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    Summary
    EudraCT Number:2015-002067-41
    Sponsor's Protocol Code Number:3475-158
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-10-30
    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 ConcernedUK - MHRA
    A.2EudraCT number2015-002067-41
    A.3Full title of the trial
    A Clinical Trial of Pembrolizumab (MK-3475) Evaluating Predictive Biomarkers in Subjects with Advanced Solid Tumors (KEYNOTE 158)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    PhII Trial of Pembrolizumab in Advanced Solid Tumors
    A.3.2Name or abbreviated title of the trial where available
    KEYNOTE-158
    A.4.1Sponsor's protocol code number3475-158
    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
    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 1374853-91-4
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPembrolizumab
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.3Other descriptive nameAnti-PD-1 monoclonal antibody
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    A-Anal Squamous Cell Carcinoma (CA)
    B-Biliary Adenocarcinoma (Gallbladder&Biliary Tree but excluding Ampulla of Vater Cancers)
    C-Neuroendocrine Tumors (well&moderately-differentiated,including Carcinoid)
    D-Endometrial CA
    E-Cervical Squamous Cell CA
    F-Vulvar Squamous Cell CA
    G-Small Cell Lung CA
    H-Malignant Pleural Mesothelioma
    I-Thyroid CA (Papillary or Follicular Subtype)
    J-Salivary Gland CA OR
    K-Other advanced solid tumor (except CRC) which is MSI-H from a newly obtained tumor biopsy
    E.1.1.1Medical condition in easily understood language
    Advanced Solid Tumors
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10065143
    E.1.2Term Malignant solid tumour
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Objective 1: To evaluate the response to Pembrolizumab, based on imaging assessments (RECIST 1.1) reviewed by independent central radiologic review in participants with any one of multiple types of advanced (metastatic and/or unresectable) solid tumours (Groups A-J) for which prior standard of care (SOC) treatments have failed. The categories of tumours being investigated as part of the principal research question are list below:
    A. Anal Carcinoma,
    B. Biliary Tract Carcinoma,
    C. Neuroendocrine Tumours (well- and moderately-differentiated, including Carcinoid),
    D. Endometrial Carcinoma,
    E. Cervical Carcinoma,
    F. Vulvar Carcinoma,
    G. Small Cell Lung Carcinoma,
    H. Mesothelioma,
    I. Thyroid Carcinoma,
    J. Salivary Gland Carcinoma,

    Objective 2: To evaluate the response to Pembrolizumab, based on imaging assessments (RECIST 1.1) reviewed by independent central radiologic review in participants with any one of multiple types of advanced (metastatic and/or unresectable) solid tumours (Groups A
    E.2.2Secondary objectives of the trial
    The following secondary objectives will be evaluated across the ten specified tumour types (Groups A-J):

    -To evaluate how long the response to treatment lasts (duration of response), based on imaging assessments in participants who receive Pembrolizumab and the relationship between durations of response and physiology/genetic substances in the tumour.

    -To evaluate the length of time during or after treatment that the disease does not worsen (progression free survival), based on imaging assessments, in participants receiving Pembrolizumab and the relationship between the length of this time and physiology/genetic substances in the tumour.

    - To evaluate the overall survival in participants receiving Pembrolizumab and the relationship between overall survival and physiology/genetic substances in the tumour.

    The following secondary objectives will be evaluated across all tumour types (Groups A-K):

    -To determine the safety and tolerability of Pembrolizumab

    Refer to protocol for comple
    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) 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/assent for the trial. The subject may also provide consent/assent 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 the day of signing informed consent.
    3. Have a histologically or cytologically-documented, advanced (metastatic and/or unresectable) solid tumor that is incurable and for which prior standard first-line treatment has failed. Patients must have progressed on or be intolerant to therapies that are known to provide clinical benefit. There is no limit to the number of prior treatment regimens.
    4. Have one of the following advanced (unresectable and/or metastatic)
    tumor types:
    (A) Anal Squamous Cell Carcinoma,
    (B) Biliary Adenocarcinoma (gallbladder or biliary tree (intrahepatic or
    extrahepatic cholangiocarcinoma) except Ampulla of Vater Cancers,
    (C) Neuroendocrine Tumors (well- and moderately-differentiated), of the lung, appendix, small intestine, colon, rectum, or pancreas,
    (D) Endometrial Carcinoma (sarcomas and mesenchymal tumors are excluded),
    (E) Cervical Squamous Cell Carcinoma,
    (F) Vulvar Squamous Cell Carcinoma,
    (G) Small Cell Lung Carcinoma,
    (H) Mesothelioma (Malignant Pleural Mesothelioma),
    (I) Thyroid Carcinoma (Papillary or Follicular Subtypes),
    (J) Salivary Gland Carcinoma (sarcomas and mesenchymal tumors are excluded)
    OR
    (K) Any advanced solid tumor (except CRC), which is MSI-H.

    5. Have submitted an evaluable tissue sample for biomarker analysis from a tumor lesion not previously irradiated (exceptions may be considered after consultation with and approval by the Sponsor) (See Procedure Manual for detailed instructions). The tumor tissue submitted for analysis must be from a single tumor tissue specimen and of sufficient quantity and quality to allow assessment of ALL required primary biomarkers.
    6. If enrollment in Groups A-J has moved to biomarker enrichment, have a tumor that is positive for one or more of the pre-specified primary biomarker(s), as assessed by the central laboratory. These enrichment biomarkers may be PD-L1 expression by IHC (at a percentage to beprespecified), a positive tumor RNA GEP score (at a prespecified cut-off), and/or tumor MSI-H.
    7. Have radiologically measurable disease based on RECIST 1.1. Independent central radiologic review must confirm the presence of radiologically measureable disease based on RECIST 1.1 for the subject to be eligible to participate in the trial (see Site Imaging Manual for detailed instructions). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
    8. Have a performance status of 0 or 1 on the ECOG Performance Scale. This performance status must be confirmed within 3 days prior to the first dose of pembrolizumab or the subject must be excluded.
    9. Life expectancy of at least 3 months.
    10. Demonstrate adequate organ function as described in the protocol
    11. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of trial medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
    12. Female subjects of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of trial medication.
    13. Male subjects of childbearing potential must agree to use an adequate method of contraception, for the course of the study through 120 days after the last dose of trial medication.
    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 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.
    3. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) or treatment with drugs (e.g. neomercazol, carbamazole, etc.) that function to decrease the generation of thyroid hormone by a hyperfunctioning thyroid gland (e.g in Graves' disease) is not considered a form of systemic treatment of an autoimmune disease.
    4. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from an AE due to mAbs administered more than 4 weeks earlier.
    5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from an AE due to a previously administered agent.
    6. Has a known additional malignancy within 2 years prior to enrollment with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or curatively resected in situ cancers.
    7. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided these brain metastases are stable(without evidence of progression by imaging over a period of at least 4 weeks and any neurologic symptoms have returned to baseline), they have no evidence of new or enlarging brain metastases (confirmed by imaging within 28 days of the first dose of trial treatment), and they are not using steroids for at least 7 days prior to trial treatment. This
    exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
    8. Has known glioblastoma multiforme of the brainstem.
    9. Has a history of (non-infectious) pneumonitis that required steroids or
    current pneumonitis.
    10. Has an active infection requiring systemic therapy.
    11. 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.
    12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
    13. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
    14. Has previously participated in any other pembrolizumab (MK-3475) trial, or received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or any other immune-modulating mAb (including ipilimumab and any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
    15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). No HIV testing is required unless mandated by local health authority.
    16. Has known active Hepatitis B (i.e. HBsAg positive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
    17. Has received a live vaccine within 30 days of planned start of study therapy.
    18. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
    19. Has a known history of active tuberculosis (TB, Bacillus tuberculosis).
    E.5 End points
    E.5.1Primary end point(s)
    The objective response rate (number of participants who experience a complete or partial response) based on imaging assessments (RECIST 1.1)
    E.5.1.1Timepoint(s) of evaluation of this end point
    The trial incorporates an adaptive design in which multiple interim analyses may be performed. Results will be reviewed by the study team. The cutoffs for the three primary biomarker assays will be selected and specified before the first interim analysis. Details regarding the timing and conduct of the initial interim analysis will be further clarified in the sSAP. The planned sample size may be modified based on the interim results. The timing of additional interim analyses, the final analysis as well as the analysis plan will be documented in the sSAP. The sSAP will also be updated as the trial evolves.
    The primary endpoint of ORR will be used for all interim analyses with or without a confirmatory assessment; however, a confirmatory assessment is required for the final analysis
    E.5.2Secondary end point(s)
    Safety and Tolerability
    Duration of response (DOR)
    Progression-free survival (PFS)
    Overall survival (OS)
    (PK) for the 200 mg iv Q3W fixed dosing regimen
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary efficacy endpoints will be summarized at the time that the primary analysis is conducted; however, these secondary endpoints are not likely to be mature at that time.
    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 No
    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) 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 No
    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 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 EEA22
    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
    Denmark
    France
    Germany
    Italy
    Netherlands
    Norway
    Spain
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months6
    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.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 675
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 675
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 500
    F.4.2.2In the whole clinical trial 1350
    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)
    At the end of treatment, each participant will be followed for 30 days to monitor for AEs and events of clinical interest; participants will be monitored for serious AEs for 90 days after the end of treatment. Participants who discontinue for reasons other than PD will have follow-up for disease status until experiencing PD, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. All participants will be followed by telephone for overall survival.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-12-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-05
    P. End of Trial
    P.End of Trial StatusOngoing
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