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    The EU Clinical Trials Register currently displays   37236   clinical trials with a EudraCT protocol, of which   6125   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2017-000976-27
    Sponsor's Protocol Code Number:ML2017-IO1
    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:2017-07-12
    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 number2017-000976-27
    A.3Full title of the trial
    Biomarker discovery study to identify patients with advanced urothelial cancer benefitting from pembrolizumab treatment
    Een fase 2 onderzoek naar nieuwe biomarkers die voorspellen welke patiënten met gevorderde blaaskanker baat voordeel hebben bij een de behandeling met pembrolizumab
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Biomarker discovery study to identify patients with advanced urothelial
    cancer benefitting from pembrolizumab treatment
    Identificeren van biomarkers in patiënten met gevorderd urotheelcelcarcinoom die reageren op behandeling met pembrolizumab
    A.3.2Name or abbreviated title of the trial where available
    RESPONDER
    A.4.1Sponsor's protocol code numberML2017-IO1
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03263039
    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 SponsorErasmus MC Cancer Institute
    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 organisationErasmus MC Cancer Institute
    B.5.2Functional name of contact pointClinical Trial Center
    B.5.3 Address:
    B.5.3.1Street AddressDr. Molewaterplein 40
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3015 GD
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031107032570
    B.5.6E-mailresponder@erasmusmc.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.2.5The 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.3.1Product namePembrolizumab
    D.3.2Product code MK-3457
    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.3.9.2Current sponsor codeMK-3475
    D.3.9.3Other descriptive nameAnti-PD-1 monoclonal antibody
    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
    advanced urothelial cancer
    gevorderde urotheelcelcarcinoom
    E.1.1.1Medical condition in easily understood language
    advanced urothelial cancer
    gevorderde urotheelcelkanker
    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 identify potential biomarkers for early identification of clinical benefit during pembrolizumab treatment in patients with advanced urothelial cancer
    Identificeren van potentiële biomarkers die vroeg kunnen voorspellen of behandeling met pembrolizumab klinisch voordelig zal zijn in patiënten met gevorderde urotheelcelcarcinoom
    E.2.2Secondary objectives of the trial
    - To identify potential mechanisms of primary and acquired resistance to pembrolizumab.
    - To assess potential correlations between biomarkers and clinical activity according to different definitions and response evaluation criteria.
    - To collect tissue, blood and urine samples for future translational experiments.
    - Identificeren van potentiële mechanismes die leiden tot pembrolizumab resistentie (primair en verworven)
    - Beoordelen van potentiële correlaties tussen biomarkers en klinische activiteit aan de hand van verschillende definities en response evaluatie criteria
    - Verzamelen van weefsel-, bloed-, en urinemonsters voor toekomstig onderzoek
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to be eligible to participate in this study, a subject must meet all of the following criteria:
    1. Should have signed informed consent for CPCT-02.
    Note: when a safe biopsy of a metastatic or locally advanced lesion is not deemed possible by the treating investigator, subject may be included in the trial without participation in the CPCT-02 trial only upon approval by the central principal investigator.
    2. Be willing and able to provide written informed consent for the trial.
    3. Be  18 years of age on day of signing informed consent.
    4. Have histologically or cytologically-confirmed urothelial cancer that is not
    amenable to curative treatment with local and/or systemic therapies.
    5. Second-line treatment: have progressive disease after platinum containing chemotherapy as defined by:
    - Disease progression after treatment with a platinum-containing regimen for recurrent (disease not amenable to curative treatment)/metastatic disease
    - Recurrence/progression within 12 months of prior therapy containing platinum
    OR
    First-line treatment: have received no prior systemic chemotherapy for advanced/unresectable (inoperable) or metastatic urothelial
    a. Adjuvant platinum based chemotherapy, following radial cystectomy, with recurrence > 12 months from completion of therapy is permitted
    b. Neoadjuvant platinum based chemotherapy, with recurrence > 12 months since completion of therapy is permitted.
    Note: Low-dose chemotherapy (e.g., low dose cisplatin, cisplatin+5FU, mytomycin+5FU, or cisplatin+paclitaxel) given concurrent with radiation to the primary tumor site is not considered as systemic therapy.
    And subject must be considered ineligible to receive cisplatin-based combination therapy, based on having at least one of the following criteria:
    a. Creatinine clearance (calculated or measured) < 60 mL/min but >30 mL/min
    Note: Subjects with a creatinine clearance (calculated or measured) < 30 mL/min or on dialysis are excluded from the trial.
    b. CTCAE v.4, Grade >2 audiometric hearing loss (25dB in two consecutive wave ranges)
    c. CTCAE v.4, Grade >2 peripheral neuropathy
    d. NYHA Class III heart failure (Appendix 13.1)
    6. Cisplatin-unfit patients should have a PD-L1 CPS of 10, determined with the use of the commercially available PD-L1 IHC 22C3 pharmDx assay on a DAKO stainer.
    PD-L1 expression may be determined prior to enrollment or during the screening phase.
    7. Have measurable disease based on RECIST 1.1. Tumor lesions located in a previously irradiated area are considered measurable if progression has been demonstrated in these lesions.
    8. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly
    8.- Note: newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor.
    - Note: when a safe biopsy of a metastatic or locally advanced lesion is not deemed possible by the treating investigator, subject may be included in the trial without providing a new core or excisional biopsy of a tumor lesion only upon approval of the central principal investigator.
    9. Have a performance status of 0 or 1 on the ECOG Performance Scale.
    10. Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 10 days of treatment initiation.
    11. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
    12. Female subjects of childbearing potential (Section 5.5.2) must be willing to use an adequate method of contraception as outlined in Section 5.5.2 Contraception, for the course of the study through 120 days after the last dose of study medication.
    Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
    13. Male subjects of childbearing potential (Section 5.5.2) must agree to use an adequate method of contraception as outlined in Section 5.5.2- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.
    E.4Principal exclusion criteria
    1. Treamtent with an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
    2. Has a diagnosis of immunodeficiency or is receiving high dose systemic steroid therapy (defined as > 20 mg prednisone or equivalent per day) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
    3. Has a known history of active TB (Bacillus Tuberculosis).
    4. Hypersensitivity to pembrolizumab or any of its excipients.
    5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
    6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
    - Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
    - Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
    - Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed at the investigator’s discretion
    7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or
    squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
    Diagnosis of prostate carcinoma in cystectomy material is not an exclusion criterium.
    8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain
    metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose
    of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and
    are not using high dose steroids (defined as > 20 mg prednisone or equivalent per day) for at least 7 days prior to trial treatment. This
    exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
    9. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents,
    corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
    10. Has known history of, or any evidence of active, (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis.
    11. Has an active infection requiring systemic therapy.
    12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
    13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
    14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the prescreening
    or screening visit through 120 days after the last dose of trial treatment.
    15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti- PD-L2 agent.
    16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
    17. Has a known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV]
    RNA [qualitative] is detected). Note: Without known history, testing needs to be performed to determine eligibility. Hepatitis C antibody (Ab)
    testing is allowed for screening purposes in countries where HCV RNA is not part of standard of care.
    18. Has received a live vaccine within 30 days of planned start of study therapy.
    Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
    E.5 End points
    E.5.1Primary end point(s)
    To identify potential biomarkers for early identification of clinical benefit
    during pembrolizumab treatment in patients with advanced urothelial
    cancer after first-line chemotherapy
    E.5.1.1Timepoint(s) of evaluation of this end point
    Clinical benefit and disease progression will be measured according to
    modified RECIST 1.1 at any time during the study, while assessment of
    the biomarkers will take place at end of the study which will be
    approximately 2 years after inclusion of the first patient.
    E.5.2Secondary end point(s)
    - To identify potential mechanisms of primary and acquired resistance to
    pembrolizumab.
    - To assess potential correlations between biomarkers and clinical
    activity according to different definitions and response evaluation
    criteria.
    - To collect tissue, blood and urine samples for future translational
    experiments.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Clinical benefit and disease progression will be measured according to
    modified RECIST 1.1 at any time during the study, while assessment of
    the biomarkers will take place at end of the study which will be
    approximately 2 years after inclusion of the first patient.
    Collection of samples will be done throughout the study, with time
    moments as described in protocol
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    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) 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 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 concerned10
    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. The trial will end when the last subject completes the last visit,
    discontinues from the trial or is lost to follow -up.
    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 months
    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: 58
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 22
    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 Yes
    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 state80
    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)
    Subject who experience radiographic disease progression after inital CR on pembrolizumab, may be eligible for up to one year of additional treatment with pembrolizumab via the Second Course Phase at the discretion of the investigator and if patient has not started any other anti tumor treatment. This is only possible if the trial remains open.

    Beside this possibilty, there are no other specific post trial treatment plans.
    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 Decision2017-07-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-26
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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