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    The EU Clinical Trials Register currently displays   43873   clinical trials with a EudraCT protocol, of which   7292   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:2021-005731-23
    Sponsor's Protocol Code Number:N21PMA
    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:2022-08-23
    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 number2021-005731-23
    A.3Full title of the trial
    Pembrolizumab for locally advanced, irresectable, non-metastatic dMMR colorectal cancers. The PUMA study.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Pembrolizumab for locally advanced, irresectable, non-metastatic dMMR colorectal cancers. The PUMA study.
    A.3.2Name or abbreviated title of the trial where available
    PUMA
    A.4.1Sponsor's protocol code numberN21PMA
    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 SponsorStichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis
    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 CORP
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationStichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis
    B.5.2Functional name of contact pointMyriam Chalabi
    B.5.3 Address:
    B.5.3.1Street AddressPlesmanlaan 121
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1066 CX
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31205129111
    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, MK-3475)
    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.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPembrolizumab
    D.3.9.1CAS number 1374853-91-4
    D.3.9.3Other descriptive nameMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    adenocarcinoma of the colon or rectum
    E.1.1.1Medical condition in easily understood language
    colorectal cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10061451
    E.1.2Term Colorectal cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the objective response rate (ORR) according to RECIST 1.1 criteria in order to assess the efficacy of pembrolizumab in patients with locally advanced, irresectable dMMR colorectal cancers
    E.2.2Secondary objectives of the trial
    • To assess the major pathological response (MPR, ≤10% viable tumor rest) in patients undergoing surgery
    • To find biomarkers and evaluation strategies able to accurately assess complete and near-complete responses in order to pursue organ-sparing treatment (omission of surgery) in this patient population,
    o Post-treatment CT-scans
    o ctDNA analysis
    • To perform translational analyses, yet to be determined, which may include the following:
    o RNA sequencing and inflammatory signatures to validate current findings and identify predictors of response;
    o Analysis of immune cell infiltration and differences between responders and non-responders
    o Immunogenic mutational load by tumor tissue DNA WES. Peripheral blood DNA WES as a control for somatic mutation sorting.
    • Date of relapse
    • Association between microbiota composition and treatment outcomes and the effect of neoadjuvant pembrolizumab on the gut microbiota composition
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Signed written informed consent;
    • Patients at least 18 years of age;
    • Locally advanced, irresectable adenocarcinoma of the colon or rectum, not amenable to surgery, or for which induction therapy is required to reconsider surgery, or where free margins can only be obtained by major extension of the surgical procedure, as defined by one of the following:
    o Invasion of the duodenum, stomach, spleen or pancreatic head, for which major extension of the surgical procedure would be required to obtain free margins, and/or for which the chances of positive resection margins are high
    o Invasion or encasement of major blood vessels (superior mesenteric vessels, iliac vessels, portal vein)
    o Invasion or encasement of the ureter
    • Histologically or cytologically confirmed microsatellite instability-high (MSI-H) or MMR-deficient (dMMR) status
    • No signs of distant metastases on CT-scan and physical examination; patients may not be eligible for first-line treatment with pembrolizumab according to SoC
    • Patients may not be eligible for standard of care first-line pembrolizumab for metastatic disease
    • Patients may not be potentially eligible for the NICHE study: patients with primarily resectable disease, for which relatively minor extension of the procedure is required to acieve free margins, such as but not limited to a small bowel segment, abdominal wall
    • ECOG performance status of 0 or 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention;
    • Screening laboratory tests must meet the criteria as defined in Table 1 and should be obtained within 10 days prior to the start of study intervention:
    Absolute neutrophil count (ANC) ≥1500/µL; Platelets ≥100 000/µL; Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L, Creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN; Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN; AST (SGOT) and ALT (SGPT) ≤2.5 × ULN; International normalized ratio (INR) OR prothrombin time (PT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants; Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants;
    • A male participant must agree to use a contraception as detailed in Appendix 2 of this protocol during the treatment period and for at least 200 days (90 days plus the time required for pembrolizumab to undergo five half-lives) after the last dose of study treatment and refrain from donating sperm during this period.
    • Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to registration (see appendix 2). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required;
    • A female participant is eligible to participate if she is not pregnant (see appendix 2), not breastfeeding, and at least one of the following conditions applies:
    o Not a woman of childbearing potential (WOCBP) as defined in appendix 2
    OR
    o A WOCBP who agrees to follow the contraceptive guidance in appendix 2 during the treatment period and for at least 120 days (30 days plus the time required for pembrolizmab to undergo five half lives) after the last dose of study treatment.
    • CT-scan must be performed within 28 days prior to registration.
    E.4Principal exclusion criteria
    • No previous treatment with immune checkpoint inhibitors targeting including but not limited to CTLA-4, PD-1 or PD-L1;
    • No previous treatment with chemotherapy for the disease under study;
    • No prior radiotherapy for the disease under study;
    • No prior radiotherapy for other indications than the disease under study within 2 weeks of start of study intervention. Participants must have recovered from al radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
    • No history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease;
    • Allergies and Adverse Drug Reaction
    o No history of allergy to study drug components
    o No history of severe hypersensitivity reaction to any monoclonal antibody
    • No intercurrent illnesses, including but not limited to infections, unstable angina pectoris;
    • No known history of Human Immunodeficiency Virus (HIV) infection and no 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.
    • No underlying medical conditions that, in the investigator’s opinion, will make the administration of the study drug hazardous or obscure the interpretation of toxicity determination of adverse events;
    • No active autoimmune disease requiring systemic treatment in the past 2 years;, or other medical conditions requiring systemic steroid or immunosuppressive medications, Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
    • No diagnosis of immunodeficiency or conditions requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease;
    • No live vaccines in the 4 weeks prior to inclusion;
    • No history of uncontrolled medical or psychiatric illness;
    • No psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule;
    • No current pregnancy or breastfeeding;
    • No active malignancies other than disease under study within 3 years prior to inclusion, except for malignancies with a negligible recurrence rate (e.g. <10% in 5 years);
    • No allogenic tissue/solid organ transplant.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy of pembrolizumab will be measured by the objective response rate (ORR) according to RECIST 1.1 criteria. The ORR (%) is defined as the proportion of patients with complete response (CR) or partial response (PR) according to RECIST 1.1 as the best observed response to pembrolizumab treatment. All subjects who were treated with at least one cycle of pembrolizumab and underwent subsequent evaluation of their disease will be considered evaluable for response.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to approximately 30 months
    E.5.2Secondary end point(s)
    • To assess the major pathological response (MPR, ≤10% viable tumor rest) in patients undergoing surgery
    • To find biomarkers and evaluation strategies able to accurately assess complete and near-complete responses in order to pursue organ-sparing treatment (omission of surgery) in this patient population,
    o Post-treatment CT-scans: can we use radiomics to accurately assess complete and near-complete response?
    o ctDNA analysis: can we use ctDNA to assess complete response and is there a difference between complete and near-complete response in terms of minimal residual disease on ctDNA and risk of relapse?
    • To perform translational analyses, yet to be determined, which may include the following:
    o RNA sequencing and inflammatory signatures to validate current findings and identify predictors of response;
    o Analysis of immune cell infiltration and differences between responders and non-responders
    o Immunogenic mutational load by tumor tissue DNA WES. Peripheral blood DNA WES as a control for somatic mutation sorting.
    • Date of relapse, as determined by disease recurrence or disease-related death during follow-up after surgery. Follow-up will be performed according to local and/or national guidelines;
    • Association between microbiota composition and treatment outcomes and the effect of neoadjuvant pembrolizumab on the gut microbiota composition
    E.5.2.1Timepoint(s) of evaluation of this end point
    Up to approximately 30 months
    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 No
    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.8.3 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 No
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    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 Decision2022-08-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-10-25
    P. End of Trial
    P.End of Trial StatusOngoing
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