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    Summary
    EudraCT Number:2017-004752-34
    Sponsor's Protocol Code Number:53998
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-02-18
    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 number2017-004752-34
    A.3Full title of the trial
    Study of pembrolizumab combined with ataluren in Patients with metastatic pMMR and dMMR colorectal cancer adenocarcinomas or metastatic dMMR endometrial carcinoma: the ATAPEMBRO study.
    Haalbaarheidsonderzoek naar de behandeling van Ataluren samen met Pembrolizumab bij patiënten met uitgezaaide dikkedarmkanker of microsatelliet instabiele baarmoederkanker: de ATAPEMBRO studie.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Combining Ataluren with immunotherapy for the treatment of colorectal and endometrial cancer: the ATAPEMBRO study.
    De toevoeging van Ataluren aan immunotherapie voor de behandeling van patiënten met uitgezaaide dikkedarm- of baarmoederkanker: de ATAPEMBRO studie.
    A.3.2Name or abbreviated title of the trial where available
    ATAPEMBRO
    ATAPEMBRO
    A.4.1Sponsor's protocol code number53998
    A.5.4Other Identifiers
    Name:ABRNumber:NL64251
    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 SponsorAmsterdam University Medical Centers location AMC
    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 supportMerck Sharp & Dohme
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportPTC Therapeutics
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportAMC Amsterdam
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmsterdam University Medical Centers location AMC
    B.5.2Functional name of contact pointAdriaan D. Bins
    B.5.3 Address:
    B.5.3.1Street AddressMeibergdreef 9
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1105AZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031205665955
    B.5.5Fax number0031206919743
    B.5.6E-maila.d.bins@amc.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 Translarna
    D.2.1.1.2Name of the Marketing Authorisation holderPTC Therapeutics International Limited
    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 Granules for oral suspension
    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 INNATALUREN
    D.3.9.1CAS number 775304-57-9
    D.3.9.4EV Substance CodeSUB89249
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number125 to 1000
    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 Keytruda
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme 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 Powder for intravesical solution
    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 INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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) Yes
    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
    Mismatch repair deficient and proficient metestatic colorectal carcinoma and mismatch repair deficient metastatic endometrial carcinoma, stomach carcinoma and small bowel carcinoma.
    Mismatch repair deficiënte en ongestoorde gemeteastaseerde colorectaal carcinomen en mismatch repair deficiente gemetastaseerde endometrium carcinomen, maagcarcinomen en dunne darm carcinomen.
    E.1.1.1Medical condition in easily understood language
    Metastastatic colon cancer, endometrial cancer, stomach cancer and small bowel cancer
    Uitgezaaide dikkedarmkanker, baarmoederkanker, maagkanker, dunne darm 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
    1. To assess safety and characterize toxicities of pembrolizumab combined with ataluren in patients with pMMR mCRC, dMMR mCRC, dMMR mEC, dMMR mSC and dMMR mSBC
    2. To determine the immune-related progression free survival (irPFS) rate at 21 weeks and objective response rate (irORR) at 30 weeks in patients with pMMR mCRC, dMMR mCRC, dMMR mEC and dMMR mSC and dMMR mSBC treated with pembrolizumab combined with ataluren using immune related response criteria (irRC).
    1. Beoordelen van de veiligheid en de toxiciteit van Ataluren in combinatie met Pembrolizumab in patienten met pMMR mCRC, dMMR mCRC, dMMR mEC, dMMR mSC and dMMR mSBC
    2. Immuungerelateerde progressievrije overleving (irPFS) vastellen bij 21 weken en immuun gerelateerde objectieve response rate (irORR) bij 30 weken in patiënten met pMMR mCRC, dMMR mCRC, dMMR mEC, dMMR mSC en dMMR mSBC gebruikmakend van immuun gerelateerde respons criteria (irRC)
    E.2.2Secondary objectives of the trial
    Overall survival (OS) at the end of study
    Response rate (RR) at the end of the study
    Immune related progression free survival (irPFS) after 30 weeks
    Progression free survival (PFS) after 30 weeks
    Comparison with MK-3475-016 study
    Exploratory objectives (biomarkers, T-cel activity, Neo-epitope validation, DNA sequencing differences, RNA level differences)
    Algehele overleving (OS) aan het einde van de studie
    Response rate (RR) aan het einde van de studie
    Immuun gerelateerde progressievrije overleving (irPFS) na 30 weken
    Progressievrije overleving (PFS) na 30 weken
    Vergelijking met MK-3475-016 studie
    Overige doelen (biomarkers, T-cel activiteit, Neo-epitope validatie, DNA sequence verschillen, RNA niveau verschillen)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Metastatic or irresectable locally advanced mismatch repair proficient or deficient colorectal carcinoma or mismatch repair deficient endometrial carcinoma or mismatch repair deficient stomach carcinoma or mismatch repair deficient small bowel carcinoma
    - Have received or refused at least one chemotherapy treatment for metastatic disease
    - Life expectancy greater than 3 months
    - Normal organ and marrow function (as defined in protocol)
    - Be willing and able to provide metastasis tissue pre and post treatment by core or excissional biopsy.
    - Gemetastaseerd of lokaal uitgebreid irresectabel mismatch repair deficient of ongestoord colorectaal carcinoom of mismatch repair deficient endometrium carcinoom of mismatch repair deficient maag carcinoom of mismatch repair deficient dunne darm carcinoom
    - Behandeld met ten minste één chemotherapie bevattend behandelschema voor gemetastaseerde ziekte of deze behandeling hebben geweigerd
    - Levensverwachting langer dan 3 maanden
    - Normale orgaan en beenmergfunctie (zoals gedefinieerd in het protocol)
    - Bereid en geschikt om weefsel materiaal van metastase af te staan voor en na behandeling middels biopsie.
    E.4Principal exclusion criteria
    - (Partner is) currently pregnant or breastfeeding or is planning to become pregnant or nurture a child during the duration of the trial and a designated period thereafter.
    - Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti OX-40, anti-CD40 or anti-CTLA-4.
    - Active central nervous system metastsasis or carcinomateus meningitis
    - (History of) auto-immune disease
    - Immunodeficiency or use of immunosuppressing drugs.
    - Active infection
    - Uncontrolled intercurrent disease (for example hearth failure)
    - (History of) active Tuberculosis
    - HIV, Hep A, Hep B.
    - (Partner) zwanger of borstvoeding of van plan om zwanger te worden of borstvoeding te geven gedurende de duur van de studie en een aangewezen periode daarna.
    - Eerder behandel met anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti OX-40, anti-CD40 of anti-CTLA-4
    - Actieve metastase in het centrale zenuwstelsel of carcinomeateuze meningitis
    - Auto-immuunziekte (in voorgeschiedenis)
    - Immunodeficientie of gebruik van immunosuppresiva
    - Actieve infectie
    - Ongecontroleerde systemische ziekte (bijv. hartfalen, ritmestoornissen)
    - Actieve tuberculose (in voorgeschiedenis)
    - HIV, Hep A, Hep B
    E.5 End points
    E.5.1Primary end point(s)
    Phase I:
    - Safety
    - Maximum tolerated dose (MTD)
    Phase II:
    - Immune related progression free survival (irPFS)
    - Objective Response rate (irORR)
    Fase I:
    - Veiligheid
    - Maximaal getolereerde dosis (MTD)
    Fase II:
    - Immuun gerelateerde progressievrije overleving (irPFS)
    - Objectieve respons rate (irORR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I:
    - Toxicity for individual patient is monitored until day 28 followed by dose escalation or reduction in next cohort.
    - After 6-12 patients MTD is set. (see phase I flow chart in protocol)
    Phase II:
    - irPFS at 21 weeks
    - irORR at 30 weeks.
    Fase I:
    - Toxiciteit voor individuele patient wordt bekeken tot dag 28, daarna volgt dosis escalatie of reductie voor nieuwe cohort.
    - Na 6-12 patient wordt MTD bepaad (zie fase I flow chart in protocol)
    Fase II:
    - irPFS bij 21 weken
    - irORR bij 30 weken
    E.5.2Secondary end point(s)
    Overall survival (OS)
    Response rate (RR)
    Immune related progression free survival (irPFS)
    Progression free survival (PFS)
    Comparison with MK-3475-016 study
    Exploratory research (biomakers, T-cel activation, DNA/RNA seq, Neo-epitope validation)
    Algehele overleving (OS)
    Response rate (RR)
    Immuun gerelateerde progressievrije overleving (irPFS)
    Progressievrije overleving (PFS)
    Vergelijking met MK-3475-016 studie
    Overig onderzoek (biomarkers, T-cel activatie, DNA/RNA seq, Neo-epitope validatie)
    E.5.2.1Timepoint(s) of evaluation of this end point
    OS, RR and comparison at end of study
    irPFS and PFS after 30 weeks
    Exploratory research during and after study
    OS, RR and comparison aan het einde van de studie
    irPFS and PFS na 30 weken
    Overig onderzoek gedurende en na afloop van 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 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 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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    First combination therapy of IMP's registered for use in humans for different indication
    Eerste combinatietherapie van IMP's die geregistreerd zijn voor andere indicatie in mensen
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    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 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 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
    90 day folow up after each patient for overall survival.
    Studie therefore ends 90 days after last patient visit (LVSV)
    90 dagen follow up na elke patiënt voor algehele overleving.
    Daarom einde van studie 90 dagen na laatste patiëntbezoek (LVSV)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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: 17
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Patients with incurable metastatic cancer
    Patienten met uitgezaaide kanker in palliatieve traject.
    F.4 Planned number of subjects to be included
    F.4.1In the member state47
    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)
    If patients end trial medication after complete remission than upon recurrence of the cancer they are elligable for studytreatment if the study is still open and additional criteria are met.
    Als patienten na staken van studiemedicatie in verband met complete remissie opnieuw een terugkeer krijgen van de kanker kunnen ze in aanmerking komen voor studiebehandeling als de studie nog steeds open is en ze aan aanvullende criteria voldoen.
    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 Decision2019-02-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-20
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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