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    Summary
    EudraCT Number:2020-001074-30
    Sponsor's Protocol Code Number:N20MAT
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-05-12
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2020-001074-30
    A.3Full title of the trial
    Neo-adjuvant nivolumab or nivolumab with ipilimumab in advanced cutaneous squamous cell carcinoma patients prior to standard of care surgery; the MATISSE trial
    Neo-adjuvante therapie met nivolumab of nivolumab in combinatie met ipilimumab bij patiënten met cutaan plaveiselcelcarcinoom in een gevorderd stadium voorafgaand aan standaardbehandeling van een operatie met eventuele na-bestraling; de MATISSE trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Neo-adjuvant immunotherpy in patients with advanced CSCC prior to standard of care
    (MATISSE)
    Neo-adjuvante immunotherapie bij patiënten met CPCC in een gevorderd stadium voorafgaand aan standaardbehandeling (MATISSE)
    A.4.1Sponsor's protocol code numberN20MAT
    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 SponsorNetherlands cancer institute (NKI) Antioni van Leeuwenhoek (AvL)
    B.1.3.4CountryNetherlands
    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 supportBristol-Myers Squibb
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAntoni van Leeuwenhoek Hospital
    B.5.2Functional name of contact pointThomas Boere
    B.5.3 Address:
    B.5.3.1Street AddressPlesmanlaan 121
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1066CX
    B.5.3.4CountryNetherlands
    B.5.6E-mailth.boere@nki.nl
    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 nameNivolumab
    D.3.2Product code BMS-936558-01
    D.3.4Pharmaceutical form 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 INNNivolumab
    D.3.9.3Other descriptive nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) No
    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 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 nameIpilimumab
    D.3.2Product code BMS-734016-01
    D.3.4Pharmaceutical form 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 INNIPILIMUMAB
    D.3.9.3Other descriptive nameIpilimumab
    D.3.9.4EV Substance CodeSUB29397
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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) No
    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
    Primary or recurrent stage III-IVA cutaneous squamous cell carcinoma of all body sites OR tage I-II cutaneous squamous cell carcinoma, only in the case of:
    • Presence of multifocal disease for which extensive and/or mutilating surgery is necessary (e.g. near-total scalp resection).
    • Situated in an anatomical localization that necessitates extensive and/or mutilating surgery (e.g. orbital exenteration).
    Primair of recidiverend stadium III-IVa cutaan plaveiselcelcarcinoom op het gehele lichaam
    OF
    stadium I-II cutaan plaveiselcelcarcinoom in het geval van:
    - aanwezigheid van multifocale ziekte waarvoor uitgebreide en of mutilerende chirurgie nodig is (bijvoorbeeld (bijna) gehele scalp resectie).
    - aanwezigheid in een anatomische lokalisatie waarbij uitgebreide of mutilerende chirurgie nodig is (orbita exenteratie)
    E.1.1.1Medical condition in easily understood language
    Squamous cell carcinoma of the skin
    Plaveiselcelcarcinoom van de huid
    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 10041834
    E.1.2Term Squamous cell carcinoma of skin
    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 21.0
    E.1.2Level PT
    E.1.2Classification code 10041823
    E.1.2Term Squamous cell carcinoma
    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 10077314
    E.1.2Term Skin squamous cell carcinoma 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 10081136
    E.1.2Term Skin squamous cell carcinoma recurrent
    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 determine the histopathological response rate to neo-adjuvant nivolumab and nivolumab plus ipilimumab at time of SOC (surgery ± RT).
    E.2.2Secondary objectives of the trial
    Secondary objectives:
    - To establish whether short-term neo-adjuvant nivolumab w/wo ipilimumab is safe prior to standard of care surgery.
    - To compare recurrence free survival (RFS) at 2 years follow-up (FU) for patients responsive and non-responsive to neo-adjuvant ICI;
    - To compare overall survival (OS) at 2 years FU for patients responsive and non-responsive to neo-adjuvant ICI
    - To assess rate and type of AE (NCI CTCAE v.5.0) up to 2 years FU after SOC
    - To assess the response of potentially additional actinic keratosis (AK) to ICI at day 14, day 28 (at time of surgery) and during FU
    - To evaluate health related quality of life

    Exploratory objectives
    - To assess the (ex vivo) kinetics* of local and systemic immunological responses upon nivolumab or nivolumab plus ipilimumab and their correlation with clinical outcome.
    - To identify parameters to be exploited for future immunotherapeutic regimens

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age 18 years or older.
    2. Patient is able to understand and comply with the protocol requirements and has signed the informed consent form.
    3. World Health Organization (WHO) Performance Status 0 or 1 (Appendix B).
    4. Patients with histologically or cytologically confirmed, primary or recurrent stage III-IVA CSCC of all body sites.
    • Primary tumor sites Head and Neck:
    o Vermillion border lip: C00.0, C00.1, C00.2
    o Skin of lip NOS: C44.0
    o External ear: C44.2
    o Skin face unspecified (ao: external lip and nasal vestibulum): C44.3
    o Skin scalp and neck: C44.4
    o Overlapping lesion of skin: C44.8
    o Primary site eyelid: C44.1
    • CSCC outside head and neck area, but not vulva, anus and penis
    OR
    Patients with histologically or cytologically proven stage I-II CSCC, only in the case of:
    • Presence of multifocal disease for which extensive and/or mutilating surgery is necessary (e.g. near-total scalp resection).
    • Situated in an anatomical localization that necessitates extensive and/or mutilating surgery (e.g. orbital exenteration).
    5. Eligible for standard-of-care, curatively intended surgery with or without adjuvant radiotherapy.
    6. Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109 /L, Neutrophils ≥1.5x109 /L, Platelets ≥100 x109 /L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN (except subjects with Gilbert Syndrome, who are eligible when total bilirubin < 3.0 mg/dL).
    7. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. They should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of the investigational drug.
    8. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25IU/L or equivalent units of HCG) prior to the start of nivolumab or nivolumab + ipilimumab.
    9. Men who are sexually active with WOCBP must use a contraceptive method with a failure rate of less than 1% per year and will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Surgically sterile or azoospermic men do not require aforementioned contraception.
    E.4Principal exclusion criteria
    4.3 Exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation in this study:
    1. Distantly metastasized (stadium IVb) CSCC.
    2. SCC localized in a mucosal surface (i.e. anus, vulva, penis or mucosal portion of lip).
    3. Patients for whom SOC consists of definitive (brachy)radiotherapy.
    4. Primary or recurrent CSCC appearing in an area that has been previously irradiated.
    5. Prior anti-CTLA4 or anti-PD1 immunotherapy.
    6. Active human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
    7. A positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C antibody (HCV Ab).
    8. Subjects with any active autoimmune disease or a documented history of autoimmune disease, except for:
    • Subjects with vitiligo
    • Resolved childhood asthma/atopy
    • Residual hypothyroidism due to an autoimmune condition requiring only hormone replacement
    • Psoriasis not requiring systemic treatment
    • Any condition not expected to recur in the absence of an external trigger.
    9. Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or AE.
    10. A concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids;
    11. Pregnant or nursing.
    12. A history of allergy to study drug components and/or a history of severe hypersensitivity to any monoclonal antibody.
    13. Use of other investigational drugs 30 days before study drug administration and 5 half times before study inclusion.
    14. Use of prohibited medication at start of study period.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be histopathological tumor response after neo-adjuvant ICI, defined as the proportion of viable tumor cells left in the resected specimen. Responses will be divided into histopathological complete response (pCR, no viable tumor cells), histopathological near complete response (near-pCR, ≤10% viable tumor cells) and histopathological partial response (pPR, ≤50% viable tumor cells). Pathological responses will be compared to responses assessed via clinical examination and imaging studies (FDG-PET and (functional)MRI) by RECIST 1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    At time of surgery.
    E.5.2Secondary end point(s)
    - Rate and type of AE (NCI CTCAE v 5.0) prior to standard of care, and no significant delay (>1 week) or cancelation of SOC surgery due to immune-related toxicity.
    - RFS at 2 years FU of responders versus non-responders to neo-adjuvant ICI
    - OS at 2 years FU of responders versus non-responders to neo-adjuvant ICI
    - Rate and type of AE (NCI CTCAE v 5.0) up to 2 years FU after SOC
    - Clinical response of potentially additional AK surface areas after ICI identified by digital clinical photography on day 0, day 14, day 28 and during FU.
    - Quality of life as measured by EORTC QLQ-C30, H&N 35, EQ5D, CWS, IT questionnaire and the sexuality questionnaire

    Exploring the TME (early) upon ICI:
    - IHC and Bulk DNA & RNA sequencing of local tumor (when feasible also lymph node metastases) specimens at the aforementioned time points before and after start of ICI*, and its correlation to clinical outcome.
    - The development of an ex vivo functional assay for CSCC (Daniela Thommen platform) to predict individual ICI response.
    - The development of an ex vivo functional assay to challenge tumor specimens (and when feasible lymph node specimens) with ICI drugs at aforementioned time-points before and after start of neoadjuvant ICI*.
    - Single cell sequencing of tumor specimens before and after start of ICI*.
    - Hyperion Mass Cytometry of tumor specimens (and when feasible lymph node specimens) before and after start of ICI*.

    Endpoints for exploring systemic immunotherapy-related alterations:
    - Fresh blood flow cytometry (with a focus on suppressive cells as monocytes, neu-trophils) will be performed pre-, on and post-treatment* on all blood samples.
    - Heparin peripheral blood mononuclear cells (PBMCs) will be analysed pre-, on and post-treatment* on all blood samples for a quantitative and qualitative assessment of circulating adaptive immune cells.
    - Serum blood will be analysed for chemokines and cytokines, pre-, on and post-treatment* on all blood samples.
    - EDTA blood will be analysed complement factors, pre-, on and post-treatment* on all blood samples.
    - T-cell receptor sequencing of baseline TILs and their potential expansion in the pe-ripheral blood compartment on-treatment (‘immunoSeq’.).
    - EDTA blood will be analysed for ctDNA (kinetics) before treatment, on treatment, and long-term after neo-adjuvant ICI*.

    *= before treatment, and one week (either day 2-3, or day 4-6 or day 7-9, at least 6 people per treatment arm), two weeks (right before 2nd infusion of immunotherapy), 4 weeks (at time of surgery) and long-term after start of ICI, see figure 1 and 2, and table 1, pages (23, 24 and 47).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Described at secondary endpoints. (2 years after treatment for OS and RFS).
    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 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) 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 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 is the end of the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state40
    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)
    Immunotherapy is given neo-aduvant to curative standard of care (surgery with or without RT)

    Thereafter, in case of recurrent disease, patients will be treated with wichever treatment is available for their situation.

    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 Decision2020-05-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-26
    P. End of Trial
    P.End of Trial StatusOngoing
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