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    Summary
    EudraCT Number:2021-001085-37
    Sponsor's Protocol Code Number:IB2021-05
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-07-22
    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 number2021-001085-37
    A.3Full title of the trial
    Randomized phase II study of neoadjuvant chemotherapy plus retifanlimab (INCMGA00012) plus in patients with selected retroperitoneal sarcomas.
    Chimiothérapie néo-adjuvante plus retifanlimab (INCMGA00012)chez les patients porteurs de sarcomes rétropéritoneaux sélectionnés : une étude randomisée de phase II.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Bintrafusp alfa and Doxorubicin Hydrochloride in Treating Patients With Advanced Sarcoma.
    Chimiothérapie néo-adjuvante plus retifanlimab (INCMGA00012)chez les patients porteurs de sarcomes rétropéritoneaux sélectionnés : une étude randomisée de phase II.
    A.3.2Name or abbreviated title of the trial where available
    TORNADO
    TORNADO
    A.4.1Sponsor's protocol code numberIB2021-05
    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 SponsorInstitut Bergonié
    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 supportIncyte Biosciences International Sarl
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInstitut Bergonié
    B.5.2Functional name of contact pointRegulatory Affairs Management Desk
    B.5.3 Address:
    B.5.3.1Street Address229 Cours de l'Argonne
    B.5.3.2Town/ cityBordeaux
    B.5.3.3Post code33076
    B.5.3.4CountryFrance
    B.5.4Telephone number+33547306196
    B.5.5Fax number+33556333330
    B.5.6E-maildrci@bordeaux.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 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 nameRetifanlimab
    D.3.2Product code INCMGA00012
    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 INNRetifanlimab
    D.3.9.1CAS number 2079108-44-2
    D.3.9.2Current sponsor codeINCMGA00012
    D.3.9.3Other descriptive nameMGA012
    D.3.9.4EV Substance CodeSUB191459
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 Yes
    D.2.1.1.1Trade name DOXORUBICIN
    D.2.1.1.2Name of the Marketing Authorisation holderACCORD HEALTHCARE
    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.3.1Product nameDOXORUBICIN
    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 INNDoxorubicin
    D.3.9.1CAS number 23214-92-8
    D.3.9.4EV Substance CodeSUB06391MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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: 3
    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 HOLOXAN (Ifosfamide)
    D.2.1.1.2Name of the Marketing Authorisation holderBAXTER S.A.S
    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.3.1Product nameHOLOXAN
    D.3.4Pharmaceutical form Powder 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 INNIFOSFAMIDE
    D.3.9.1CAS number 3778-73-2
    D.3.9.4EV Substance CodeSUB08125MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2000
    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.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
    retroperitoneal sarcomas
    sarcomes rétropéritonéaux
    E.1.1.1Medical condition in easily understood language
    retroperitoneal sarcomas
    sarcomes rétropéritonéaux
    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 LLT
    E.1.2Classification code 10039494
    E.1.2Term Sarcoma NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10077289
    E.1.2Term Retroperitoneal sarcoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate the antitumor activity of retifanlimab (INCMGA00012) when prescribed in association with neoadjuvant chemotherapy (Doxorubicin + Ifosfamide) in patients with selected retroperitoneal sarcomas. Primary efficacy endpoint is histological response based on surgical sample.
    Evaluer l’activité antitumorale du retifanlimab (INCMGA00012) prescrit en association avec la chimiothérapie néo-adjuvante (doxorubicine + ifosfamide) en termes de réponse histologique sur la pièce opératoire, chez les patients porteurs de sarcomes rétropéritonéaux sélectionnés.
    E.2.2Secondary objectives of the trial
    - To investigate the antitumor activity of retifanlimab when prescribed in association with neoadjuvant chemotherapy (Doxorubicin + Ifosfamide) in terms of additional efficacy endpoints: progression-free (PFS) and overall survival (OS), assessed at one and three years.
    - To evaluate the safety profile of retifanlimab when prescribed in association with neoadjuvant chemotherapy (Doxorubicin + Ifosfamide) (NCI-CTCAE v5).
    - To perform pharmacodynamics (PD) / mechanisms of action biomarker analysis as well as analysis of predictive biomarkers (levels of immunologic biomarkers in blood / tissue / stool at baseline and different time points.
    - Evaluer l’activité antitumorale du retifanlimab prescrit en association avec la chimiothérapie néo-adjuvante (doxorubicine + ifosfamide) en termes de survie sans progression à 1 et 3 ans et de survie globale à 1 et 3 ans.
    - Evaluer le profil de toxicité de l’association retifanlimab + chimiothérapie néo-adjuvante (doxorubicine + ifosfamide) (NCI-CTCAE v5).
    - Etude de pharmacodynamie avec recherche de biomarqueurs prédictifs de la réponse au traitement (sang, tissu et microbiote)

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients with retroperitoneal sarcoma histologically confirmed and reviewed by the RRePS Network (Réseau de Référence en Pathologie des Viscères et des tissus mous) as recommended by the French National Cancer Institute(Inca),
    2. For TLS status determination: available archived FFPE (Formalin-Fixed Paraffin-Embedded) tumor tissue sample. In case of archived material is not available, presence of tumor lesion that can be biopsied for research purpose,
    3. Presence of mature tertiary lymphoid structures. Except if presence of TLS have been already confirmed by Biopathological platform at Bergonié Institute, presence of TLS should be confirmed by central review based on FFPE (Formalin-Fixed Paraffin-Embedded) tumor tissue sample (archived or newly obtained by biopsy for research purpose). Note that the presence of TLS could be determined by central analysis if not available before,
    4. Non-metastatic and resectable disease,
    5. At least one lesion that can be biopsied for research purpose,
    6. No prior treatment for the disease under study,
    7. Age ≥ 18 years,
    8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1,
    9. Life expectancy > 3 months,
    10. Patients must have measurable disease (lesion in previously irradiated field can be considered as measurable if progressive at inclusion according to RECIST v1.1) defined as per RECIST v1.1 with at least one lesion that can be measured in at least one dimension (longest diameter to be recorded) as ≥10 mm with spiral CT scan.
    11. Adequate hematological, renal, metabolic and hepatic function:
    a. Hemoglobin ≥ 8.0 g/dl; leucocytes ≥ 2.0 G/l, absolute neutrophil count (ANC) > 1.0 G/l and platelet count > 100 G/l,
    b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normality (ULN) ,
    c. Total bilirubin ≤ 1.5 x ULN
    d. Albumin ≥ 25g/l
    e. Serum creatinine ≤ 1.5 x ULN OR Calculated creatinine clearance (CrCl) ≥ 60 ml/min (calculated per institutional standard) for subject with creatinine levels > 1.5 x ULN.
    f. Thyroid function within normal laboratory ranges (TSH, free T3, free T4)
    12. Left ventricular ejection fraction (LVEF) ≥ 50% assessed by ECHO or MUGA within 6 months from study entry,
    13. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to study entry. Pregnancy test (serum or urine) should be repeated within 72 hours prior to receiving the first dose of trial medication.
    14. Both women and men must agree to use a highly effective method of contraception throughout the treatment period and for one year after discontinuation of treatment for women and 4 months for men.
    15. No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated in situ carcinoma of the cervix, concomitant endometrial carcinoma stage IA grade 1, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma,
    16. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5),
    17. Voluntarily signed and dated written informed consent prior to any study specific procedure,
    18. Patients with a social security in compliance with the French law.
    1. Sarcome rétropéritonéal histologiquement confirmé. Diagnostic confirmé et revu dans le cadre du réseau RRePS selon les recommandations de l’Inca.
    2. Pour la détermination du statut TLS : disponibilité de matériel tumoral archivé (bloc FFPE) ou, le cas échéant, présence d’une lésion tumorale qui puisse être biopsiée pour la recherche.
    3. Présence de structures lymphoïdes tertiaires matures. Sauf si les résultats ont déjà été confirmés par la plateforme de Biopathologie de l’Institut Bergonié, la présence de TLS devra être confirmée en centralisé à partir d’un échantillon tumoral fixé en paraffine (cf. CI n°2). Note : l’analyse pour évaluer la présence de TLS pourra être réalisée en centralisée si non disponible.
    4. Maladie non métastatique et opérable,
    5. Présence d’au moins une lésion qui puisse être biopsiée pour la recherche,
    6. Pas de traitement antérieur pour le sarcome,
    7. Age ≥ 18 ans,
    8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1,
    9. Espérance de vie > 3 mois,
    10. Maladie mesurable selon les critères RECIST v1.1 en dehors de champs d’irradiation (sauf si progressive à l’inclusion). Au moins une lésion ≥ 10 mm (≥15 mm en cas d’adénopathie),
    11. Fonctions hématologiques, rénales, métaboliques et hépatiques :
    a) Hémoglobine ≥ 8 g/dl ; taux de leucocytes ≥ 2.0 G/l, taux de neutrophiles > 1.0 G/l et taux de plaquettes > 100 G/l
    b) Alanine aminotransférase (ALT) et aspartate aminotransférase (ASP) ≤ 2.5 x limite normale supérieure (ULN)
    c) Bilirubine totale ≤ 1.5 x ULN
    d) Albumine ≥ 25g/l.
    e) Créatinine sérique ≤ 1.5 x ULN ou clairance de la créatinine (CrCl) ≥ 60 ml/min (calculée selon les standards institutionnels) pour les patients ayant un taux de créatinine > 1.5 x ULN
    f) Fonction thyroïdienne dans les limites de la normale (TSH, T3 libre, T4 libre).
    12. Fraction d’éjection ventriculaire (LVEF) ≥ 50%, évaluée par ECHO ou MUGA dans les 6 mois avant la randomisation,
    13. Les femmes susceptibles d’être enceintes doivent avoir un test de grossesse (sérique) négatif, dans les 7 jours avant la randomisation. A noter que ce test sérique devra être répété dans les 72 heures avant le début du traitement,
    14. Les femmes susceptibles d’être enceintes et les hommes doivent utiliser une méthode de contraception hautement efficace durant toute la période de l’étude et jusqu’à 1 an après l’arrêt pour les femmes, et 4 mois après l’arrêt pour les hommes,
    15. Pas de pathologie maligne antérieure ou concomitante, diagnostiquée ou traitée au cours des deux dernières années, à l’exception des carcinomes in situ du col utérin, carcinomes basocellulaires / spinocellulaires de la peau ou les carcinomes in situ de la vessie,
    16. Retour à un grade ≤ 1 de toxicité suite à un traitement antérieur (sauf alopécie quel que soit le grade et pour les neuropathies périphériques non douloureuses de grade ≤ 2) selon la classification NCI-CTCAE version 5.0,
    17. Consentement éclairé (daté et signé) avant toute procédure spécifique à l’étude,
    18. Affiliation à un régime de sécurité sociale en accord avec la loi française.
    E.4Principal exclusion criteria
    1. Previous treatment for retroperitoneal sarcoma including surgery, chemotherapy or radiotherapy
    2. Previous treatments with doxorubicin, daunorubicin, epirubicin, idarubicin and/or other anthracyclines or anthracenediones at the maximum cumulative dose,
    3. Known hypersensitivity to any involved study drug or any of its formulation components,
    4. Has an active or ongoing infection requiring systemic therapy,
    5. Known central nervous system malignancy (CNS),
    6. Women who are pregnant or breast feeding,
    7. Has known active hepatitis B or hepatitis C,
    8. Has a known history of Human Immunodeficiency Virus (HIV),
    9. Previous enrolment in the present study,
    10. Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons,
    11. Has received a live attenuated vaccine or a live vaccine within 30 days prior to the first dose of trial treatment,
    Note: the killed virus vaccines used for seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
    12. Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:
    a. Myocardial infarction or stroke/transient ischemic attack within the 6 months prior to study entry.
    b. Uncontrolled angina within the 3 months prior to study entry.
    c. Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes, or poorly controlled atrial fibrillation).
    d. Corrected QT (QTc) prolongation > 480 msec.
    e. History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, poorly controlled venous thrombus).
    13. Uncontrolled or significant renal disease including, but not limited to, any of the following:
    a. Acute or uncontrolled urinary infection at study entry,
    b. Hemorrhagic cystitis at study entry,
    c. Presence of blood on dipstick at study entry,
    d. Vesical atony,
    e. Known urinary tract obstruction.
    14. Patients with known history of active inflammatory bowel diseases, including those with small or large intestine inflammation, such as Crohn’s disease or ulcerative colitis, will be excluded from the study,
    15. Has received systemic antibiotics within 14 days before the first dose of study treatment. Participants receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible.
    16. History of organ transplant, including allogeneic stem cell transplantation.
    17. Receiving probiotics as of the first dose of study treatment.
    18. Has an active autoimmune disease
    - Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible,
    - Patients requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at dose ≤ 10 mg or 10 mg equivalent prednisone day,
    - Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intra-ocular, intra-articular or inhalation) are acceptable.
    19. Evidence of interstitial lung disease, history of interstitial lung disease, or active, noninfectious pneumonitis.
    20. Palliative radiation therapy administered within 1 week of first dose of study treatment or radiation therapy in the thoracic region that is > 30 Gy within 6 months of the first dose of study treatment. Note: Participants must have recovered from all radiation-related toxicities (to Grade >1 or baseline), not require corticosteroids for this purpose, and not have had radiation pneumonitis.
    21. Person under judicial protection or deprived of liberty.
    1. Traitement antérieur pour le sarcome rétropéritonéal, incluant chirurgie, chimiothérapie ou radiothérapie,
    2. Traitement antérieur par doxorubicine, daunorubicine, épirubicine, idarubicine et/ou autres anthracyclines ou anthracenediones à doses cumulatives maximales,
    3. Hypersensibilité connue à l’un des produits de l’étude ou à l’un de ses composants,
    4. Infection active ou en cours nécessitant un traitement systémique,
    5. Atteinte maligne du système nerveux central,
    6. Femmes enceintes ou allaitantes,
    7. Hépatite B ou hépatite C connue active,
    8. Antécédent connu de VIH,
    9. Précédente inclusion dans l’étude,
    10. Facteurs géographiques, sociaux ou psychologiques rendant le patient incapable de se soumettre au suivi et aux procédures de l’étude,
    11. Administration de vaccin vivant atténués ou de vaccin vivant dans les 30 jours avant l’initiation du traitement. Note les vaccins inactivés utilisés en injection pour la grippe saisonnière sont autorisés, alors que les vaccins contre la grippe administrés en intranasal (i.e., FluMist®) sont des vaccins vivants atténués et sont donc interdits.
    12. Pathologie vasculaire non contrôlée ou significative, incluant mais non limitée à :
    - Infarctus du myocarde ou accident vasculaire cérébral ou accident ischémique transitoire dans les 6 mois avant la randomisation,
    - Angor instable dans les 3 mois avant la randomisation,
    - Tout antécédent d’arythmie cardiaque cliniquement significative (tel que tachycardie ventriculaire, fibrillation ventriculaire, torsades de pointe, ou fibrillation atriale mal contrôlée),
    - Prolongation de l’intervalle QT corrigé (QTc) > 480 msec,
    - Antécédent de toute autre pathologie cardiovasculaire non contrôlée (i.e., cardiomyopathie, insuffisance cardiaque congestive grade III-IV selon New York Heart Association (NHYA), péricardite, épanchement péricardique significatif, occlusion significative d’un stent coronarien, thrombose veineuse mal contrôlée).
    13. Pathologie rénale non contrôlée ou significative, incluant mais non limitée à :
    - Infection urinaire aigüe ou non contrôlée au moment de la randomisation,
    - Cystite hémorragique au moment de la randomisation,
    - Présence de sang sur la bandelette urinaire à la randomisation,
    - Atonie vésicale,
    - Obstruction des voies urinaires connue.
    14. Antécédent connu de maladie inflammatoire de l’intestin, incluant le côlon et l’intestin grêle, telle que la Maladie de Crohn ou une colite ulcéreuse,
    15. Traitement par antibiotique systémique dans les 14 jours avant l’initiation du traitement à l’étude. Les patients traités par antibiothérapie prophylaxique (e.g., prévention d’une infection des voies urinaires ou BPCO) sont éligibles.
    16. Antécédent de transplantation d’organe, incluant la greffe allogénique de cellules souches,
    17. Utilisation de probiotiques à l’entrée dans l’étude,
    18. Maladie auto-immune active:
    - Les patients présentant l’une des maladies suivantes : diabète de type I, vitiligo, psoriasis, hypo- ou hyperthyroïdie ne nécessitant pas de traitement immunosuppresseur sont éligibles,
    - Les patients traités par substitution hormonale avec des corticostéroïdes sont éligibles si les stéroïdes sont administrés dans ce but et si la dose n’excède pas 10 mg/jour de prednisone ou équivalent,
    - L’administration de stéroïdes par voie nasale, cutanée, intraoculaire, intra-articulaire ou par inhalation est autorisée.
    19. Preuve actuelle ou antécédent d’une pathologie pulmonaire interstitielle, ou pneumonie non infectieuse active,
    20. Radiothérapie palliative dans la semaine avant l’initiation du traitement à l’étude OU radiothérapie thoracique > 30 Gy dans les 6 mois avant. Note : les patients doivent avoir récupéré de toute toxicité liée à la radiothérapie (grade 1 ou baseline), ne pas nécessiter de traitement par corticostéroïdes en lien avec la radiothérapie, et ne pas présenter de pneumonie radio-induite.
    21. Personne sous protection judiciaire ou privée de liberté.
    E.5 End points
    E.5.1Primary end point(s)
    The antitumor activity of retifanlimab (INCMGA00012) when prescribed in association with neoadjuvant chemotherapy (Doxorubicin + Ifosfamide) will be assessed based on histological response defined as less than 10% of viable tumor cells on surgical sample.
    • L’activité antitumorale du retifantlimab (INCMGA00012) prescrit en association avec la chimiothérapie néo-adjuvante (doxorubicine + ifosfamide) sera évaluée en termes de réponse histologique sur la pièce opératoire.
    • La réponse histologique est définie par la présence de moins de 10% de cellules tumorales viables.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At surgery after neoadjuvant chemotherapy (an expected average of 14 weeks after treatment onset)
    A la chirurgie qui sera réalisée après le traitement néoadjuvant (environ 14 semaines après l'initiation du traitement)
    E.5.2Secondary end point(s)
    • Progression-free survival (PFS) is defined as the time from study treatment initiation to the first occurrence of disease progression or death (of any cause), whichever occurs first.
    • Overall Survival (OS) is defined as the time from study treatment initiation to death (of any cause).
    • Safety will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0. Toxicity will be graded using the CTCAE v5.0. Adverse events, serious and non-serious, will be coded as per the MedDRA dictionary.
    - Survie sans progression (PFS) définie par le délai entre la date de début de traitement et la date du premier des évènements suivants : progression ou décès (quelle que soit la cause).
    - La survie globale (OS) est définie par le délai entre la date de début de traitement et la date de décès (quelle que soit la cause).
    - Le profil de tolérance de l’association sera évalué selon l’échelle de sévérité de la NCI-CTCAE v5.0. Les évènements indésirables graves ou non graves seront codés selon le dictionnaire MedDRA.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1- and 3-year PFS rates and median PFS will be reported.
    1- and 3-year OS rates and median OS will be reported.
    Safety will be evaluated throughout the treatment period (an expected average of 5 months)
    Les taux de PFS à 1 et 3 ans et la médiane de PFS seront reportés.
    Les taux d’OS à et 3 ans et la médiane d’OS seront reportés.
    La toxicité sera évaluée tout au long de la période de traitement (durée estimée à environ 5 mois)
    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 Yes
    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 Yes
    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
    Association de la doxorubicine et de l'ifosfamide
    Association of doxorubicin and Ifosfamide
    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 concerned4
    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
    Dernière visite du dernier patient
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months6
    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: 44
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 22
    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 state66
    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 Decision2021-10-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-09-09
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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