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    Summary
    EudraCT Number:2020-004544-28
    Sponsor's Protocol Code Number:MK-3475-04A
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-10-03
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2020-004544-28
    A.3Full title of the trial
    A Phase 1/2 Open-Label Rolling-Arm Umbrella Platform Study of Investigational Agents With or Without Pembrolizumab in Participants with PD-1/L1 Refractory Locally Advanced or Metastatic Urothelial Carcinoma (KEYMAKER-U04): Substudy 04A
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 1/2 Substudy of Investigation Agents in PD-1/L1 Refractory Locally Advanced (Inoperable) or Metastatic Urothelial (Bladder) Cancer
    A.3.2Name or abbreviated title of the trial where available
    Phase 1/2 Substudy of Investigational Agents in PD-1/L1 Refractory Locally Advanced or mUC
    A.4.1Sponsor's protocol code numberMK-3475-04A
    A.5.4Other Identifiers
    Name:INDNumber:152554
    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 organisation
    B.5.2Functional name of contact point
    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 No
    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 nameZilovertamab vedotin
    D.3.2Product code MK-2140
    D.3.4Pharmaceutical form Lyophilisate 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 INNZilovertamab vedotin
    D.3.9.2Current sponsor codeMK-2140
    D.3.9.4EV Substance CodeSUB216408
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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
    Locally advanced or metastatic urothelial cancer
    E.1.1.1Medical condition in easily understood language
    Locally Advanced (inoperable) or metastatic urothelial (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 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To assess the safety and tolerability of investigational treatments
    2. To evaluate objective response rate (ORR) of each investigational treatment arm as assessed by BICR per RECIST 1.1
    E.2.2Secondary objectives of the trial
    1. To evaluate the duration of response (DOR) of each investigational treatment arm as assessed by BICR per RECIST 1.1
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Has a histologically or cytologically confirmed diagnosis of locally advanced/unresectable or mUC of the renal pelvis, ureter (upper urinary tract), bladder, or urethra. Participants with nonurothelial tumors, including pure squamous cell carcinoma, pure adenocarcinoma including urachal adenocarcinomas, neuroendocrine tumors, and mesenchymal tumors, are not eligible.
    2. Has measurable disease as assessed by the site and verified by BICR according to RECIST 1.1.
    3. Has PD-1/L1 refractory locally advanced or mUC as evidenced by:
    EITHER disease progression while on treatment or after treatment with an anti-PD-1/L1 mAb for locally advanced/unresectable or mUC administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. In these participants, anti-PD-1/L1 mAb treatment is defined by meeting ALL of the following criteria:
    a. Has received at least 2 doses of an approved anti-PD-1/L1 mAb.
    b. Has demonstrated radiographic disease progression while on treatment or after treatment with an anti-PD-1/L1 mAb by investigator assessment.
    c. Disease progression has been documented radiographically by the investigator within 12 weeks from the last dose of anti-PD-1/L1 mAb.
    OR
    Has experienced disease recurrence while on treatment or after treatment with an anti-PD-1/L1 mAb for MIUC administered as monotherapy. In these participants, anti-PD-1/L1 mAb treatment is defined by meeting ALL of the following criteria:
    a. Has received at least 2 doses of an approved anti-PD-1/L1 mAb.
    b. Has demonstrated radiographic disease recurrence while on treatment with an anti-PD-1/L1 mAb or within 6 months from treatment completion by investigator assessment.
    4. Participants who received an anti-PD-1/L1 mAb for the treatment of locally advanced/unresectable or mUC must have demonstrated disease progression while on treatment or after treatment with an anti-PD-1/L1 mAb based on investigator assessment. If available, scans before treatment with an anti-PD-1/L1 or showing nadir during treatment with an anti-PD-1/L1 mAb and scans that document radiographic disease progression within 12 weeks (84 days) from the last dose of an anti-PD-1/L1 mAb should be submitted to the iCRO.
    Participants who received an anti-PD-1/L1 mAb for the treatment of MIUC must have demonstrated disease recurrence while on treatment or within 6 months from treatment completion based on investigator assessment. If available, scan before treatment with an anti-PD-1/L1 mAb and scan that documents radiographic recurrence should be submitted to the iCRO.
    5. Participants must provide an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion demonstrating UC, not previously irradiated, and adequate for biomarker evaluation. A newly obtained biopsy is strongly preferred, but not required if archival tissue is evaluable.
    6. Has an ECOG performance status of 0 to 1 (as assessed within 7 days of the first dose of study intervention).
    7. Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). If the participant received major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity (resolved to ≤ Grade 1) and/or complications from the intervention.
    8. Has adequate organ function. Specimens must be collected within 7 days before the start of study intervention.
    9. Participants are male or female, ≥18 years of age at the time of providing documented informed consent.
    10. Male participants are eligible to participate if they agree to follow the contraception requirements for the investigational treatment arm to which they are assigned.
    • 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.
    11. Female participants are eligible to participate if they agree to follow the contraception requirements for the investigational treatment arm to which they are assigned.
    12. The participant (or legally acceptable representative) has provided documented informed consent for the study.
    E.4Principal exclusion criteria
    1. Has a known additional nonurothelial malignancy that is progressing or has required active treatment within 3 years prior to study randomization/allocation.
    2. Has known active CNS metastases and/or carcinomatous meningitis.
    3. Has known hypersensitivity to active substances or any of their excipients including previous clinically significant hypersensitivity reaction to treatment with pembrolizumab or other investigational agents being evaluated within this study.
    4. Has received prior systemic anticancer therapy including investigational agents within 4 weeks before randomization/allocation.
    5. Has an active infection requiring systemic therapy.
    6. Has received prior radiotherapy within 2 weeks of first dose of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
    7. Has had major surgery (<3 weeks before first dose of study intervention).
    8. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
    9. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.
    10. Has known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies).
    11. Has known history of hepatitis B (defined as HBsAg reactive) or known hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
    12. Has a history or has current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the 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.
    13. Has had an allogeneic tissue/solid organ transplant.
    E.5 End points
    E.5.1Primary end point(s)
    1. Percentage of Participants Who Experienced At Least One Adverse Event (AE)
    2. Percentage of Participants Who Discontinued Study Treatment Due to an AE
    3. Objective Response Rate (ORR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 5 years
    2. Up to approximately 5 years
    3. Up to approximately 2 years
    E.5.2Secondary end point(s)
    1. Duration of Response (DOR)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 2 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 Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    First administration of the investigational agents in the specified population
    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 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 Yes
    E.8.1.7.1Other trial design description
    rolling-arm, adaptive design
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    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
    Australia
    Canada
    Israel
    Korea, Republic of
    Taiwan
    United States
    France
    Netherlands
    Spain
    Italy
    Denmark
    United Kingdom
    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 years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    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: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 40
    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)
    Once the study objectives are achieved or the study has ended, participants will be discontinued from this study protocol and may be enrolled in an extension study to continue assessments and treatment, if available.
    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 Decision2022-11-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-10-14
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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