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    The EU Clinical Trials Register currently displays   44334   clinical trials with a EudraCT protocol, of which   7366   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2016-002257-37
    Sponsor's Protocol Code Number:UC-0105/1611
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-02-17
    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 ConcernedFrance - ANSM
    A.2EudraCT number2016-002257-37
    A.3Full title of the trial
    Secured access to nivolumab for adult patients with selected rare cancer types
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Secured access to nivolumab for adult patients with selected rare cancer types
    A.3.2Name or abbreviated title of the trial where available
    AcSé Nivolumab
    A.4.1Sponsor's protocol code numberUC-0105/1611
    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 SponsorUNICANCER
    B.1.3.4CountryFrance
    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.4.2CountryFrance
    B.4.1Name of organisation providing supportInstitut National du Cancer
    B.4.2CountryFrance
    B.4.1Name of organisation providing supportLa Ligue Contre le Cancer
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUNICANCER
    B.5.2Functional name of contact pointProject Manager (Daniel Couch)
    B.5.3 Address:
    B.5.3.1Street Address101 rue de Tolbiac
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75654
    B.5.3.4CountryFrance
    B.5.4Telephone number+33180501296
    B.5.5Fax number+33171936167
    B.5.6E-maild-couch@unicancer.fr
    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 Opdivo
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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 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 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.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 locally advanced or metastatic, non-clear cell renal cell carcinoma, rare head and neck cancer, rare skin cancer, MSI-nonCRC or penile cancer, which is resistant or refractory to standard therapy, or for which standard therapy does not exist, or is not considered appropriate, and for which no other experimental treatment options are available.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the trial is to evaluate the efficacy response to nivolumab monotherapy in cohorts of patients with unresectable locally advanced or metastatic, non-clear cell RCC, rare head and neck cancer, rare skin cancer, MSI-nonCRC or penile cancer, which is resistant or refractory to standard therapy, and for which no other treatment options are available.
    E.2.2Secondary objectives of the trial
    • To identify populations, for which the IP is expected to have a clinical benefit.
    • To assess the efficacy of nivolumab monotherapy in each cohort in terms of survival, progression occurrence and quality of response.
    • To assess the safety profile of nivolumab monotherapy.
    • To define predictive factors including biomarkers related to the response to nivolumab; in particular to explore whether the immunohistochemical expression of PD-L1 and other immune markers (CD3, CD4, FOXP3, CD8 or CD68/CD163) in the tumour samples (both in the tumour cells and the immune cells) is correlated with response to nivolumab.
    • To test if the mutational load measured in tumour samples from some of the studied cohorts can be correlated with response to nivolumab.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Biological Ancillary Study :
    The aim of the proposed ancillary studies is to address specific scientific questions related to potential predictive biomarkers of efficacy and the mechanism of action of the antitumour immune response, such as:
    • Which biomarkers are specifically associated with tumour response to treatment?
    • Which biomarkers are specifically associated with treatment-related toxicity?
    • What are the common immune parameters modified by the treatment in all patients?
    • Which tumour immune infiltration patterns are seen in responding versus non-responding patients?
    • Are identified biomarkers unique to a particular tumour, or universally present across all tumour types
    E.3Principal inclusion criteria
    1. Patient information sheet and written informed consent (PIS/ICF) form signed.
    2. Histologically confirmed diagnosis of a pathology corresponding to one of the following selected cancer types:
    • Non-clear cell renal-cell carcinomas: papillary renal cell carcinoma (pRCC, type I, type II and non-classified pRCC), chromophobe RCC (ChRCC), renal medullary carcinoma (RMC), collecting duct/Bellini duct carcinoma (CDC), microphthalmia-associated transcription (MiT) family translocation renal cell carcinoma (tRCC), renal cell carcinoma with a prominent sarcomatoid component (sarcRCC).
    • Rare head and neck cancers: principal and accessory salivary gland tumours, facial tissue tumours.
    • Rare skin cancers: adnexal carcinomas, basal cell carcinoma resistant to vismodegib.
    • Non-colorectal cancers with microsatellite instability determined locally by immunohistochemistry or polymerase chain-reaction (PCR)
    • Squamous cell carcinoma of penis.
    3. Metastatic disease or unresectable locally advanced malignancy that is resistant or refractory to standard therapy or for which standard therapy does not exist or is not considered appropriate by the Investigator.
    4. Aged ≥ 18 years old.
    5. Measurable disease according to RECIST v1.1 guidelines for solid tumours (Eisenhauer, 2009; Appendix 1).
    6. Able to provide a FFPE biopsy sample of a metastatic site or primitive tumour tissue.
    Note: Patients for whom suitable archived biopsy material is not available must be willing to undergo a biopsy of a tumour lesion prior to study entry, unless this is medically contraindicated (e.g. site inaccessible or patient safety concerns).
    7. Patients must have a mandatory treatment-free interval of at least 21 days following previous systemic anti-cancer treatments.
    8. Patients who have received previous systemic anticancer treatment and/or radiotherapy should have recovered from any treatment related toxicity, to a level of ≤ grade 1 (according to NCI-CTCAE criteria, v 4.0, Appendix 2) with the exception of Grade 2 alopecia.
    9. Adequate hematologic function (absolute neutrophil count [ANC] ≥ 1.0 x109/L, platelets ≥ 100 x109/L, haemoglobin (Hb) ≥ 9 g/L) measured within 14 days of treatment initiation.
    10. Adequate renal function (creatinine clearance ≥ 50 mL/ using the MDRD or CKI EPI method) measured within 14 days of treatment initiation.
    11. Adequate hepatic function (serum bilirubin ≤ 1.5 x the reference upper limit of normal (ULN) unless due to Gilbert’s syndrome; aspartate aminotransferase [ASAT] and alanine aminotransferase [ALAT] ≤ 2,5 xULN) measured within 14 days of treatment initiation. For patients with documented liver metastasis ASAT/ALAT ≤ 5x ULN is acceptable.
    12. Strictly normal blood levels of calcium and magnesium, measured within 14 days of treatment initiation.
    13. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1 (Oken, 1982; Appendix 3).
    14. Estimated life expectancy ≥ 90 days.
    15. Patients who are sexually active must agree to use a medically accepted method of contraception (e.g. implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner, for participating women; condoms for participating men) or practice complete abstinence, beginning 14 days before the first administration of IP, while on treatment and for at least 5 months after the last administration of IP for female patients, and 7 months after the last administration of IP for male patients.
    16. Women of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to the first administration of IP. If urine test results are positive or cannot be confirmed as negative, a serum pregnancy test will be required.
    17. Women who are breastfeeding should discontinue nursing prior to the first administration of IP and for at least 90 days after the last administration of IP.
    18. Patients must be affiliated to a Social Security System or equivalent.
    E.4Principal exclusion criteria
    1. Prior treatment with an anti-PD1 or anti-PD-L1 antibody
    2. Eligible, and willing, to participate in a clinical trial of an alternative anticancer therapy targeting their disease which is open to accrual in France.
    3. Concurrent steroid medication at a dose greater than prednisone 10 mg/day or equivalent (Appendix 4).
    4. 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
    5. History of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
    6. History of severe hypersensitivity reaction to any monoclonal antibody therapy
    7. Radiotherapy (except for brain and extremities) within 21 days prior to the first administration of IP.
    8. Treatment with other investigational drugs or participation in another clinical trial within 21 days prior to the first administration of IP or concomitantly with the trial.
    9. Has known symptomatic central nervous system (CNS) metastases. Patients 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.
    10. Has known carcinomatous meningitis or a history of leptomeningeal disease.
    11. Serum creatinine > 1.5 xULN or glomerular filtration rate (GFR) < 50 ml/min.
    12. Lymphocytes count below 1,000/mm3 and CD4+ count below 500/mm3 as assessed by routine blood phenotyping.
    13. Other malignancies within the past 5 years other than basal cell skin cancer or carcinoma in situ of the cervix.
    14. Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy.
    15. Active or chronic hepatitis B, hepatitis C and/or human immunodeficiency virus (HIV) infection (HIV 1/2 antibodies), or a known history of active Tuberculosis bacillus.
    16. Has received a live vaccine within 30 days of planned start of study treatment.
    Note: Seasonal influenza vaccines for injection are generally inactivated vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed.
    17. Active alcohol or drug abuse.
    18. Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule.
    19. Any condition which in the Investigator’s opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Objective response rate per cohort, defined as the percentage of patients in each cohort with a CR or PR measured at the first scheduled disease assessment following study treatment initiation (Day 84, ± 7 days) as assessed by an Independent Review Committee (IRC) according to the Response Evaluation Criteria in Solid Tumours version 1.1. (RECIST v1.1; Eisenhauer, 2009; Appendix 1).
    Patients who withdraw from the study prior to this time point and patients with non-evaluable disease will be considered as ’non-responders’ in the analysis.
    E.5.1.1Timepoint(s) of evaluation of this end point
    An initial analysis will be performed separately for each cohort after 10 patients have been enrolled and completed one on treatment disease assessment. For cohorts which continue to recruit patients, subsequent analysis of the primary endpoint will be performed after each 5 additional patients enrolled until recruitment is stopped or maximum sample size (25 patients) is reached.
    E.5.2Secondary end point(s)
    • Progression-free survival, defined as the time from inclusion until documented disease progression (PD) according to RECIST v1.1 or death, whichever occurs first.
    • Overall survival, defined as the time from inclusion until death due to any cause.
    • Best response to treatment according to RECIST v1.1, measured at any disease assessment during the course of the study.
    • Response duration, defined as the time from first observation of objective response (i.e. PR or CR) according to RECIST v.1.1 until PD or death, whichever occurs first.
    • Time to response, defined as the time from inclusion until observation of objective response (i.e. PR or CR) according to RECIST v.1.1.
    • Frequency and severity of adverse events assessed according to the National Cancer Institute (NCI) Common terminology criteria for adverse events, version 4 (CTCAE v4, Appendix 2).
    • Progression-free survival, OS and ORR in subgroups of subjects according to expression level of PD L1 and other immune markers (high versus low expression with a cutoff value set at the median for the population measured).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints will be analysed after all enrolled patients have completed the specified follow-up period.
    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 Yes
    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 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 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 concerned100
    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
    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: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 state250
    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)
    None
    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 Decision2017-02-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-01-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-11-16
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