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    Summary
    EudraCT Number:2015-003644-40
    Sponsor's Protocol Code Number:MK-3475-199
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-06-28
    Trial results View 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 ConcernedFrance - ANSM
    A.2EudraCT number2015-003644-40
    A.3Full title of the trial
    Phase II Trial of Pembrolizumab (MK-3475) in Subjects with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Previously Treated with Chemotherapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase II Trial of MK-3475 in Subjects with mCRPC with Prior Chemotherapy
    A.3.2Name or abbreviated title of the trial where available
    Phase II Trial of MK-3475 in Subjects with mCRPC with Prior Chemotherapy
    A.4.1Sponsor's protocol code numberMK-3475-199
    A.5.4Other Identifiers
    Name:Keynote Number:199
    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 Corp., a subsidiary of Merck & Co., Inc.
    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 Corp., a subsidiary of Merck & Co., Inc.
    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 Corp., a subsidiary of Merck & Co., Inc.
    B.5.2Functional name of contact pointGlobal Clinical Trials Operations
    B.5.3 Address:
    B.5.3.1Street AddressOne Merck Drive
    B.5.3.2Town/ cityWhitehouse Station, New Jersey
    B.5.3.3Post code08889-0100
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1267305 0929
    B.5.6E-mailstephen.keefe@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 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 namePembrolizumab
    D.3.2Product code MK-3475
    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 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 milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    Metastatic Castration-Resistant Prostate Cancer (mCRPC)
    E.1.1.1Medical condition in easily understood language
    Metastatic Prostate Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10076506
    E.1.2Term Castration-resistant prostate cancer
    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) Objective: To estimate the objective response rate (ORR) by RECIST 1.1 and duration of response (DOR) by PCWG3-modified RECIST 1.1 in subjects with measurable disease (Cohorts 1 and 2), assessed by central imaging vendor for Cohorts 1 and 2 combined and by each cohort.
    E.2.2Secondary objectives of the trial
    1) Objective: To determine the safety and tolerability of pembrolizumab for all cohorts combined (Cohorts 1, 2, and 3) and by each cohort.

    2) Objective: To estimate disease control rate (DCR) and radiographic progression-free survival (rPFS) by PCWG3-modified RECIST 1.1 assessed by central imaging vendor, and PSA response rate, time to PSA progression, and overall survival (OS) for all cohorts combined (Cohorts 1, 2 and 3) and by each cohort.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Merck will conduct Future Biomedical Research on DNA (blood and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.
    E.3Principal inclusion criteria
    1. Be willing and able to provide written informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
    2. Be ≥18 years of age on day of signing informed consent.
    3. Have histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology. Diagnosis must be stated in a pathology report and confirmed by the Investigator.
    4. Have RECIST 1.1-measurable prostate cancer on computed tomography (CT) or magnetic resonance imaging (MRI) scans (Cohorts 1 and 2) or detectable bone metastases by whole body bone scintigraphy and no RECIST 1.1-measurable tumors (Cohort 3), as determined by central review. Disease must be either metastatic or locally confined inoperable disease that cannot be treated with definitive intent.
    5. Have supplied tumor tissue from either a newly obtained biopsy or an archival specimen from a site not previously irradiated (tumors progressing in a prior site of radiation are allowed for PD-L1 characterization; other exceptions may be considered after Sponsor consultation). Adequacy of these specimens for PD-L1 biomarker analysis will be evaluated by a central laboratory prior to enrollment. Subjects in Cohorts 1 and 2 must provide a newly obtained biopsy performed after the last line of systemic therapy (required for at least the first 150 subjects screened and up to 300 subjects screened) and an archival specimen, if available. Subjects in Cohort 3 must provide an archival specimen.
    6. Have been treated with:
    a. At least one targeted endocrine therapy (defined as second generation antiandrogen therapies that include but are not limited to abiraterone acetate with prednisone, enzalutamide, and next generation targeted agents such as ARN-509).
    b. At least one regimen / line of chemotherapy that contained docetaxel.
    c. No more than two chemotherapy regimens.
    d. No more than three regimens / lines of the aforementioned treatments (chemotherapy and targeted endocrine therapy).
    7. Have documented prostate cancer progression within 6 months prior to screening, as determined by the Investigator, by means of one of the following:
    a. PSA progression as defined by a minimum of three rising PSA levels with an interval of ≥ 1 week between each assessment where the PSA value at screening should be ≥ 2 ng/mL.
    b. Radiographic disease progression in soft tissue or bone with or without PSA progression
    8. Have ongoing androgen deprivation with serum testosterone < 50 ng/dL (< 2.0 nM). If the subject is currently being treated with LHRH agonists (subjects who have not undergone an orchiectomy), this therapy must have been initiated at least 4 weeks prior to first dose of trial treatment. This treatment must be continued throughout the study.
    9. Subjects receiving bone resorptive therapy (including but limited to bisphosphonate or RANK-L inhibitor) must have been on stable doses for ≥ 4 weeks prior to first dose of trial treatment.
    10. Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
    11. Male subjects of reproductive potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
    12. Demonstrate adequate organ function as defined in protocol
    E.4Principal exclusion criteria
    1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of trial treatment.
    2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor (replacement therapy for adrenal insufficiency is permitted).
    3. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the first dose of trial treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to mAbs administered more than 4 weeks earlier.
    4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to the first dose of trial treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
    5. Has a known additional malignancy that has had progression or has required active treatment in the last 3 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
    6. 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 steroids for at least 7 days prior to the first dose of trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
    7. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
    8. Has evidence of interstitial lung disease.
    9. Has an active infection requiring systemic therapy.
    10. 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.
    11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
    12. Has previously participated in any other pembrolizumab (MK-3475) trial, or received prior therapy with an anti-PD-1, anti-PD-L1, and anti-PD-L2 (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
    13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
    14. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
    15. Has received a live vaccine within 30 days of planned start of study therapy.
    E.5 End points
    E.5.1Primary end point(s)
    1. Objective Response Rate (ORR) - assessed by central imaging vendor
    Proportion of subjects in the analysis population who have complete response (CR) or partial response (PR) where responses are determined by RECIST 1.1 assessed by central imaging vendor.

    2. Duration of Response (DOR) - assessed by central imaging vendor
    For subjects who demonstrated CR or PR, DOR is defined as the time from first documented evidence of CR or PR until disease progression assessed by central imaging vendor where progressive disease (PD) in bone-only tumors will be determined by radionuclide bone scan using PCWG3 criteria and PD for all other tumors will be determined using RECIST 1.1 or death due to any cause, whichever occurs first.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Final Analysis = Full Enrollment plus 9 months
    E.5.2Secondary end point(s)
    1. Disease Control Rate (DCR) - assessed by central imaging vendor
    a. Proportion of subjects in the analysis population who have CR or PR or stable disease (SD) for at least 6 months, by central imaging vendor where progressive disease (PD) in bone-only tumors will be determined by radionuclide bone scan using PCWG3 criteria and PD for all other tumors will be determined using RECIST 1.1

    2. PSA Response Rate
    a. Proportion of subjects in the analysis population who have PSA response defined as more than 50% decline from baseline measured twice at least 3 weeks apart.

    3. Time to PSA Progression
    a. Time to PSA progression is defined as the time from first day of study treatment to the date of PSA progression. Subjects without PSA progression will be censored at the last PSA assessment date. PSA progression is defined as the date that an increase of 25% or more and an absolute increase of 2 ng/mL or more from the nadir are documented. For subjects who had an initial PSA decline during treatment, this must be confirmed by a second value 3 or more weeks later.

    4. Radiographic progression-free survival (rPFS) - assessed by central imaging vendor
    a. Progression-free-survival (rPFS) is defined as the time from first day of study treatment to the documented disease progression by central imaging vendor where progressive disease (PD) in bone-only tumors will be determined by radionuclide bone scan using PCWG3 criteria and PD for all other tumors will be determined using RECIST 1.1 or death due to any cause, whichever occurs first.

    5. Overall Survival (OS)
    Overall survival (OS) is defined as the time from first day of study treatment to the time of death.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Interim Analysis = 36 weeks after the 100th PD-L1 negative subject has been enrolled
    Final Analysis = Full Enrollment plus 9 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 Yes
    E.6.7Pharmacodynamic Yes
    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) 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.8.2.4Number of treatment arms in the trial1
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA53
    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
    Brazil
    Canada
    Estonia
    Finland
    France
    Germany
    Hong Kong
    Israel
    Italy
    Japan
    Korea, Republic of
    Netherlands
    New Zealand
    Poland
    Spain
    Sweden
    Switzerland
    Taiwan
    Turkey
    United Kingdom
    United States
    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
    The overall trial ends when the last subject completes the last study-related phone-call or trial visit, discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the investigator).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    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: 150
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 179
    F.4.2.2In the whole clinical trial 250
    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)
    The protocol does not include any plans for treatment or care following completion of the protocol.
    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 Decision2016-06-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-03-31
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