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    Summary
    EudraCT Number:2018-003808-39
    Sponsor's Protocol Code Number:MK-3475-866
    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:2019-04-01
    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 number2018-003808-39
    A.3Full title of the trial
    A Phase 3, Randomized Double Blind Study to Evaluate Peri-operative Pembrolizumab (MK-3475) + Neoadjuvant Chemotherapy versus Perioperative Placebo + Neoadjuvant Chemotherapy in Cisplatin-Eligible Participants with Muscle-invasive Bladder Cancer (KEYNOTE-866)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 Trial of Perioperative Pembrolizumab + Neoadjuvant Chemotherapy vs. Perioperative Placebo + Neoadjuvant Chemotherapy for Cis-Eligible MIBC
    A.4.1Sponsor's protocol code numberMK-3475-866
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03924856
    A.5.4Other Identifiers
    Name:INDNumber:122753
    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 pointGlobal Clinical Trial Operations
    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
    B.5.4Telephone number+12673056303
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Muscle Invasive Bladder Cancer
    E.1.1.1Medical condition in easily understood language
    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 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) between Arm A (perioperative pembrolizumab + neoadjuvant chemotherapy + Radical Cystectomy [RC] + Pelvic Lymph Node Dissection [PLND]) and Arm B (perioperative placebo + neoadjuvant chemotherapy + RC + PLND).
    E.2.2Secondary objectives of the trial
    1. To compare pathologic complete response (pCR) rates obtained in Arm A (preoperative pembrolizumab + neoadjuvant chemotherapy + RC + PLND) and Arm B (preoperative placebo + neoadjuvant chemotherapy + RC + PLND).
    2. To compare the overall survival (OS) between Arm A (perioperative pembrolizumab + neoadjuvant chemotherapy + RC + PLND) and Arm B (perioperative placebo + neoadjuvant chemotherapy + RC + PLND).
    3. To assess disease-free survival (DFS) in participants from Arm A (perioperative pembrolizumab + neoadjuvant chemotherapy + RC + PLND) and Arm B (perioperative placebo + neoadjuvant chemotherapy + RC + PLND).
    4. To compare the rate of pathologic downstaging (pDS) between Arm A and Arm B.
    5. To evaluate the safety and tolerability of pembrolizumab + chemotherapy + RC + PLND.
    6. To evaluate changes in patient reported outcomes from baseline and time to deterioration (TTD) using the FACT-BI-Cys instrument and EQ-5D-5L.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To be eligible for inclusion in this study, the participant must:
    1. Have a histologically confirmed diagnosis of UC/MIBC (clinical stage T2 T4aN0M0 or T1 T4aN1M0) with predominant (≥50%) urothelial histology and PD-L1 expression (CPS ≥10 or CPS <10, for PD-L1 CPS
    score not evaluable refer to inclusion criterion #4) to be confirmed by BICR (central pathology and/or imaging):
    -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 neuroendocrine histology are not eligible.
    -UCs not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible.
    2. Have clinically non-metastatic bladder cancer (N≤1 M0) determined by imaging (CT or MRI of the chest/abdomen/pelvis), confirmed by BICR.
    3. Be deemed eligible for RC + PLND by a urologist and/or oncologist and agree to undergo curative-intent standard RC + PLND (including prostatectomy if applicable) as per AUA/ASTRO/ASCO/SUO guidelines.
    4. Have a TUR of a bladder tumor (obtained as early as 60days [+14days] prior to enrollment [providing documented informed consent]) 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. Have ECOG performance status of 0 or 1.
    6. Have adequate organ function (all screening labs should be performed within 14 days prior to randomization).
    7. Participant is male or female and at least 18 years of age inclusive, at the time of providing documented informed consent.
    8. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of study intervention.
    -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) as detailed below:
    *Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
    9. Female Participant
    -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 180 days 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 investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
    -A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours for urine or within 72 hours for serum) 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.
    -The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
    10. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the study without participating in FBR.
    E.4Principal exclusion criteria
    The participant must be excluded from the study if the participant:
    1. Has a known additional malignancy that is progressing or has required active anticancer treatment ≤3 years of study randomization.
    2. Has received any prior systemic treatment, chemoradiation, and/or radiation therapy for MIBC or NMIBC.
    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
    - ECOG Performance Status ≥2
    - CTCAE v.4 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)
    - CTCAE v.4 Grade ≥2 peripheral neuropathy
    - New York Heart Association (NYHA) Class III or greater heart failure
    5. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
    6. Has received prior systemic anticancer therapy including investigational agents within 3 years before randomization.
    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 before 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 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 autoimmune disease. Physiologic replacement (10 mg/day prednisone equivalent) doses of corticosteroids are permitted for participants with adrenal insufficiency.
    12. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
    13. Has severe hypersensitivity (≥Grade 3) to cisplatin and/or gemcitabine and any of their excipients.
    14. Has an active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy is not considered a form of systemic treatment and is allowed.
    15. Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
    16. Has an active infection requiring systemic therapy (IV/oral). Participant may be rescreened once after resolution of the infection.
    17. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
    18. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active HCV (defined as detectable HCV RNA via qualitative nucleic acid testing) infection.
    19. 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.
    20. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
    21. 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 60 months
    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)
    6. Number of Participants Who Discontinued Study Treatment Due to an AE
    7. Number of Participants Who Experienced Perioperative Complications
    8. Change in Patient-Reported Outcomes from Baseline in the Total Score of Functional Assessment of Cancer Therapy – General (FACT-G)
    9. Change in Patient-Reported Outcomes from Baseline in the Total Score of FACT-Bladder- (FACT-BI-Cys)
    10. Change in Patient-Reported Outcomes from Baseline in FACT-BI-Cys-Trial Outcome Index (TOI)
    11. Change in Patient-Reported Outcomes from Baseline in European Quality of Life Questionnaire (EQ-5D-5L) Visual Analog Score (VAS)
    12. Time to Deterioration (TTD) in the Total Score of FACT-G
    13. TTD in EQ-5D-5L VAS
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 60 months
    2. Up to approximately 72 months
    3. From approximately 20 Weeks to up to approximately 72 months
    4. Up to approximately 60 months
    5. Up to approximately 72 months
    6. Up to approximately 12 months
    7. Up to approximately 12 months
    8. Up to approximately 72 months
    9. Up to approximately 72 months
    10. Up to approximately 72 months
    11. Up to approximately 72 months
    12. Up to approximately 72 months
    13. Up to approximately 72 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 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 Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    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 EEA76
    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
    Ukraine
    Australia
    Canada
    Israel
    Japan
    Korea, Republic of
    Mexico
    Russian Federation
    Thailand
    Turkey
    United Kingdom
    United States
    Belgium
    Denmark
    France
    Germany
    Hungary
    Ireland
    Italy
    Poland
    Spain
    Sweden
    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
    The overall study ends when the last participant completes the last study-related contact, withdraws consent, or is lost to follow-up. For purposes of analysis and reporting, the overall study ends when the Sponsor receives the last laboratory result or at the time of final contact with the last participant, whichever comes last.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    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: 450
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 450
    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 state45
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 450
    F.4.2.2In the whole clinical trial 900
    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 Decision2019-06-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-13
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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