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    Summary
    EudraCT Number:2019-000657-31
    Sponsor's Protocol Code Number:EMCR2015-7741
    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:2019-05-13
    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 number2019-000657-31
    A.3Full title of the trial
    Adoptive therapy with TCR gene-engineered T cells to treat patients with MAGE-C2-positive melanoma and head and neck cancer.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Gene therapy for patients with MAGE-C2-positive melanoma and head and neck cancer.
    A.3.2Name or abbreviated title of the trial where available
    MC2 TCR T cell therapy
    A.4.1Sponsor's protocol code numberEMCR2015-7741
    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 SponsorErasmus MC Cancer Institute
    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 supportErasmus MC
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportDutch Cancer Foundation KWF
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus MC
    B.5.2Functional name of contact pointPrincipal investigator
    B.5.3 Address:
    B.5.3.1Street AddressDr. Molewaterplein 40
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3015 GD
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031107034447
    B.5.6E-maila.vanderveldt@erasmusmc.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 nameMAGE-C2 TCR Transduced autologous T cells
    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.3.11 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) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    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
    unresectable stage IIIc and IV melanoma (including unknown primary, mucosal and uveal melanoma), and unresectable recurrent/metastatic(R/M) HNSCC.
    E.1.1.1Medical condition in easily understood language
    non-removable melanoma skin cancer and metastatic 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 20.0
    E.1.2Level PT
    E.1.2Classification code 10025670
    E.1.2Term Malignant melanoma stage III
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10071536
    E.1.2Term Head and neck cancer stage IV
    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 20.0
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10025671
    E.1.2Term Malignant melanoma stage IV
    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 study the feasibility, safety and objective response rate of the pretreatment with epigenetic drugs followed by adoptive transfer of autologous MAGE-C2 TCR gene-modified T cells in advanced stage melanoma and HNSCC patients with disease progression upon standard therapy.
    E.2.2Secondary objectives of the trial
    • To study the efficacy of this treatment strategy by assessing the presence of MAGE-C2 specific T cells in peripheral blood samples on several time points following adoptive transfer.
    • To study whether infusion of MAGE-C2 specific TCR transduced T cells induces systemic release of inflammatory cytokines.
    • To study the 1-year progression-free survival and overall survival.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) patients with inoperable stage IIIc/IV melanoma with progressive disease after standard therapy
    2) patients with R/M HNSCC who are ineligible for or unwilling to get platinum-based chemotherapy or for whom no standard treatment is available.
    4.2 Inclusion criteria
    Subjects eligible for inclusion in this study have to meet all of the following criteria:
    • Written informed consent must be obtained prior to any screening procedures.
    • Male or female must be ≥ 18 years of age at time of providing informed consent.
    • One of the following three malignancies:
    1. Previously treated for unresectable or metastatic cutaneous or mucosal melanoma for whom no standard treatment is available (anymore):
    2. Metastatic uveal melanoma, progressing after standard of care therapy, if available.
    3. R/M HNSCC for whom no standard treatment is available anymore.
    • Patients must be HLA-A*0201 positive.
    • Primary tumor and/or metastasis (archival or fresh biopsy) is positive for MC2 (>1% of tumor cells) according to immunohistochemistry.
    • Measurable disease according to RECIST v1.1.
    • At least one lesion, suitable for sequential mandatory tumor biopsies.
    • ECOG performance status of 0 or 1. Life expectancy ≥ 12 weeks.
    • Patients with melanoma must have had objective evidence of disease progression while on or after standard systemic therapy. The last dose of prior therapy (e.g. anti-PD-1, chemotherapy) must have been received more than 4 weeks prior to the start of study treatment. For melanoma patients who are treated with BRAF- and MEK inhibitors, an interval of 2 weeks between discontinuation of BRAF- and MEK inhibition and start of study treatment is sufficient.
    • Patients with R/M HNSCC must have had objective evidence of disease progression and are ineligible for or unwilling to get platinum-based chemotherapy or for whom no standard treatment is available.
    • Patients of both genders must be willing to practice a highly effective method of birth control during treatment and for four months after receiving the preparative regimen.

    Patients must meet the following laboratory values at the screening visit in the absence of growth factors and/or transfusion support:
    • Hematology:
    o Absolute neutrophil count greater than 1.5x109/L.
    o Platelet count greater than 75x109/L.
    o Hemoglobin greater than 5 mmol/L or 8.0 in g/dl.
    • Chemistry:
    o Serum ALAT/ASAT less than 3 times the upper limit of normal (ULN), unless patients have liver metastases (< 5 times ULN).
    o Serum creatinine < 1.5 ULN
    o Total bilirubin less than or equal to 20 micromol/L, except in patients with Gilbert’s Syndrome who must have a total bilirubin less than 50 micromol/L.
    • Serology:
    o Seronegative for HIV antibody.
    o Seronegative for hepatitis B antigen, and hepatitis C antibody.
    o Seronegative for lues.
    E.4Principal exclusion criteria
    • Subjects who meet any of the following criteria will be excluded from participation in this study:
    • Presence symptomatic brain metastases. Note: Subjects with symptomatic brain
    lesions who have been definitively treated with stereotactic radiation therapy, surgery or gamma knife therapy are eligible.
    • Presence of malignant pleural effusion or ascites.
    • Systemic chronic steroid therapy (˃ 10mg/day prednisone or equivalent) or any other immunosuppressive therapy a within 7 days prior to leukapheresis or 72 hours prior to infusion of the MC2 TCR T cells. Note: Local steroids such as topical, inhaled, nasal and ophthalmic steroids are allowed.
    • Active, known or suspected autoimmune disease or a documented history of autoimmune disease. Note: Subjects with vitiligo, controlled type I diabetes mellitus on stable insulin dose, residual autoimmune-related hypothyroidism only requiring hormone replacement or psoriasis not requiring systemic treatment are permitted.
    • Any active systemic infections, coagulation disorders or other active major medical illnesses, such as active autoimmune diseases requiring anti-TNF treatment.
    • History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of enrollment.
    • AEs of previous treatment. Toxicities associated with prior systemic and non-systemic treatment must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures or palliative radiotherapy (for non-target lesions) within the past 4 weeks, as long as all toxicities have recovered to grade 1 or less.
    • Women who are pregnant or breastfeeding. A negative pregnancy test before inclusion in the trial is required for all women of child bearing age.
    • Use of any live vaccines against infectious diseases within the last 3 months.
    • Active infection requiring systemic antibiotic therapy at start of study treatment.
    • Prior allogenic bone marrow or solid organ transplant.
    • History of known hypersensitivity to any of the investigational drugs used in this study.
    • Malignant disease, other than being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to start of study treatment; completely resected basal cell and squamous cell skin cancers and any completely resected carcinoma in situ.
    E.5 End points
    E.5.1Primary end point(s)
    Phase I- primary study endpoint
    - AEs according to CTCA CTCAE v5.0.
    - Recommended phase II dose.
    - Feasibility to deliver this sequence of treatment.
    Phase II - primary study endpoint
    - Objective response rate according to RECIST v1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I- Evaluation will take place after last patient completed phase I of the study protocol.
    Phase II - Evaluation will take place after last patient completed phase II of the study protocol.
    E.5.2Secondary end point(s)
    Phase II - secondary endpoints
    • PFS
    • OS

    Phase I and phase II - Secondary and exploratory endpoints
    • Persistence of MC2 TCR T cells, their differentiation state and ability to recognize tumor cells at regular intervals following start of T cell treatment.
    • Presence of immune and T cell parameters in blood, and micro-environment of tumor tissues using advanced flow cytometry and in situ stainings.
    • Global DNA hypomethylation and histone acetylation in PBMC
    • Response rate according to immune related Response Criteria (irRC).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Evaluation will take place after last patient completed the study protocol.
    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 Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Feasibility
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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 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.8.3 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 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 years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    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) No
    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 state20
    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)
    Patients will enroll in standard of care follow up protocol as advised in national protocols.
    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 Decision2019-04-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-05
    P. End of Trial
    P.End of Trial StatusOngoing
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