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    Summary
    EudraCT Number:2018-001327-39
    Sponsor's Protocol Code Number:C/37/2017
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-09-19
    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 number2018-001327-39
    A.3Full title of the trial
    A Phase II, Two-Stage, Trial of Pembrolizumab in Cancer of unknown primary - CUPem
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase II, Two-Stage, Trial of Pembrolizumab in Cancer of unknown primary
    A.3.2Name or abbreviated title of the trial where available
    CUPem
    A.4.1Sponsor's protocol code numberC/37/2017
    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 SponsorImperial College London
    B.1.3.4Country
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationImperial College London
    B.5.2Functional name of contact pointClinical Trial Manager
    B.5.3 Address:
    B.5.3.1Street AddressHammersmith hospital,Du Cane road
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeW12 0HS
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44 (0) 203 311 5203
    B.5.5Fax number+44 (0)203 311 7443
    B.5.6E-mailp.badman@imperial.ac.uk
    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.2.1.1.1Trade name Keytruda
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V
    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 nameKeytruda
    D.3.2Product code MK3475
    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 codeMK3475
    D.3.9.3Other descriptive nameAnti- PD-1 monoclonal antibody
    D.3.9.4EV Substance CodeAS2
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    CUP, Cancer of Unknown Primary
    E.1.1.1Medical condition in easily understood language
    Cancer which place of tumour origin is not clear
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    What is the overall survival(OS) & Progression Free Survival (PFS) for the 1st cohort

    What is the overall response rates (OS) & Progression Free Survival (PFS)in a first-line setting for the 2nd cohort
    E.2.2Secondary objectives of the trial
    • Incidence of adverse events up to 8 weeks after the last dose of Pembrolizumab in the second line setting

    • Incidence of adverse events up to 8 weeks after the last dose of Pembrolizumab in Performance Status 2 (PS2) patients in any setting
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Be willing and able to provide written informed consent/assent for the trial.
    2. Be 18 years of age on day of signing informed consent.
    3. Have measurable disease based on RECIST 1.1.
    4. Be willing to provide consent for archival tumour (in the form of formalin fixed paraffin embedded (FFPE) block) or fresh tumour material (if judged technically feasible by radiologist is mandatory for diagnosis and biomarker analysis.
    5. Have a performance status of 0 to 2 on the ECOG Performance Scale.
    6. Cohort 1 - have had at least one prior line / regimen of chemotherapy appropriate for CUP, have not had a RECIST response to first-line chemotherapy, or are progressing after an initial response, or are treatment intolerant to first-line chemotherapy, due to unacceptable toxicity.
    Cohort 2 - be chemo-naïve for CUP (Previous chemotherapy for other cancers is allowed)
    7. Adequate organ and bone marrow function
    - Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    - Platelets ≥ 100 x 109/L
    - Haemoglobin ≥ 9 g/dL (≥90 g/L) without transfusion or EPO dependency
    - Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN) or Creatinine clearance ≥ 60 mL/min for patients with creatinine levels > 1.5 x ULN
    - Serum total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN for patients with total bilirubin levels >1.5 ULN
    - Aspartate aminotransferase [AST] ≤ 2.5 x ULN (< 5 x ULN if liver metastases are present)
    - Alanine aminotransferase [ALT]) ≤ 2.5 x ULN (< 5 x ULN if liver metastases are present)
    - Albumin ≥ 2.5g/dL
    - International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN
    - Activated Partial Thromboplastin Time (APTT) ≤1.5 X ULN (unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants)

    8. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
    9. Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section 6.9.2 – Contraception, for the course of the study through 120 days after the last dose of study medication.
    Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
    10. Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in Section 6.9.2 - Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.
    Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
    E.4Principal exclusion criteria
    Patients who meet any of the following exclusion criteria will not be eligible for this study:
    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 investigational 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.
    3. Has a known history of active TB (Bacillus Tuberculosis)
    4. Hypersensitivity to pembrolizumab or any of its excipients.
    5. 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 adverse events due to agents administered more than 4 weeks earlier.
    6. 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 adverse events due to a previously administered agent.
    - Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
    - Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
    7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
    8. 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 trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
    9. Has 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, etc.) is not considered a form of systemic treatment.
    10. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
    11. Has an active infection requiring systemic therapy.
    12. 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.
    13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
    14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
    15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
    16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
    17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
    18. Has received a live vaccine within 30 days of planned start of study therapy.
    Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed
    E.5 End points
    E.5.1Primary end point(s)
    Primary Objectives and Hypothesis

    Objectives: In the context of the two sequential cohorts:-
    • Overall response rates by immune-related (irRECIST) and RECIST criteria in a second-line setting
    o Overall Survival (OS) & Progression Free Survival (PFS)

    • Overall response rates by immune-related (irRECIST) and RECIST criteria in a first-line setting
    o OS & PFS


    Hypothesis:
    Pembrolizumab has Efficacy in CUP
    • as a first-line treatment in terms of Response which translates into improved PFS and OS

    • as a second-line treatment in terms Response which translates into improved PFS and OS

    • and treatment leads to rapid improvement in quality of life (QOL) in high metastatic disease burden (in any line of therapy)
    E.5.2Secondary end point(s)
    Secondary Objectives and Hypothesises
    Objective:
    • Incidence of adverse events up to 8 weeks after the last dose of Pembrolizumab in the second line setting

    • Incidence of adverse events up to 8 weeks after the last dose of Pembrolizumab in Performance Status 2 (PS2) patients in any setting

    Hypothesis:
    • Pembrolizumab is much better tolerated than conventional chemotherapy in CUP patients and PS2 patients may also benefit.


    Exploratory Objective:

    • Identification of genomic biomarkers predictive of immune response to Pembrolizumab

    Hypotheses:
    • CUP patients have identifiable biomarkers predictive for Pembrolizumab efficacy

    • CUP patients have high mutational loads and this correlates with increased efficacy with Pembrolizumab
    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 No
    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.8.3 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 concerned3
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 end of the trial is defined as the last data capture for the last patient on study; this will be 6 months after the last patient stops study treatment or up to 12 months after the last patient is entered whichever is sooner
    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 months11
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days30
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 37
    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 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 state77
    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)
    There is no guarantee that the study drug will be available to subjects at the end of the study. The study doctor will decide on the best treatment for the subject at the end of the study
    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 Decision2018-10-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-05
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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