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    Summary
    EudraCT Number:2018-000626-60
    Sponsor's Protocol Code Number:UC-0130/1804
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-11-20
    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 number2018-000626-60
    A.3Full title of the trial
    A multicenter, randomized, open label, phase II study evaluating the feasibility and tolerance of nivolumab neoadjuvant immunotherapy in high risk HPV driven Oropharynx Cancer.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    _
    A.3.2Name or abbreviated title of the trial where available
    IMMUNEBOOST-HPV
    A.4.1Sponsor's protocol code numberUC-0130/1804
    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 supportProgramme Hospitalier en Recherche Clinique
    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
    B.5.3 Address:
    B.5.3.1Street Address101, rue de Tolbiac
    B.5.3.2Town/ cityParis cedex 13
    B.5.3.3Post code75654
    B.5.3.4CountryFrance
    B.5.4Telephone number33144 23 55 77
    B.5.5Fax number33171 93 61 65
    B.5.6E-mailj-delaye@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.2.1.2Country which granted the Marketing AuthorisationFrance
    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 Concentrate for 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 INNCISPLATIN
    D.3.9.2Current sponsor codeCisplatine
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number0.5 to 1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    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) 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 nameNivolumab
    D.3.2Product code BMS-936558
    D.3.4Pharmaceutical form Concentrate for 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
    High risk Human Papilloma Virus (HPV)-driven oropharynx cancer patients
    E.1.1.1Medical condition in easily understood language
    High risk Human Papilloma Virus (HPV)-driven oropharynx cancer patients
    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
    To assess the feasibility and tolerance of neoadjuvant nivolumab treatment before chemoradiation (RT-CT) in “high risk” HPV-driven Oropharyngeal squamous cell carcinomas (OPSCC).
    E.2.2Secondary objectives of the trial
    - To assess safety with acute and late toxicities (according to NCI CTC-AE v5.0)
    - To assess the efficacy with Objective Response Rate (ORR) after nivolumab infusion and after completion of chemoradiation by CT-scan and MRI according to RECIST 1.1 and PET-scan.
    - To assess the efficacy with Overall Survival (OS), Locoregional control (LRC) and Progression-Free Survival (PFS)
    - To evaluate potential predictive biomarkers of clinical response secondary to nivolumab infusions.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    - To assess the tumor microenvironment alteration before and after the infusion of Nivolumab by multiple fluorescent staining (CD8/CD4/PDL-1/PDL-2/Tim3/FoxP3/PD-1/CD103/CD68) and by analyzing the expression of PD-L1, PD-L2 and INF gamma mRNA ,within tumoral samples, using specific RNAscope probes (Advanced Cell Diagnostics Inc, CA, USA).
    - To assess the effect of Nivolumab and chemoradiation on circulating immune cells profile and HPV-specific T-cell responses.
    E.3Principal inclusion criteria
    1. Age ≥ 18 years old
    2. Histologically confirmed HPV-positive OPSCC amenable to curative treatment with RT-CT.
    (HPV status is defined on the basis of the combination of 2 assays: p16 protein overexpression assessed by immunohistochemistry (IHC) and high-risk HPV DNA identification by in-situ Hybridization (ISH) orPCR. An HPV-driven OPSCC is defined as a tumor that is positive for both p16 IHC and HPV-DNA ISH or PCR)
    3. According to the 8th TNM edition, eligible stages are as follow:
    - Irrespective of tobacco consumption: Stage T4 (any N), N2 or N3 (any T)
    - Only if tobacco consumption ≥ 10 pack- years: T1-3N1 and T3N0 (T1N0 and T2N0 irrespective of tobacco consumption are not eligible for the study)
    4. Planned date of chemoradiation allowing 2 Nivolumab infusions, 2 weeks apart.
    5. ECOG performance status ≤1
    6 Adequate cardiac, haematological, hepatic and renal function allowing treatment with cisplatin and nivolumab
    7. Potentially reproductive patients must agree to use a highly effective contraceptive method while on treatment and up to 6 months after the end of chemoradiation.
    8. Women of childbearing potential must have a negative serum or urine pregnancy test done within 72 hours before randomisation.
    9. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures (including mandatory study-specific biopsies)
    10. Subjects must have at least one lesion amenable to biopsy.
    11. Consent to provide archived tumor tissue sample, if available.
    12. Patients must be affiliated to a Social Security System.
    13. Patient information and written informed consent form signed.
    E.4Principal exclusion criteria
    1. Prior treatment for OPSCC
    2. Prior treatment with anti-PD-1/PD-L1 and CTLA-4
    3. Distant metastases
    4. Tumor embolization within 28 days prior to the randomisation
    5. Contra-indication to receive high-dose cisplatin
    6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or psychiatric illness and social situations that would limit compliance with study requirement or compromise the ability of the subject to give written informed consent.
    7. Current or prior use of immunosuppressive medication within 14 days before randomisation, including intranasal and inhaled corticosteroids or systemic corticosteroids.
    8. Active or prior documented autoimmune or inflammatory disease within the 2 years prior to randomisation (including inflammatory bowel disease [e.g., ulcerative colitis, Crohn’s disease], celiac disease, irritable bowel disease, or other serious chronic gastrointestinal conditions associated with diarrhea; systemic lupus erythematosus; Wegener syndrome [granulomatosis with polyangiitis]; myasthenia gravis; Graves’ disease; rheumatoid arthritis; hypophysitis, uveitis, etc.) The following are exceptions to these criteria:a) Subjects with vitiligo or alopecia, b) Subjects with hypothyroidism (e.g.,Hashimoto syndrome) stable on hormone replacement and c) Subjects with psoriasis not requiring systemic treatment (within the past 2 years).
    9. History of primary immunodeficiency or organ transplant requiring immunosuppressive drugs
    10. Patients with a known HIV, active hepatitis B or C infection.
    11. Other invasive malignancy within 3 years of randomisation except for noninvasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that has/have been surgically cured.
    12. Pregnant women or women who are breast-feeding.
    13. Patients with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the study.
    14. Individuals deprived of liberty or placed under the authority of a tutor.
    E.5 End points
    E.5.1Primary end point(s)
    The rate of patients :
    (1) who can receive the 2 nivolumab infusions planned at D1 and between D14 to D16 among patients in the experimental arm
    And (2) who can receive chemoradiation at D30 (-2 /+7) after the second nivolumab infusion, without delay of more than 7 days with respect to the planned start of chemoradiation (RT-CT) (i.e., with RT-CT starting at the latest on D37) among patients in the experimental arm
    And (3) with no radiotherapy break of one week or more, among patients in the experimental arm and patients in the control arm separately
    And (4) with minimal dose of radiotherapy (dose received >95% of theoretical dose) among patients in the experimental arm and patients in the control arm separately
    And (5) with minimal dose of chemotherapy of ≥ 200 mg/m2 of cisplatin (CDDP) among patients in the experimental arm and patients in the control arm separately
    In the experimental arm, a success is defined by the achievement of the 5 criteria. In the control arm, a success is defined by the achievement of the three criteria number (3), (4), and (5).
    E.5.1.1Timepoint(s) of evaluation of this end point
    _
    E.5.2Secondary end point(s)
    - Acute toxicity assessed according to NCI CTC-AE v5.0 during and after nivolumab treatment and RT-CT
    - Delayed toxicity assessed according to NCI CTC-AE v5.0
    - Objective Response Rate between baseline and 12 to 17 days after the 2nd infusion of nivolumab (for patients receiving nivolumab). Radiological response will be assessed by CT-scan and MRI according to RECIST 1.1. SUV (standardized uptake value) evolution will be assessed by PET-scan. These examinations will be scheduled at patient’s inclusion.
    - Tumor response between baseline and 3 months after the end of RT-CT for all patients. Radiological response will be assessed by CT-scan and MRI according to RECIST 1.1. SUV evolution will be assessed by PET-scan.
    - Overall Survival (OS), defined as the time from randomization to death from any cause. Patients still alive at the time of analysis will be censored at the last known alive date.
    - Locoregional control (LRC), defined as the absence of disease progression or recurrence at the site of the primary tumor and loco-regional lymph nodes.
    - Progression-Free Survival (PFS), defined as the time from randomization to progression or death from any cause. Patients still alive at the time of analysis without documented progression will be censored at last known alive date.
    E.5.2.1Timepoint(s) of evaluation of this end point
    _
    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 Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3.1Comparator description
    control arm : radiochemotherapy standard
    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 concerned11
    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 years
    E.8.9.1In the Member State concerned months45
    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: 41
    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 state61
    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 Decision2019-01-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-04
    P. End of Trial
    P.End of Trial StatusOngoing
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