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    The EU Clinical Trials Register currently displays   42564   clinical trials with a EudraCT protocol, of which   7007   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2013-005406-54
    Sponsor's Protocol Code Number:M14TIL
    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:2014-04-09
    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 number2013-005406-54
    A.3Full title of the trial
    Randomized phase III study comparing a non-myeloablative lymphocyte depleting regimen of chemotherapy followed by infusion of tumor infiltrating lymphocytes and interleukin-2 to standard ipilimumab treatment in metastatic melanoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study that randomly compares a treatment with the patients own blood
    cells with the standard therapy given for skin cancer
    A.3.2Name or abbreviated title of the trial where available
    Lymphodepletion, TIL and Interleukin 2 compared to ipilimumab
    A.4.1Sponsor's protocol code numberM14TIL
    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 SponsorAntoni van Leeuwenhoek ziekenhuis
    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 supportAntoni van Leeuwenhoek ziekenhuis
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAntoni van Leeuwenhoek ziekenhuis
    B.5.2Functional name of contact pointStudy coordinator John Haanen
    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.5.4Telephone number31205129111
    B.5.6E-mailj.haanen@nki.nl
    D. IMP Identification
    D.IMP: 1
    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.2.1.1.1Trade name Yervoy
    D.2.1.1.2Name of the Marketing Authorisation holderBMS
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 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 nameYervoy
    D.3.9.4EV Substance CodeSUB29397
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    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 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.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 nameTumor Infiltrating Lymphocytes
    D.3.2Product code TIL
    D.3.4Pharmaceutical form 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 INNTIL
    D.3.9.2Current sponsor codeTIL
    D.3.9.3Other descriptive nameAUTOLOGOUS T-LYMPHOCYTES
    D.3.9.4EV Substance CodeSUB96123
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number5000000000 to 200000000000
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    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
    Patients with irresectable and metastatic (stage IIIc and IV) melanoma will be randomized to either treatment arm A (ipilimumab) or treatment arm B (TIL) after metastasectomy and feasibility of culturing of TIL.
    E.1.1.1Medical condition in easily understood language
    Patients with metastatic skin cancer will randomly receive either
    ipilimumab or white blood cells.
    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 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 LLT
    E.1.2Classification code 10027481
    E.1.2Term Metastatic melanoma
    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 compare progression free survival (according to RECIST 1.1) between patients treated with ipilimumab as compared to patients treated with TIL therapy.
    E.2.2Secondary objectives of the trial
    Progression free survival at 6 months according to RECIST 1.1 and progression free survival according to irRC. Overall response rate according RECIST version 1.1 and irRC, complete response rate, overall survival and safety (according to CTCAE v. 4.0).

    To evaluate the impact of the TIL treatment on patient, organizational and economic consequences, a constructive technology assessment will be performed. In this CTA Health Related Quality of Life is evaluated using a questionnaire. Additionally, patient impact of receiving TIL treatment is evaluated by a semi-structured interview with patients receiving TIL treatment and finally the incremental costs per Quality Adjusted Life Year (QALY) gained will be estimated (cost-effectiveness).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Histologically confirmed unresectable AJCC stage IIIc or stage IV melanoma
    • Patients must have metastatic melanoma with a resectable metastatic lesion(s) of sufficient size (≥ 2-3 cm in total) and must be willing to undergo such a resection for experimental purposes. Resected metastases during stage IV disease that were removed at much earlier time points, but were used to grow clinical grade TIL up to Rapid Expansion Protocol may be used as well with informed consent of the patient.
    • Patients should have received maximum one line of systemic therapy (except for ipilimumab) for unresectable or metastatic melanoma.[Note that prior adjuvant or neoadjuvant melanoma therapy is permitted if it was completed at least 6 weeks prior to randomization, and all related adverse events have either returned to baseline or stabilized.]
    • Patients must be ≥ 18 years and ≤ 75 years of age and must have measurable disease by CT or MRI per RECIST 1.1 criteria (in addition to the resected lesion).
    • Patients must have a clinical performance status of ECOG 0 or 1 (Appendix B) (38).
    • 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 be able to understand and sign the Informed Consent document.
    Laboratory Parameters (Note: patients may undergo resection with lab values outside of the parameters listed below if it is anticipated that the resection will correct the abnormality).
    • Hematology:
    - Absolute neutrophil count greater than 1.5 x 109/L without support of filgrastim.
    - Platelet count greater than 100 x 109/L.
    - Hemoglobin greater than 5 mmol/L, or 80 g/L.
    • Chemistry
    - Serum ALAT/ASAT less than 3 times the upper limit of normal, unless patients have liver metastases (< 5 times ULN).
    - Serum creatinine clearance 50 ml/min or higher.
    - 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.
    - LDH ≤ 2x ULN
    • Serology:
    - Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune-competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)
    - Seronegative for hepatitis B antigen, and hepatitis C antibody.
    - Seronegative for syphilis.
    - HSV, EBV, and CMV (positivity for HSV, EBV, or CMV is not an exclusion criterion for participation, but prophylactic medication can be started when deemed necessary prior to chemotherapy treatment in the case patients randomize for the TIL treatment arm).
    E.4Principal exclusion criteria
    • Life expectancy of less than three months.
    • Patients with metastatic ocular/ mucosal or other non-cutaneous melanoma.
    • Adjuvant treatment with ipilimumab within 6 months prior to randomization.
    • Requirement for immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive drugs within the last 3 weeks prior to randomization.
    • Patients who have more than two CNS metastases.
    • Patients who have any CNS lesion that is symptomatic, greater than 1 cm in diameter or show significant surrounding edema on MRI scan will not be eligible until they have been treated and demonstrated no clinical or radiologic CNS progression for at least 2 months.
    • The following patients will be excluded because of inability to receive high dose interleukin-2 (also see Appendix C):
    - History of coronary revascularization
    - Documented LVEF of less than 45% in patients with:
    o Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, 2° or 3° heart block
    - Documented FEV1 less than or equal to 60% predicted for patients with:
    o A prolonged history of cigarette smoking (greater than 20 pack/year within the past 2 years)
    o Symptoms of respiratory distress
    • All patients’ toxicities due to prior non-systemic treatment must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures or focal palliative radiotherapy (to 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, because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
    • Any active systemic infections, coagulation disorders or other active major medical illnesses.
    • Any autoimmune disease: patients with a documented history of inflammatory bowel disease, including ulcerative colitis and Crohn’s disease are excluded from this study as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, autoimmune thyroiditis (e.g. Hashimoto’s disease), autoimmune hepatitis, systemic progressive sclerosis (scleroderma), Systemic Lupus Erythematosus, autoimmune vasculitis (e.g., Wegener’s Granulomatosis). Subjects with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barré Syndrome) are excluded from this study. Patients with vitiligo are eligible to enter the study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is progression free survival (according to RECIST 1.1).
    E.5.1.1Timepoint(s) of evaluation of this end point
    During follow-up, until progression.
    E.5.2Secondary end point(s)
    The secondary endpoints are PFS at 6 months (according to RECIST 1.1) and PFS according to irRC, the overall response rate, complete response rate, overall survival and safety.
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 6 months of FU and after 5 years 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 Yes
    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 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 Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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 years7
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial 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: 144
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 24
    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 state110
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 168
    F.4.2.2In the whole clinical trial 168
    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)
    That depends on the condition of the patient at the time.
    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 Decision2014-04-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-06-10
    P. End of Trial
    P.End of Trial StatusOngoing
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