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    The EU Clinical Trials Register currently displays   44334   clinical trials with a EudraCT protocol, of which   7366   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2022-003922-27
    Sponsor's Protocol Code Number:PAM-UMCG-002
    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:2024-02-08
    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 number2022-003922-27
    A.3Full title of the trial
    Neo-adjuvant Pembrolizumab as alternative to radio(chemo)therapy in MMRd uterine cancer
    Neo-adjuvante Pembrolizumab als alternatief voor radio(chemo)therapie in MMRd endometriumcarcinoom
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial studying immune therapy as treatment option for uterine cancer prior to surgery.
    Onderzoek naar immuuntherapie als behandeling van baarmoederkanker voorafgaand aan chirurgie.
    A.3.2Name or abbreviated title of the trial where available
    PAM-II
    PAM-II
    A.4.1Sponsor's protocol code numberPAM-UMCG-002
    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 SponsorUniversity Medical Center Groningen (UMCG)
    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
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUMCG
    B.5.2Functional name of contact pointDept. Obstetrics and Gynecology
    B.5.3 Address:
    B.5.3.1Street AddressHanzeplein 1
    B.5.3.2Town/ cityGroningen
    B.5.3.3Post code9713 GZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031503613008
    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 KEYTRUDA (pembrolizumab, MK3475)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    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 Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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 Yes
    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
    Primary uterine cancer characterized with dMMR
    Primair endometriumcarcinoom met dMMR
    E.1.1.1Medical condition in easily understood language
    Primary uterine cancer characterized by high mutational load
    Primaire baarmoeder kanker gekenmerkt door hoog aantal mutaties
    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
    The primary objective of this phase 2 trial is to establish the fraction of patients that achieve a major pathologic response (MPR) after 9 cycles of pembrolizumab, with the ultimate aim of informing a follow-up randomized trial. MPR was chosen as primary endpoint to align with ongoing randomized phase 3 ICB trials on neo-adjuvant vs. adjuvant treatment in other tumor types (e.g. the NADINA trial in melanoma; NCT04949113).
    Het primaire doel van deze fase 2 studie is om vast te stellen welke fractie patiënten een majeure pathologische response (MPR) bereiken na 9 cycli pembrolizumab, met als ultiem doel een follow-up randomized controlled trial studie uit te voeren. MPR is gekozen als primair eindpunt in lijn met reeds gestarte gerandomiseerde fase 3 ICI studies waarin neo-adjuvante vs. adjuvante behandeling vergeleken wordt in andere tumortypes (bijv. de NADINA studie bij melanomen; NCT4949113)
    E.2.2Secondary objectives of the trial
    1. To establish the objective response rate by radiologic assessment using MRI and RECIST 1.1.
    2. To establish recurrence free survival (RFS) defined as the number of patients alive without any progress or recurrence at 2 years from disease diagnosis.
    3. To assess safety and tolearbility of 9 cycles of neo-adjuvant pembrolizumab in the treatment of MMRd UC.
    1. Het verkrijgen van een objective responsie waarde door radiologische beoordeling middels MRI en recist 1.1.
    2. Bepalen van de recidief vrije overleving welke wordt gedefinieerd als het aantal patiënten zonder recidief 2 jaar na de diagnose.
    3. Bepalen van Veiligheid en verdraagzaamheid van 9 kuren neo-adjuvante pembrolizumab bij de behandeling van MMRd endometrium carcinoom.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed primary diagnosis of G3/CC
    MMRd uterine cancer who are intended to be treated with hysterectomy.
    - A female participant is eligible to participate if she is not pregnant, not breastfeeding, is not a woman of childbearing potential (WOCBP) or agrees to
    follow contraceptive guidance during the treatment period and at least until standard-of-care hysterectomy.
    - The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
    - Vrouwelijke deelneemster, ouder dan 18 jaar, met histologisch bevestigde G3/CC MMRd baarmoederkanker waarbij het behandeldoel een
    hysterectomie is.
    - De deelneemster is niet vruchtbaar of stemt er mee in anticonceptie te gebruiken tijdens de studie
    - De deelneemster geeft schriftelijk toestemming voor deelname aan de studie.
    E.4Principal exclusion criteria
    - A WOCBP who has a positive serum pregnancy test at screening.
    - Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
    - Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks [could consider shorter interval for kinase inhibitors or other short half-life drugs] prior to allocation.
    - Has received prior radiotherapy within 2 weeks of start of study treatment or radition-related toxicities requiring corticosteroids. Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease with a 1-week washout is permitted.
    - Has received a live vaccine or live-attenuated vaccine within 30 days before to the first dose of study intervention. Administration of killed vaccines and Covid vaccines is allowed.
    - Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
    - Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
    - Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
    - Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
    - Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
    - Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid).
    - Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
    - Has an active infection requiring systemic therapy.
    - Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required unless mandated by local health authority.
    - Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
    - Has not adequately recovered from major surgery or has ongoing surgical complications.
    - Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
    - Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
    - Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
    - Een positieve serum zwangerschapstest tijdens de screening
    - Eerdere behandeling met anti-PD-1, anti-PD-L1, anti-PD-L2 of andere T-cel remmer
    - Behandeling met systemische anti-kanker therapie 4 weken voor aanvang van de studie
    - Radiotherapie 2 weken voor aanvang van de studie
    - Levende vaccinatie ontvangen 30 dagen voor de eerste toediening van studiemedicatie
    - Deelname aan een andere studie of eerdere deelname aan een studie met studiemedicatie tot 4 weken voor start studiemedicatie.
    - Immuun gecompromitteerden of behandeling met chronische systemische steroïden
    - Een andere bekende maligniteit waarvoor actieve behandeling noodzakelijk was in de afgelopen 3 jaar
    - Actieve metastase in het centrale zenuwstelsel
    - Ernstige hypersensitiviteit (> graad 3) tegen pembrolizumab
    - actieve auto-immuun ziekte waarvoor behandeling heeft plaatsgevonden in de afgelopen 2 jaar
    - Voorgeschiedenis met pneumonitis waarvoor steroïden behandeling nodig was
    - Actieve infectie waarvoor systemische therapie nodig is
    - HIV
    - Hepatitis B of C
    - Voorgeschiedenis of huidige conditie die volgens de onderzoeker de studie kan beïnvloeden
    - Bekende psychiatrische stoornis of middelenmisbruik
    - Zwangerschap of borstvoeding
    E.5 End points
    E.5.1Primary end point(s)
    The main study endpoint is the fraction of patients that achieve a MPR. that the study is considered positive if neo-adjuvant pembrolizumab induces MPRs in at least 74% of patients.
    Het belangrijkste studie eindpunt is de fractie patiënten die een MPR behaald. De studie is geslaagd wanneer neo-adjuvante pembrolizumab in 74% van de patiënten een MPR geeft.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Two independent pathologists will evaluate the collected tumor material after planned surgery to assess the major pathological response (MPR). Hematoxylin and eosin staining on endometrium tissue collected during surgery will be assessed by an experienced pathologist for the evidence of necrosis and/or viable tumor cells.
    Twee onafhankelijke pathologen zullen het verzamelde tumorweefsel evalueren na de geplande operatie om de MPR te bepalen. Hemotoxyline en eosine kleuring op endometrium weefsel zal geanalyzeerd worden om te kijken naar onder andere necrose en vitale tumorcellen.
    E.5.2Secondary end point(s)
    1. The objective response rate of the tumor determined by radiologic assessment using MRI and RECIST1.1.
    2. Recurrence-free survival 2 years from disease diagnosis.
    3. The safety and tolerability of 9 cycles of neo-adjuvant pembrolizumab in the treatment of MMRd UC.
    1. Het verkrijgen van een objective responsie waarde door radiologische beoordeling middels MRI en recist 1.1.
    2. Bepalen van de recidief vrije overleving welke wordt gedefinieerd als het aantal patiënten zonder recidief 2 jaar na de diagnose.
    3. Bepalen van Veiligheid en verdraagzaamheid van 9 kuren neo-adjuvante pembrolizumab bij de behandeling van MMRd endometrium carcinoom.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. In order to establish the objective response rate (ORR), MRI will be performed at baseline (week 4) and will be compared to MRI performed after the second, fourth, sixth and ninth cycle of pembrolizumab (weeks 11, 17, 23 and 32, respectively). Tumor response will be classified according to RECIST 1.1.
    2. Recurrence free survival will be assessed at the 2-year mark from initial disease diagnosis.
    3. All AEs will be followed until they have abated, or until a stable situation has been reached.
    All AEs from the first study treatment to 30 days after the surgery will be documented. AEs occurring later than this must only be documented if a relationship to the study drug is suspected.

    1. Om een objective response rate (OOR) te kunnen bepalen, zal er een baseline MRI worden verricht en nadien zal deze vergeleken worden met een MRI na 2, 4, 6 en 9 kuren pembrolizumab (weken 11, 17, 23 en 32, respectievelijk). Tumor respons zal worden geclassificeerd volgens RECIST 1.1.
    2. Recidief vrije overleving zal worden onderzocht 2 jaar na de initiële diagnose.
    3. Alle AEs worden gevolgd tot ze zijn opgelost of tot een stabiele situatie is bereikt. Alle AEs van de eerste studie behandeling tot 30 dagen na de operatie worden gedocumenteerd. AEs die nadien voorkomen worden alleen gedocumenteerd als er een waarschijnlijke relatie is tot het studie medicijn.
    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 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) 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.8.2.4Number of treatment arms in the trial1
    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
    LVLS
    LVLS
    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 months6
    E.8.9.1In the Member State concerned days
    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: 3
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 9
    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 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 state12
    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)
    All patients will be monitored after discontinuation of pembrolizumab for 6 months according to standard-of-care UMCG guidelines for uterine cancer patients and/or patients treated with pembrolizumab
    Alle patiënten worden na de studie gevolgd voor 6 maanden volgens de standaard behandeling richtlijnen van patiënten met baarmoederkanker en/of patiënten behandeld met pembrolizumab.
    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 Decision2024-02-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-08-30
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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