaststellen van het effect van ouderdom (leeftijd ≥ 70 jaar) op everolimus farmacokinetiek (AUC0-24hr)
    - Vaststellen van het effect van obesitas (BMI ≥ 30 kg/m2) op everolimus farmacokinetiek (AUC0-24hr)
    E.2.2Secondary objectives of the trial
    - To evaluate whether early metabolic response is correlated with clinical benefit
    - To evaluate whether early metabolic response is correlated with everolimus exposure
    - To evaluate whether everolimus dose escalation based on AUC results in a higher metabolic response compared to no dose escalation and compared to before dose escalation
    - To evaluate whether everolimus exposure is correlated with the incidence and severity of adverse events
    - To evaluate whether everolimus exposure is correlated with clinical benefit
    Secundaire doelstellingen:
    - Vaststellen van de correlatie tussen vroege metabole respons (FDG-PET) en klinische respons (CT)
    - Vaststellen van de correlatie tussen vroege metabole respons en everolimus blootstelling
    - Vaststellen of everolimus dosis escaltie op basis van farmacokinetiek (AUC) leidt tot een verbetering in metabole respons ten op zichte van geen dosis escalatie en ten op zichte van voor dosis escalatie.
    - Vaststellen of everolimus blootstelling is gecorreleerd met incidentie en ernst van bijwerkingen
    vanwhether everolimus exposure is correlated with the incidence and severity of adverse events
    - Vaststellen of everolimus blootstelling is gecorreleerd met klnische respons
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer not
    amenable to curative treatment by surgery or radiotherapy.
    - Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer
    - Postmenopausal women
    - Progression following a non-steroidal aromatase inhibitor
    - Radiological or clinical evidence of recurrence or progression on last systemic therapy prior to enrollment.
    - Falling into one of the following categories:
    o elderly patients (age ≥ 70 years and BMI < 30 kg/m2); or
    o obese patients (BMI ≥ 30 kg/m2 and age < 70 years); or
    o control patients (BMI < 30 kg/m2 and age < 70 years);
    - Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 x ULN
    - Adequate renal function: calculated creatinine clearance (as estimated by GFR using the MDRD formula) is MDRD ≥ 30ml/min/1.73m2
    - Performance status ECOG 0 - 2 (Karnofsky index: 60 - 100)
    - Patient is willing and able to sign the Informed Consent Form prior to screening evaluations
    - Volwassen vrouwen (≥ 18 jaar oud) met gemetastaseerd borstkanker, die niet in aanmerking komen voor curatieve behandeling met chirurgie of radiotherapie.
    - Histologisch of cytologisch bewezen oestrogeen receptor positief borstkanker
    - postmenopauzale vrouwen
    - progressieve ziekte na een niet-steroidale aromatose remmer
    - radiologische of klinische progressie na de laatste systemische behandeling op moment van inclusie
    - patiente valt in een van de volgende categorieen:
    o ouderen (leeftijd ≥ 70 jaar én BMI < 30 kg/m2); of
    o obese patiënten (BMI ≥ 30 kg/m2 én leeftijd < 70 jaar); of
    o controle patienten (BMI < 30 kg/m2 én leeftijd < 70 jaar);
    - Serum aspartate aminotransferase (AST) en alanine aminotransferase (ALT) ≤ 5 x bovengrens van normaal
    - Adequate nierfunctie: berekende creatinine klaring zoals geschat met behulp van de MDRD formule MDRD ≥ 30ml/min/1.73m2
    - niveau van functioneren: Performance status ECOG 0 - 2 (Karnofsky index: 60 - 100)
    - Patiente is bereid en in staat om de toestemmingsverklaring te tekenen voor start van screeningsonderzoeken
    E.4Principal exclusion criteria
    - Patients aged ≥ 70 years AND BMI ≥ 30 kg/m2
    - HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive)
    - Previous treatment with exemestane or mTOR inhibitors. Except for the treatment with exemestane in the adjuvant setting
    - Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin)
    - Patients with a known history of HIV seropositivity
    - Any severe and / or uncontrolled medical condition such as:
    o Unstable angina pectoris, serious uncontrolled cardiac arrhythmia
    o Patients with severe hepatic impairment (Child-Pugh A/B/C)
    o Uncontrolled diabetes mellitus
    o Impairment of gastrointestinal function or gastrointestinal disease that may
    significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
    - Patients who test positive for hepatitis B or C (Patients who test negative for HBV-DNA, HBsAg, and HBcAb but positive for HBsAb with prior history of vaccination against Hepatitis B will be eligible). Only patients at higher risk for hepatitis B or C have to be tested.
    - Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A within the last 5 days prior to enrollment
    - History of non-compliance to medical regimens or patients unwilling to or unable to comply with the protocol
    - Patiënten ouder dan 70 jaar met tevens een BMI ≥ 30 kg/m2
    - HER2-overexpressie (IHC 3+ kleuring of positieve in situ hybridizatie)
    - Eerdere behandeling met exemestaan of een mTOR inhibitor. Eerdere behandeling met exemestaan in de adjuvante setting is wel toegestaan.
    - Bekende overgevoeligheid voor mTOR inhibitors, zoals sirolimus (rapamycin)
    - Patiënten die HIV seropositief zijn
    - Een ernstige of ongecontroleerde aandoening zoals:
    o Instabiele angina pectoris, ernstige ongecontroleerde cardiale ritmestoornis
    o Ernstige leverinsufficiëntie (Child-Pugh A/B/C)
    o Ongecontroleerde diabetes mellitus
    o Gestoorde gastrointestinale functie, of een gastrointestinale aandoening met een significant effect op de opname van everolimus (zoals colitis ulcerosa, ongecontroleerde misselijkheid/braken/diarree, malabsorptie)
    - Patiënten die positief zijn voor hepatitis B or C. Alleen patienten met een verhoogd risico op hepatitis B or C hoeven getest te worden
    - Patiënten die binnen 5 dagen voor start van de behandeling met everolimus nog behandeld worden met medicatie die een sterke invloed heeft op isoenzyme CYP3A
    - Patiënten bekend met non-compliance betreft medische regimes of patiënten die niet bereid zijn of niet in staat zijn zich aan het protocol te houden.
    E.5 End points
    E.5.1Primary end point(s)
    The primary aim is to show a difference in everolimus exposure (AUC0-24hr) of at least 25% in elderly patients (≥70 years) and obese patients (BMI ≥ 30 kg/m2) compared to the control group ( ≤ 70 years ; BMI ≤ 30 kg/m2), after reaching steady state everolimus pharmacokinetics (day 14, but at least after 7 days of everolimus therapy).
    De primaire uitkomstmaat is het vinden van een verschil in everolimus blootstelling (AUC0-24hr) van minimaal 25% in ouderen (≥70 jaar oud) en/of obese patienten (BMI ≥ 30 kg/m2) ten opzichte van controle patienten( ≤ 70 jaar EN BMI ≤ 30 kg/m2). Dit wordt gemeten na het bereiken van steady state everolimus farmacokinetiek op dag 14.
    E.5.1.1Timepoint(s) of evaluation of this end point
    pharmacokinetics for AUC will be performed on day 14 after start of treatment with everolimus and exemestane
    farmacokinetiek (AUC) wordt uitgevoerd op dag 14 na start van de behandeling met everolimus en exemestane
    E.5.2Secondary end point(s)
    - To explore and calculate the correlation of early metabolic response assessment with progression free survival (PFS; defined as disease progression according to RECIST version 1.1 or death, whichever occurs first) as primary outcome measure.
    - To explore, quantify and describe the correlation between early metabolic response and everolimus exposure (AUC0-24hr), on steady-state pharmacokinetics.
    - To explore, quantify and describe whether dose escalation in patients who are hypothetically underexposed will result in an increase in metabolic response.
    - To explore, quantify and describe the correlation between everolimus exposure and the frequency of adverse events as graded with CTCAE v4.0.
    Het vaststellen van de correlatie tussen vroege metabole respons (FDG-PET) met progressie vrije overleving (gedefinieerd als progressieve ziekte volgens RECIST versie 1.1 of sterfte, welke van deze het eerst optreedt)
    - Het vaststellen van de correlatie tussen vroege metabole respons (FDG-PET) en everolimus blootstelling (AUC0-24hr) ten tijde van steady-state farmacokinetiek
    - Beschrijven en kwantificeren of dosis escaltie in patienten die mogelijk onderbehandeld worden leidt tot een toename in metabole respons (FDG-PET)
    - Het vaststellen van de correlatie tussen everolimus blootstelling (AUC0-24hr) en de incidentie van bijwerkingen zoals vastgelegd met CTCAE v4.0.
    E.5.2.1Timepoint(s) of evaluation of this end point
    day 36 and day 90
    dag 36 and day 90
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned6
    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
    last visit of the last subject
    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
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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 state75
    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)
    None
    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 Decision2013-08-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-08-26
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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