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    Summary
    EudraCT Number:2017-002122-20
    Sponsor's Protocol Code Number:0460
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-01-22
    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 number2017-002122-20
    A.3Full title of the trial
    Randomized phase II study of immune stimulation with Pembrolizumab and radiotherapy in second line therapy of metastatic head and neck squamous cell carcinoma (IMPORTANCE)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Pembrolizumab and radiotherapy in therapy of metastatic head and neck cancer
    A.3.2Name or abbreviated title of the trial where available
    IMPORTANCE
    A.4.1Sponsor's protocol code number0460
    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 SponsorDean of the Medical Faculty of the Friedrich-Alexander University Erlangen-Nürnberg Prof. Dr. med. Markus F. Neurath
    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 supportMedical Faculty of the Friedrich-Alexander University Erlangen-Nürnberg
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversitätsklinikum Erlangen, Strahlenklinik
    B.5.2Functional name of contact pointStudiensekretariat
    B.5.3 Address:
    B.5.3.1Street AddressUniversitätsstr. 27
    B.5.3.2Town/ cityErlangen
    B.5.3.3Post code91054
    B.5.3.4CountryGermany
    B.5.4Telephone number0049091318533998
    B.5.5Fax number0049091318533996
    B.5.6E-mailstudiensekretariat.ST@uk-erlangen.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 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 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 antiobody
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Metastatic head and neck squamous cell carcinoma (LLT, 20.1)
    10060121 (LLT, 20.1)
    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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Assessment of the effect of local radiotherapy on systemic response to pembrolizumab
    E.2.2Secondary objectives of the trial
    Assessment of the effect of local radiotherapy on different response criteria to pembrolizumab
    • Response rate according to RECIST
    • changes of (not irradiated) target lesion
    • duration of response
    • progression free survival
    • overall survival

    Assessment of safety and tolerability of the combination of pembrolizumab and radiotherapy

    Assessment of changes of the immunophenotype in peripheral blood after pembrolizumab without and with radiotherapy (longitudinal analysis)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to be eligible for participation in this trial, the subject must:
    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. Metastatic HNSCC or metastatic squamous cell CUP (carcinoma of unknown primary) of the neck (at least two distinct lesions: Lesion planned for radiotherapy with ≥2ml tumor volume, or ≥3 lesions: 1 lesion planned for radiotherapy with ≥2ml tumor volume or 2 lesions planned for radiotherapy with a cumulative tumor volume ≥2ml)
    AND/ OR
    Locally recurrent HNSCC not suitable for curative local treatment within or outside the previously irradiated tissue (at least two distinct lesions: Lesion planned for radiotherapy with ≥2 ml tumor volume, or ≥3 lesions: 1 lesion planned for radiotherapy with ≥2 ml tumor volume or 2 lesions planned for radiotherapy with a cumulative tumor volume ≥2ml).

    At least in one of these lesions must be a need for radiotherapy in near future (as defined in inclusion criterion 4).

    4. Need for radiotherapy in near future as defined in the following. At least one of the following criteria must be fulfilled:
    • Primary tumor causing mild pain or swallowing problems
    • Lymph node or soft tissue metastasis with distance less than 1 cm to the skin (radiotherapy to prevent weeping tumor infiltration of the skin or fistula)
    • Bone metastases causing mild pain (without risk of fracture)
    • Lung metastases, lymph node metastases, liver metastases or adrenal gland metastases with a diameter above 1 cm in an oligometastatic situation (defined as a maximum of 5 tumor lesions)
    • Lung metastases or mediastinal lymph node metastases causing hemoptysis or permanent severe dry cough
    • Lung metastases or mediastinal lymph node metastases close to trachea or main bronchus (radiotherapy to prevent tumor infiltration and bleeding)
    • Liver metastases causing intrahepatic bile duct obstruction.

    5. Progression after first line platinum-based or any second/ third line chemotherapy
    OR
    Progression within 6 months after platinum-based radiochemotherapy of locally advanced disease
    OR
    First line treatment if PD-L1 CPS (combined positive score) ≥1.
    6. Histological confirmation of HNSCC or squamous cell CUP (carcinoma of unknown primary) of the neck.
    7. Have at least one measurable lesion according to iRECIST that receives less than 10% of the prescribed dose of the irradiated lesion(s) (not considering doses from previous radiotherapy).
    8. Have a performance status of 0-1 on the ECOG Performance Scale.
    9. Demonstrate adequate organ function as defined in table 2, all screening labs should be performed within 10 days of treatment initiation.
    10. 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. A highly sensitive pregnancy test must be used. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
    11. Female subjects of childbearing potential (Section 5.7.2) must be willing to use a highly effective contraceptive measure as defined in the Clinical Trial Facilitation Group (CTFG) guideline (“Recommendations related to contraception and pregnancy testing in clinical trials.”) For details see Section 5.7.2 of the study protocol. Highly effective contraception is required for the course of the study through 120 days after the last dose of study medication.
    12. Generative male subjects (Section 5.7.2) must agree to use a highly effective method of contraception as outlined in Section 5.7.2- 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
    The subject must be excluded from participating in the trial if the subject:
    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 need for palliative radiotherapy for symptomatic metastases. This includes the following situations:
    • New or progressive central nervous system metastases
    • Metastases causing significant pain
    • Instable bone metastases
    • Lung metastases or mediastinal lymph node metastases with active bleeding
    3. Other metastases that require prompt radiotherapy in the opinion of the investigatorHas only a tumor lesion perspectively requiring re-irradiation after prior radiotherapy less than three months ago.
    4. 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.
    5. Has a known history of active TB (Bacillus Tuberculosis).
    6. Hypersensitivity to pembrolizumab or any of its excipients.
    7. 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 AEs due to agents administered more than 4 weeks earlier.
    8. 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 AEs 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.
    9. Has known history or concurrent other malignancy. Exceptions include patients, who have been disease free for at least five years. Further exceptions are completely resected basal cell carcinoma or squamous cell carcinoma of the skin or successfully treated in situ carcinoma.
    10. 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.
    11. 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.
    12. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
    13. Has an active infection requiring systemic therapy.
    14. 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.
    15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
    16. 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.
    17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (One single administration of an anti-PD1, anti-PD-L1 or anti-PD-L2 agent as induction treatment in locally advanced disease is no exclusion criteria).
    18. Has a known history of human immunodeficiency virus (HIV) (HIV ½ antibodies).
    19. Has known active hepatitis B (e.g., HbsAg reactive) or hepatitis C (e.g., HCV RNA [qualitative] is detected).
    20. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
    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.
    21. Have a performance status of ≥2 on the ECOG Performance Scale.
    E.5 End points
    E.5.1Primary end point(s)
    Response to treatment according to iRECIST (irradiated lesion are excluded).
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of follow up
    E.5.2Secondary end point(s)
    Response rate according to RECIST
    changes of (not irradiated) target lesion
    duration of response
    progression free survival
    overall survival
    safety and tolerability of the combination of pembrolizumab and radiotherapy
    changes of the immunophenotype in peripheral blood after pembrolizumab without and with radiotherapy (longitudinal analysis)
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of follow up
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    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 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 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
    36 months
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months36
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months36
    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: 130
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 130
    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 state130
    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)
    Normal treatment of that condition
    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 Decision2018-05-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-06
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2024-10-01
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