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    Summary
    EudraCT Number:2020-003106-31
    Sponsor's Protocol Code Number:MK-3475-B15
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2020-12-16
    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 ConcernedGermany - PEI
    A.2EudraCT number2020-003106-31
    A.3Full title of the trial
    A Phase 3, Randomized, Open-label Study to Evaluate Perioperative
    Enfortumab Vedotin Plus Pembrolizumab (MK-3475) Versus Neoadjuvant Gemcitabine and Cisplatin in Cisplatin-eligible Participants with Muscle-invasive Bladder Cancer
    (KEYNOTE-B15 / EV-304)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Ph3 Trial of Perioperative EV and Pembro vs. Chemo in Cis-E MIBC
    A.3.2Name or abbreviated title of the trial where available
    Perioperative EV + Pembrolizumab vs Neoadjuvant Chemotherapy for Cisplatin-eligible MIBC
    A.4.1Sponsor's protocol code numberMK-3475-B15
    A.5.4Other Identifiers
    Name:INDNumber:122,753
    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 SponsorMerck Sharp & Dohme LLC
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Sharp & Dohme LLC
    B.5.2Functional name of contact pointGCTO
    B.5.3 Address:
    B.5.3.1Street Address126 East Lincoln Ave., P.O. Box 2000
    B.5.3.2Town/ cityRahway, New Jersey
    B.5.3.3Post code07065
    B.5.3.4CountryUnited States Minor Outlying Islands
    B.5.4Telephone number+14102536435
    B.5.6E-mailritesh.kataria@merck.com
    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.3.9.2Current sponsor codeMK-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.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 PADCEV (enfortumab vedotin-ejfv) for injection, for intravenous use
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma US , Inc
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 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 INNENFORTUMAB VEDOTIN
    D.3.9.3Other descriptive nameENFORTUMAB VEDOTIN
    D.3.9.4EV Substance CodeSUB185524
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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) No
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Cisplatin Teva® 1 mg/ml concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 Concentrate for 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 INNCisplatin
    D.3.9.1CAS number 15663-27-1
    D.3.9.3Other descriptive nameCisplatin
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 Gemcitabine 100mg powder for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderSun Pharmaceutical Industries Europe BV
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 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 INNGEMCITABINE
    D.3.9.1CAS number 95058-81-4
    D.3.9.3Other descriptive nameGEMCITABINE
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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: 5
    D.1.2 and D.1.3IMP RoleComparator
    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 Gemcitabine
    D.2.1.1.2Name of the Marketing Authorisation holderSun Pharmaceutical Industries Europe BV
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 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 INNGEMCITABINE
    D.3.9.1CAS number 95058-81-4
    D.3.9.3Other descriptive nameGEMCITABINE
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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
    Urothelial Carcinoma and Muscle Invasive Bladder Cancer
    E.1.1.1Medical condition in easily understood language
    Urothelial Carcinoma and Muscle Invasive Bladder Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10064467
    E.1.2Term Urothelial carcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10005003
    E.1.2Term Bladder 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
    1. To compare event-free survival (EFS) in Arm A (perioperative EV + pembrolizumab and RC + PLND) versus Arm B (neoadjuvant gemcitabine + cisplatin and RC + PLND).
    E.2.2Secondary objectives of the trial
    1. To compare pathologic complete response (pCR) rates obtained in Arm A (preoperative EV+pembrolizumab&RC+PLND) versus Arm B (neoadjuvant gemcitabine+cisplatin and RC+PLND).
    2. To compare overall survival (OS) in Arm A (perioperative EV+pembrolizumab&RC+PLND) versus Arm B (neoadjuvant gemcitabine+cisplatin&RC+PLND).
    3. To assess disease-free survival (DFS) in Arm A (perioperative EV+pembrolizumab&RC+PLND) & Arm B (neoadjuvant gemcitabine+cisplatin&RC+PLND), participants who are disease free after surgery.
    4. To compare rate of pathologic downstaging (pDS) in Arm A (preoperative EV+pembrolizumab & RC+PLND) & Arm B (neoadjuvant gemcitabine+cisplatin & RC+PLND.
    5. To evaluate safety & tolerability of perioperative EV+pembrolizumab+RC+PLND in Arm A.
    6. To evaluate changes from baseline in health-related quality of life (HRQoL) & time to deterioration, using 2 general instruments (EORTC
    QoL questionnaire-QLQ-C30, & EuroQoL- EQ-5D-5L), & 1 disease-specific instrument (BCI).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Exploratory Biomarker Research
    Objective: To identify molecular (genomic, metabolic, and/or proteomic) biomarkers that may be indicative of clinical response/resistance, safety, pharmacodynamic activity, and/or the mechanism of action of pembrolizumab+ EV
    E.3Principal inclusion criteria
    1. Has a histologically confirmed diagnosis of urothelial carcinoma (clinical stage T2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology and PD-L1 expression (CPS ≥10 or CPS <10, for PD-L1 not evaluable refer to inclusion criterion #4) to be confirmed by BICR (central pathology and/or central imaging assessment).
    • T1 disease (eligible only with N1 disease) and T2 disease will be confirmed by central pathology review and T3, T4a, N0 and N1 disease will be confirmed by central imaging review
    • Participants with mixed histology are eligible provided the urothelial component is ≥50% as noted above (participants whose tumors contain predominant (≥50%) plasmacytoid variant are not eligible)
    • Participants whose tumors contain any component of neuroendocrine histology are not eligible
    • Urothelial carcinomas not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible. Urothelial carcinomas invading into the prostatic stroma with no histologic muscle invasion are allowed, provided that the extent of disease is confirmed via imaging.

    2. Has clinically non-metastatic bladder cancer (N≤1, M0) determined by imaging (CT or MRI of the chest/abdomen/pelvis), confirmed by BICR.

    3. Is deemed eligible for RC + PLND by a urologist and/or oncologist and agrees to undergo curative intent standard RC + PLND (including prostatectomy if applicable) as per AUA/ASTRO/ASCO/SUO guidelines.

    4. Has a TUR of a bladder tumor (obtained within 60 days [+14 days] prior to enrollment [ICF documented]) that is submitted for central pathology assessment and adequate to determine urothelial histology and PD-L1 expression. (In the event the sample is not
    evaluable for PD-L1, the participant will be assigned to the CPS <10 group for stratification).

    5. Is male or female, and at least 18 years of age, at the time of providing documented informed consent.

    6. Male participants are eligible to participate if they agree to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows:
    - Enfortumab Vedotin: 180 Days
    - Gemcitabine/Cisplatin: 95 Days
    - Pembrolizumab: 0 Days (no requirement)
    • Refrain from donating sperm
    PLUS either:
    • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
    OR
    • Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause)
    • Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    • If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.

    7. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
    • Is not a WOCBP
    OR
    • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows:
    - Enfortumab Vedotin: 180 days
    - Gemcitabine/Cisplatin: 180 days
    - Pembrolizumab: 120 days
    • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 72 hours (serum) or 24 hours (urine) before the first dose of study intervention
    • If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy
    result is positive.

    8. Provides documented informed consent/assent for the study (either the participant or a legally acceptable representative, if applicable).

    9. Has an ECOG performance status of 0 or 1.

    10. Has adequate organ function as defined in the study protocol. (All screening labs must be collected within 14 days prior to randomization.)

    E.4Principal exclusion criteria
    1. Has a known additional non-urothelial malignancy that is progressing or has required active anticancer treatment ≤3 years prior to study randomization.

    2. Has received any prior systemic treatment, chemoradiation, and/or radiation therapy treatment for MIBC.

    3. Has ≥ N2 disease or metastatic disease (M1) as identified by imaging.

    4. Is cisplatin-ineligible, as defined by meeting any one of the following criteria:
    • Impaired renal function with measured or calculated CrCl <60 mL/min (calculated by one of the following methods: Cockcroft-Gault method, MDRD formula or 24-hour urine collection)
    • ECOG performance status ≥ 2
    • CTCAE v.5.0 Grade ≥ 2 peripheral neuropathy
    • CTCAE v 5.0 Grade ≥2 audiometric hearing loss (Audiometric abnormalities without corresponding clinical symptoms of Grade ≥2 hearing loss will not be grounds for exclusion); testing is not required at screening; it may be performed at investigator’s discretion
    • NYHA Class III or greater heart failure

    5. 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).

    6. Has received prior systemic anticancer therapy including investigational agents within 3 years prior to randomization. (Participants who have previously received EV or other MMAE-based ADCs are excluded)

    7. Has received any prior radiotherapy to the bladder.

    8. Has undergone partial cystectomy of the bladder to remove any NMIBC or MIBC.

    9. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. Administration of killed vaccines is allowed.

    10. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.

    11. Has ongoing sensory or motor neuropathy Grade 2 or higher.

    12. 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 the first dose of study intervention.
    Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement (10 mg/day prednisone equivalent) doses of corticosteroids are permitted for participants with adrenal insufficiency.

    13. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.

    14. Has known severe (≥Grade 3) hypersensitivity to any excipient contained in the drug formulation of EV (including histidine, trehalose dihydrate, and polysorbate 20).

    15. Has severe hypersensitivity (≥Grade 3) to cisplatin and/or gemcitabine and/or any of their excipients.

    16. Has active keratitis or corneal ulcerations. Participants with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator.

    17. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
    Replacement therapy is allowed.

    18. Has a history of uncontrolled diabetes. Uncontrolled diabetes is defined as HbA1c ≥8% or HbA1c 7% to <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.

    19. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

    20. Has an active infection requiring systemic therapy. Participant may be rescreened once after resolution of the infection.

    21. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.

    22. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.

    23. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to
    participate, in the opinion of the treating investigator.

    24. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.

    25. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through the time periods stated in Inclusion Criteria #6 and #7.

    26. Has had an allogenic tissue/solid organ transplant.
    E.5 End points
    E.5.1Primary end point(s)
    1. Event-Free Survival (EFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 5.5 years
    E.5.2Secondary end point(s)
    1. Pathologic Complete Response (pCR) Rate
    2. Overall Survival (OS)
    3. Disease Free Survival (DFS)
    4. Pathologic Downstaging (pDS) Rate
    5. Number of Participants Who Experienced An Adverse Event (AE) (Arm A only)
    6. Number of Participants Who Discontinued Study Treatment Due to An AE (Arm A only)
    7. Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC)-Quality of Life Questionnaire-Core 30 (QLQ- C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score
    8. Change from Baseline in EORTC QLQ-C30 Physical Functioning Scale
    9. Change From Baseline in Urinary, Bowel and Sexual Domains per Bladder Cancer Index (BCI)
    10. Change from Baseline in EuroQoL-5 Dimensions, 5-level Questionnaire (EQ- 5D-5L) Visual Analogue Score (VAS)
    11. Time to Deterioration (TTD) in the EORTC-QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30)
    12. TTD in the Physical Functioning Scale per EORTC QLQ-C30
    13. TTD in the Urinary, Bowel and Sexual Domains per BCI
    14. TTD in the EQ-5D-5L VAS
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 42 months
    2. Up to approximately 5.5 years
    3. From approximately 12 months to up to approximately 5 years
    4. Up to approximately 42 months
    5. Up to approximately 5.5 years
    6. Up to approximately 52 weeks within each treatment cycle
    7. Baseline, Up to approximately 5.5 years
    8. Baseline, Up to approximately 5.5 years
    9. Baseline, Up to approximately 5.5 years
    10. Baseline, Up to approximately 5.5 years
    11. Up to approximately 5.5 years
    12. Up to approximately 5.5 years
    13. Up to approximately 5.5 years
    14. Up to approximately 5.5 years
    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 Yes
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA79
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Colombia
    Malaysia
    Philippines
    Singapore
    Ukraine
    Australia
    Bulgaria
    Canada
    Croatia
    Czechia
    France
    Germany
    Greece
    Hungary
    Israel
    Italy
    Japan
    Korea, Republic of
    Poland
    Portugal
    Romania
    Russian Federation
    South Africa
    Spain
    United Kingdom
    United States
    Viet Nam
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial 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: 392
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 392
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 370
    F.4.2.2In the whole clinical trial 784
    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 Decision2021-04-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-04-15
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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