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    Summary
    EudraCT Number:2016-004576-22
    Sponsor's Protocol Code Number:IRI28
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-05-18
    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 number2016-004576-22
    A.3Full title of the trial
    SAFETY, FEASIBILITY AND COST-ANALYSIS OF UGT1A1 GENOTYPE-GUIDED DOSING OF IRINOTECAN
    Geïndividualiseerd doseren van irinotecan door middel van genotyperen
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Personalized treatment of irinotecan
    Geïndividualiseerd doseren van irinotecan
    A.3.2Name or abbreviated title of the trial where available
    UGT1A1 genotype-guided dosing of irinotecan
    Geïndividualiseerd doseren van irinotecan op basis van UGT1A1 genotype
    A.4.1Sponsor's protocol code numberIRI28
    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 SponsorCatharina Hospital Eindhoven
    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 supportCatharina Hospital Eindhoven
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCatharina Hospital Eindhoven
    B.5.2Functional name of contact pointClinical Pharmacy
    B.5.3 Address:
    B.5.3.1Street AddressMichelangelolaan 2
    B.5.3.2Town/ cityEindhoven
    B.5.3.3Post code5623 EJ
    B.5.3.4CountryNetherlands
    B.5.6E-mailmaarten.deenen@catharinaziekenhuis.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.2.1.2Country 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 Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIRINOTECAN
    D.3.9.1CAS number 97682-44-5
    D.3.9.4EV Substance CodeSUB08295MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    Cancer
    kanker
    E.1.1.1Medical condition in easily understood language
    Cancer
    kanker
    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 develop a dosing nomogram of irinotecan in patients homozygous polymorphic for UGT1A1*28 and *93 in order to reduce the incidence of severe irinotecan-associated toxicity, defined as febrile neutropenia during the first two cycle of irinotecan treatment
    Het ontwikkelen van een doseeralgoritme voor irinotecan bij homozygoot mutante patienten voor UGT1A1*28 en *93 om de incidentie van febriele neutropenie te verminderen gedurende de eerste 2 cycli.
    E.2.2Secondary objectives of the trial
    • To determine the effect of UGT1A1*28 and *93 genotype-guided dosing of irinotecan on the incidence of grade ≥3 toxicity, toxicity-related hospital admissions, treatment delay and early treatment withdrawal.
    • To confirm adequate drug exposure of UGT1A1*28 and *93 genotype-guided dosing by determining the pharmacokinetics of irinotecan in homozygous variant allele carriers.
    • To determine the feasibility of UGT1A1 genotype-guided dosing defined as no delay of treatment due to prospective screening of UGT1A1 genotype
    • To demonstrate that UGT1A1 genotype-guided dosing of irinotecan is cost-saving
    • To determine the effect of the dosing nomogram on efficacy of treatment
    • To determine the specificity and sensitivity of the bilirubin / conjugated bilirubin concentration ratio as a marker for the added value of genotyping for UGT1A1*28 and *93.
    • To retrospectively determine the effect of additional polymorphisms other than UGT1A1*28 and *93 on treatment outcome
    • Vaststellen effect van UGT1A1*28 en *93 genotype-geleid doseren van irinotecan op de incidentie van graad ≥3 toxiciteit, ziekenhuisopnames, behandeluitstel en vroegtijdig stoppen met behandeling
    • Vastellen van adequate bloostelling aan irinotecan bij UGT1A1*28 en*93 genotype-geleid doseren
    • haalbaarheid UGT1A1*28 en*93 genotype-geleid doseren
    • kosteneffectiviteit UGT1A1*28 en*93 genotype-geleid doseren
    • effectiviteit UGT1A1*28 en*93 genotype-geleid doseren
    • vaststellen specificiteit en sensitiviteit bilirubine/geconjugeerd bilirubine ratio
    • retrospectief bepalen van effect van additionele polymorphismes anders dan UGT1A1*28 en *93 op uitkomst behandeling
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Pathologically confirmed malignancy for which treatment with irinotecan is indicated at
    a dosing regimen of ≥ 180 mg/m2 or 450-600mg flat dose in 2- or 3-weekly treatment schedules (see table 1)
    2. Age ≥ 18 years
    3. Able and willing to give written informed consent
    4. WHO performance status 0-2
    5. Minimal acceptable safety laboratory values defined as
    a. ANC of ≥ 1.5 x 109 /L
    b. Platelet count of ≥ 100 x 109 /L
    c. Hepatic function as defined by serum bilirubin ≤ 1.5 x ULN, ALAT and ASAT ≤ 2.5 x ULN; in case of liver metastases ALAT and ASAT ≤ 5 x ULN.
    d. Renal function (eGFR) ≥ 50 ml/min OR creatinine ≤ 1.5 x ULN
    1. pathologisch vastgestelde maligniteit waarbij behandeling met irinotecan geinidceerd is in een dosering van ≥ 180 mg/m2 of 450-600mg vaste dosis in 2- of 3-wekelijkse schema's
    2.Leeftijd ≥ 18 jaar
    3. In staat om informed consent te geven
    4. WHO performance status 0-2
    5. minimale acceptable lab waarden tav veiligheid:
    a. Absoluut aantal neutrofielen ≥ 1.5 x 109 /L
    b. Aantal bloedplaatjes ≥ 100 x 109 /L
    c. Leverfunctie: serum bilirubine ≤ 1.5 x ULN, ALAT en ASAT ≤ 2.5 x ULN; in het geval van levermetastase: ALAT and ASAT ≤ 5 x ULN.
    d. nierfunctie (eGFR) ≥ 50 ml/min OF kreatinine ≤ 1.5 x ULN
    E.4Principal exclusion criteria
    1. Prior treatment with irinotecan
    2. Patients with known substance abuse, psychotic disorders, and/or other diseases expected to interfere with study or the patient’s safety
    3. Patients of Asian origin
    4. Patients unable or unwilling to stop the use of (over the counter) medication or (herbal) supplements which can interact with irinotecan (e.g. by induction of inhibition of CYP3A4) (see Appendix 2 study protocol).
    1. eerdere behandeling met irinotecan
    2. patienten met verslavingsproblematiek, psychische stoornissen, en/of andere ziektes die kunnen interfereren met de studie of de veiligheid van de patient.
    3. Aziatische patienten
    4. Patienten met OTC medicatie of (kruiden)supplementen die interacteren met irinotecan (inductie CYP3A4) die niet met deze interacterende middelen willen of kunnen stoppen (zie bijlage 2 van het onderzoeksprotocol).
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study is the incidence of febrile neutropenia of UGT1A1 genotype-guided dosing during the first two cycles of irinotecan treatment
    Incidentie van febriele neutropenie
    E.5.1.1Timepoint(s) of evaluation of this end point
    see study protocol, annex 14.1 study procedures
    zie onderzoeksprotocol, annex 14.1 study procedures
    E.5.2Secondary end point(s)
    • Incidence of grade ≥3 toxicity
    • Incidence of toxicity-related hospital admissions
    • Number of patients with treatment delay, defined as a delay of more than 2 days
    • Incidence of early treatment withdrawal
    • Pharmacokinetics of irinotecan and its metabolite SN-38 in UGT1A1*28 and/or *93 homozygous variant allele carriers.
    • Incidence of treatment delay due to prospective screening of UGT1A1
    • Direct medical costs of irinotecan-based treatment
    • Progression free survival and overall survival
    • Bilirubin / conjugated bilirubin concentration ratio
    • The effect of additional polymorphisms other than UGT1A1*28 and *93 on treatment outcome in terms of toxicity and efficacy (survival and progression-free survival)
    • Incidentie van ≥graad 3 toxiciteit
    • Incidentie van toxiciteit gerelateerde ziekenhuisopnames
    • Aantal patienten met uitstel van behandeling, gedefinieerd als >2 dagen uitstel.
    • Incidentie van vroegtijdig stoppen van behandeling
    • Farmacokinetiek van irinotecan en metaboliet SN-38 in UGT1A1*28 en/of *93 homozygote variant dragers
    • Incidentie van uitstel van behandeling door prospectieve screening met UGT1A1
    • Directe medische kosten van de behandeling
    • Progressie vrije overleving en overleving
    • Bilirubine / geconjugeerde bilirubine concentratie ratio
    • Het effect van additionele polymorfismen anders dan UGT1A1*28 en/of *93 op de behandeling in de vorm van toxiciteit en effectiviteit (overleving en progressievrije overleving
    E.5.2.1Timepoint(s) of evaluation of this end point
    see study protocol, annex 14.1 study procedures
    zie onderzoeksprotocol, annex 14.1 study procedures
    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 No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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 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 Yes
    E.8.1.7.1Other trial design description
    Prospectieve, multi-center, niet-gerandomiseerde klinische implementatie studie
    Prospective, multi-center, non-randomized clinical implementation study
    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
    LVLS
    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
    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: 300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 88
    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 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 state388
    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
    geen
    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 Decision2017-05-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-14
    P. End of Trial
    P.End of Trial StatusOngoing
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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