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    Summary
    EudraCT Number:2016-001331-12
    Sponsor's Protocol Code Number:AIO-KHT-0115
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-12-23
    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 number2016-001331-12
    A.3Full title of the trial
    A randomized phase II study comparing pembrolizumab with methotrexate in elderly, frail or cisplatin-ineligible patients with head and neck cancers
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomized phase II study comparing pembrolizumab with methotrexate in elderly, frail or cisplatin-ineligible patients with head and neck cancers
    A.3.2Name or abbreviated title of the trial where available
    ELDORANDO
    A.4.1Sponsor's protocol code numberAIO-KHT-0115
    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 SponsorAIO-Studien-gGmbH
    B.1.3.4CountryGermany
    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 supportMSD SHARP & DOHME GMBH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAIO-Studien-gGmbH
    B.5.2Functional name of contact pointDr. Aysun Karatas
    B.5.3 Address:
    B.5.3.1Street AddressKuno-Fischer-Straße 8
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code14057
    B.5.3.4CountryGermany
    B.5.4Telephone number004930814534431
    B.5.5Fax number004930322932926
    B.5.6E-mailinfo@aio-studien-ggmbh.de
    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®
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme Limited
    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 Concentrate 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.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.2Country 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.3.1Product nameMethotrextate
    D.3.4Pharmaceutical form Concentrate for solution for injection/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 INNmethotrexate
    D.3.9.3Other descriptive nameMETHOTREXATE
    D.3.9.4EV Substance CodeSUB08856MIG
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    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
    Squamous carcinoma of the head and neck (SCCHN)
    E.1.1.1Medical condition in easily understood language
    head and neck cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10071540
    E.1.2Term Head and neck cancer metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10067821
    E.1.2Term Head and neck 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
    To assess antitumor activity of pembrolizumab in SCCHN
    E.2.2Secondary objectives of the trial
    • To assess quality of life (QoL), predictive biomarkers, and efficacy of pembrolizumab in SCCHN.
    • Safety and tolerability of MTX and pembrolizumab in SCCHN
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Cooperation and willingness to complete all aspects of the study including participation in the translational research
    2. Signed and dated written informed consent must be given prior to study inclusion
    3. Histological or cytological confirmed recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) not amenable to local therapies
    4. Progressive disease at study entry
    5. At least 1 measurable lesion according to RECIST 1.1
    6. No previous systemic treatment for metastatic disease
    7. Not eligible for cisplatin-based chemotherapy, defined as:
    - ECOG 2
    and/or
    - calculated CrCl <60 mL/min (measured by MDRD)
    8. Age ≥ 18 years
    9. ECOG performance status 0 - 2
    10. Brain metastases require completion of local therapy with discontinuation of steroids prior to start of treatment
    11. If of childbearing potential, willingness to use highly effective contraceptive method for the duration of the study and 120 days after last dose, such as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), vasectomized partner, bilateral tubal occlusion, sexual abstinence. If an oral contraception is used, a barrier method of contraception (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge) has to be applied additionally.
    12. Adequate bone marrow function, liver and renal function:
    a. Absolute neutrophil count ≥ 1.5 x 109/L
    b. Thrombocytes ≥ 100 x 109/L
    c. Hemoglobin ≥ 9 g/dL
    d. INR ≤ 1.5 and PPT ≤ 1.5 x lower limit during the last 7 days before therapy
    e. Bilirubin < 1.5 x lower limit and
    f. AST (GOT) and ALT (GPT) < 3 x lower limit (5 x lower limit in case of liver metastases)
    13. Tumor block or 20 slides must be available at study inclusion for central pathology testing
    E.4Principal exclusion criteria
    1. Live expectancy less than 3 months
    2. Nasopharynx carcinoma
    3. Anticancer treatment during the last 30 days prior to start of treatment, including systemic therapy, radiotherapy or major surgery
    4. Participation in a clinical trial within the last 30 days prior to study treatment
    5. History of allogeneic tissue/solid organ transplant
    6. History of pneumonitis that has required oral or i.v. steroids
    7. Evidence of interstitial lung disease
    8. Minor surgery ≤ 24 hours prior first dose of study treatment
    9. Symptomatic acute cardiovascular or cerebrovascular disease
    10. Known active HBV, HCV or HIV infection
    11. Has any other active infection requiring systemic therapy.
    12. Patients with active tuberculosis
    13. Prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-PD-L1, anti-programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand, a member of the Tumor Necrosis Factor Receptor [TNFR] family), or anti-cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
    14. A diagnosis of immunodeficiency or patient is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
    15. Patient has had a prior monoclonal antibody, which does significantly interfere with the immune system or which does have a systemic therapeutic effect on the tumor within 4 weeks prior to randomization.
    16. Patient has not recovered (i.e., ≤ Grade 1 or at baseline) from any toxicities due to agents administered more than 4 weeks earlier. [Subjects with ≤ Grade 2 neuropathy or alopecia are an exception to this criterion and may qualify for the study.]
    17. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s syndrome will not be excluded from the study.
    18. Has received a live vaccine within 30 days prior to the first dose of trial treatment.
    19. Has known hypersensitivity to methotrexate or pembrolizumab or any constituent of the products.
    20. Other active malignancy requiring treatment
    21. Lactating or pregnant women, women of child-bearing potential who do not agree to the usage of highly effective contraception methods (allowed methods of contraception, meaning methods with a rate of failure of less than 1% per year combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), vasectomized partner, bilateral tubal occlusion, sexual abstinence. If an oral contraception is used, a barrier method of contraception (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge) has to be applied additionally. Women of childbearing potential must have a negative pregnancy test (serum β-hCG) at Screening.
    22. Any psychiatric illness that would affect the patient’s ability to understand the demands of the clinical trial
    23. Patient has already been recruited in this trial (does not include screening failures)
    24. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
    25. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].

    E.5 End points
    E.5.1Primary end point(s)
    overall survival (OS) rate at 1 year
    E.5.1.1Timepoint(s) of evaluation of this end point
    one year after inclusion of the subject into trial
    E.5.2Secondary end point(s)
    Key secondary endpoints:
    • Time to failure of strategy (TTFS) at 1 year, defined as death, progressive disease (PD), treatment discontinuation (due to toxicity) or deterioration of Instrumental Activities of Daily Living (IADL score) by 2 points
    • objective response rate (ORR) according to modified RECIST 1.1

    other secondary endpoints:
    • progression free survival (PFS)
    • overall survival (OS)
    • ORR according to RECIST 1.1
    • duration of response
    • duration of treatment beyond progression
    • treatment discontinuation rate
    • safety and tolerability

    Exploratory:
    • predictive value of PD-L1 expression
    • prognostic value of tumor shrinkage
    • QoL response, defined as improvement of 5-10 points in QLQC30 and HN35
    E.5.2.1Timepoint(s) of evaluation of this end point
    TTFS: one year after inclusion of a patient into study
    ORR: after last visit of a patient
    PFS: after progression/death/loss-to follow-up
    OS: after death/ cut off

    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 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 Yes
    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 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) Yes
    E.8.2.2Placebo No
    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 concerned10
    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
    LVLS
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    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 state100
    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)
    After completion of study at the End-of-Treatment-Visit, patients will generally be treated at the discretion of the investigator according to medical routine.
    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 Decision2017-04-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-04-28
    P. End of Trial
    P.End of Trial StatusOngoing
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