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    Summary
    EudraCT Number:2020-002366-13
    Sponsor's Protocol Code Number:IB2020-02
    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:2021-10-21
    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 number2020-002366-13
    A.3Full title of the trial
    Combination of pembrolizumab and cabozantinib in patients with advanced sarcomas
    Association du Pembrolizumab et du Cabozantinib chez les patients porteurs d’un sarcome avancé
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Combination of pembrolizumab and cabozantinib in patients with advanced sarcomas
    Association du Pembrolizumab et du Cabozantinib chez les patients porteurs d’un sarcome avancé
    A.3.2Name or abbreviated title of the trial where available
    PEMBROCABOSARC
    PEMBROCABOSARC
    A.4.1Sponsor's protocol code numberIB2020-02
    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 supportGroupement Interrégional de Recherche Clinique et d’Innovation Sud-ouest Outre-mer Hospitalier
    B.4.2CountryFrance
    B.4.1Name of organisation providing supportIPSEN PHARMA
    B.4.2CountryFrance
    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 Yes
    D.2.1.1.1Trade name KEYTRUDA
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    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.3.1Product namePEMBROLIZUMAB
    D.3.2Product code MK-3475
    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 INNPembrolizumab
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK3475
    D.3.9.3Other descriptive namePembrolizumab
    D.3.9.4EV Substance CodeSUB167136
    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) Yes
    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 CABOMETYX
    D.2.1.1.2Name of the Marketing Authorisation holderIpsen Pharma
    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 nameCABOZANTINIB
    D.3.2Product code XL184
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCabozantinib
    D.3.9.1CAS number XL184
    D.3.9.2Current sponsor code849217-68-1
    D.3.9.3Other descriptive nameCabozantinib
    D.3.9.4EV Substance CodeSUB93452
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number20 to 40
    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
    Advanced /metastatic sarcomas: undifferentiated pleomorphic sarcoma, osteosarcoma and Ewing sarcoma
    Sarcomes localement avancés et/ou métastatiques : sarcomes indifférenciés, ostéosarcomes et sarcomes d’Ewing
    E.1.1.1Medical condition in easily understood language
    Advanced /metastatic sarcomas: undifferentiated pleomorphic sarcoma, osteosarcoma and Ewing sarcoma
    Sarcomes localement avancés et/ou métastatiques : sarcomes indifférenciés, ostéosarcomes et sarcomes d’Ewing
    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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Assessment of the efficacy of Pembrolizumab and Cabozantinib in terms of 6-month non-progression (as per RECIST v1.1 criteria) independently for 3 stratas:
    • Advanced undifferentiated pleomorphic soft-tissue sarcoma
    • Advanced osteosarcoma
    • Advanced Ewing sarcoma
    Evaluation de l’efficacité du pembrolizumab en l’associant avec du cabozantinib, en termes de non-progression à 6 mois (selon RECIST v1.1) et indépendamment pour 3 strates :
    • Sarcomes pléomorphes indifférenciés des tissus mous avancés
    • Ostéosarcomes avancés
    • Sarcomes d’Ewing avancés
    E.2.2Secondary objectives of the trial
    Each strata will be analysed independently.
    • Assessment of the efficacy of the treatment strategy in terms of best overall response (as per RECIST v1.1 criteria), 1-year Progression-free survival (PFS, as per RECIST v1.1 criteria), and 1-year overall survival (OS).
    • Assessment of the safety profile of the treatment strategy using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0.
    • Assessment of the Growth modulation index (GMI), defined for each patient as the ratio of the PFS on the current treatment strategy to the PFS on the previous line of therapy (Von Hoff 1998), in patients with documented progression under a previous line at inclusion.
    • Assessment of the efficacy of the treatment strategy in terms of 6-month non-progression according to iRECIST (Seymour 2017; central radiological review data)
    • Translational research on blood and tumor samples obtained at baseline and several time points during treatment.
    Pour chaque strate
    • Evaluation de l’efficacité de la stratégie de traitement en termes de meilleure réponse globale (RECIST v1.1), survie sans progression à 1 an (PFS, RECIST v1.1), et survie globale à 1 an (OS).
    • Evaluation du profil de tolérance de la stratégie de traitement selon la classification NCI-CTCAE v5.0.
    • Growth modulation index (GMI), défini par le ratio de la PFS sous la stratégie de traitement en cours par la PFS sous ligne de traitement antérieur (Von Hoff 1998), au sein des patients avec documentation de maladie progressive à l’inclusion.
    • Evaluation de la réponse immunologique à 6 mois (non-progression) selon iRECIST (Seymour, 2017 ; relecture radiologique centralisée)
    • Recherche translationnelle réalisée à partir de sang et de tissu tumoral collectés à différents temps.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histology: undifferentiated pleomorphic sarcoma (stratum 1), osteosarcoma (stratum 2) or Ewing sarcoma (stratum 3). Diagnosis must be reviewed or confirmed by the RRePS Network as recommended by the French NCI (Inca),
    2. Advanced non resectable / metastatic disease,
    3. Recurrent disease or progression after standard therapy,
    4. Documented progression according to RECIST criteria. Progression on the last line of treatment should be confirmed by central review with two radiological assessments identical (CT scans or MRI) obtained at less than 6 months interval within the 12 months before inclusion, except if first line of recurrence,
    5. Have provided tissue of a tumor lesion from < 3 months old archival tissue sample obtained on locally advanced disease, or metastatis with no subsequent treatment since or from a newly obtained core or excisional biopsy,
    6. No more of three previous lines of systemic therapy for advanced disease,
    7. Age ≥ 18 years,
    8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1,
    9. Measurable disease according to RECIST v1.1 outside any previously irradiated field. At least one site of disease must be uni-dimensionally ≥ 10 mm,
    10. Life expectancy > 3 months,
    11. Participant must have advanced disease and must not be a candidate for other approved therapeutic regimen known to provide significant clinical benefit based on investigator judgement,
    12. No symptomatic central nervous system disease,
    13. No chronic use of glucocorticoids.
    14. Adequate hematological, renal, metabolic and hepatic function:
    a. Hemoglobin ≥ 9 g/dl (without erythropoietin dependency and without red blood cel transfusion within the last two weeks); absolute neutrophil count (ANC) ≥ 1.5 G/l, lymphocytes count ≥ 0.5 G/l and platelet count ≥ 100 G/l,
    b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of liver metastasis).
    c. Total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels ≥ 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. Creatine phosphokinase (CPK) ≤ 2.5 x ULN
    g. International normalized ratio (INR) OR prothrombin time (PT), activated partial thromboplastine time (aPTT) ≤ 1.5 x ULN.,
    h. Lipase ≤ 2 x ULN and no radiological or clinical evidence of pancreatitis,
    i. Urine protein/creatinine ratio (UPCR) ≤ 1,
    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, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma,
    16. At least three weeks since last chemotherapy, immunotherapy and two weeks for any other pharmacological treatment and/or radiotherapy,
    17. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia of any grade, non-painful peripheral neuropathy grade ≤ 2 and endocrine-related grade ≤ 2 requiring treatment or hormone replacement) (according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE, version 5.0). For patients previously treated by radiotherapy, they must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis,
    18. Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication. Both women and men must agree to use 2 medically acceptable methods of contraception throughout the treatment period and for 180 days after discontinuation of treatment. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for ≥ 1 year,
    19. Voluntary signed and dated written informed consents prior to any specific study procedure,
    20. Patients with a social security in compliance with the French Law.
    1. Histologie : sarcome pléomorphe indifférencié des tissus mous (strate 1), ostéosarcome (strate 2) ou sarcome d’Ewing (strate 3) histologiquement confirmé. Conformément aux recommandations de l’Inca, le diagnostic devra être lu ou relu dans le cadre du réseau RRePS (Réseau de Référence en Pathologie des Sarcomes et des Tissus Mous et des Viscères),
    2. Maladie localement avancée inopérable et/ou métastatique,
    3. Rechute ou progression après traitement standard,
    4. Progression documentée selon les critères RECIST. Maladie progressive sur la dernière ligne de traitement, sur la base de deux scanners ou IRM réalisés à moins de 6 mois d’intervalle dans les 12 mois précédant l’inclusion, et confirmée par la relecture centralisée ; exception faite des patients en première ligne de rechute.
    5. Echantillon tumoral archivé disponible obtenu sur métastase ou maladie localement avancée, ou micro-biopsie de la lésion tumorale récemment réalisée. Le matériel tumoral archivé doit dater de moins de 3 mois et le patient ne devra avoir eu aucun traitement depuis, ou matériel obtenu sur biopsie nouvellement réalisée,
    6. Pas plus de trois lignes de traitement systémique antérieur pour une maladie avancée,
    7. Age ≥ 18 ans,
    8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1,
    9. Maladie mesurable selon les critères RECIST v1.1 en dehors de champs d’irradiation. Au moins une lésion ≥ 10 mm,
    10. Espérance de vie > 3mois,
    11. Patient avec une maladie avancée, et qui selon le jugement de l’investigateur, ne sont pas éligibles à une autre thérapie standard connue pour fournir un bénéfice clinique significatif,
    12. Pas de pathologie symptomatique du système nerveux central,
    13. Pas d’usage chronique des glucocorticoïdes,
    14. Fonctions hématologiques, rénales, métaboliques et hépatiques :
    a. Hémoglobine ≥ 9 g/dl (sans traitement par erythropoiétine et sans transfusion préalable de globules rouges dans les deux semaines précédentes); neutrophiles (ANC) ≥ 1.5 x 109/l, lymphocytes ≥ 0.5 x 109/l et, plaquettes ≥ 100 x 109/l et
    b. Alanine aminotransférase (ALT) et aspartate aminotransférase (AST) ≤ 2.5 x limite normale supérieure (ULN) (≤ 5 en cas de metastases hépatiques).
    c. Bilirubine totale ≤ 1.5 x ULN OU Bilirubine directe ≤ ULN pour les patients avec une 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 (calculé selon les standards institutionnels) pour les patients avec un niveau de créatinine ≥ 1.5 x ULN.
    f. Créatine phosphokinase (CPK) ≤ 2.5 x ULN
    g. PT ou INR ; aPTT ≤ 1.53 x ULN,
    h. Lipase ≤ 2 x ULN et sans preuve clinique ou radiologique d’une pancréatite,
    i. Ration protéinurie/créatinurie ≤ 1.
    15. Pas de pathologie maligne antérieure ou concomitante, diagnostiquée ou traitée dans les 2 dernières années, exception faite des carcinomes in situ du col de l’utérus, des carcinomes basocellulaires ou squameux de la peau, et des carcinomes in situ de la vessie correctement traités,
    16. Au moins trois semaines de latence depuis la dernière chimiothérapie, et 14 jours de wash-out depuis la dernière immunothérapie ou tout autre traitement pharmacologique et/ou radiothérapie,
    17. Retour à un grade ≤ 1 de toxicité suite à un traitement antérieur (sauf pour l’alopécie quel que soit le grade, et pour les neuropathies périphériques non douloureuse de grade ≤ 2) selon CTCAE, version 5.0. Pour les patients précédemment traités par radiothérapie, récupération des toxicités radio-induites, ne pas nécessiter de traitement par corticostéroïdes et absence de pneumonie radio-induite,
    18. Test de grossesse (sérum) négatif dans les 72 heures avant le début du traitement à l’étude pour les femmes susceptibles d’être enceinte. Utilisation de deux méthodes de contraception durant la durée du traitement et 180 jours suivant l’arrêt. Ne sont pas concernés les patients n’ayant pas subi une stérilisation chirurgicale ou les femmes ménopausées ≥ 1 an.
    19. Consentement éclairé du patient (daté et signé) avant toute procédure spécifique à l’essai,
    20. Affiliation à un régime de sécurité sociale selon la loi française.
    E.4Principal exclusion criteria
    1. Previous treatment with Pembrolizumab or Cabozantinib,
    2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumabor any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways),
    3. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases,
    4. Men or women of childbearing potential who are not using an effective method of contraception; women who are pregnant or breast feeding, men or women who are planning to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment,
    5. Participation to a study involving a medical or therapeutic intervention in the last 21 days,
    6. Previous enrolment in the present study,
    7. Patient unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons,
    8. Patient unable to swallow,
    9. Known hypersensitivity to any involved study drug or of its formulation components,
    10. 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 and is allowed.
    11. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment,
    12. History of idiopathic pulmonary fibrosis, history of non-infectious pneumonitis that required steroids, current pneumonitis/interstitial lung disease, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted,
    13. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
    14. Has a known history of Human Immunodeficiency Virus (HIV) infection (HIV1/2 antibodies) and/or of active TB (Bacillus Tuberculosis),
    15. Treatment with anticoagulants such as anti-Vitamin K, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel),
    16. Previous allogenic bone marrow transplant or solid organ transplantation,
    17. Has an active infection requiring systemic treatment at study entry,
    18. The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before treatment. Note: if initial QTcF is found to be > 500 ms, two additional ECGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard,
    19. The subject requires chronic concomitant treatment of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John’s Wort). Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians’ Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product,
    20. The subject has experienced any of the following:
    a. Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
    b. Hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment
    c. Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
    d. The subject has radiographic evidence of cavitating pulmonary lesion(s).
    e. The subject has tumor in contact with, invading or encasing any major blood vessels.
    f. The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib.
    1. Traitement antérieur par pembrolizumab ou cabozantinib,
    2. Thérapie antérieure par des anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, ou anti-CTLA4,
    3. Preuve de l’existence de métastases cérébrales ou leptoméningées, progressives ou symptomatiques,
    4. Hommes ou femmes susceptibles de procréer n’utilisant pas de méthode de contraception, les femmes enceintes ou en cours d’allaitement, hommes ou femmes ayant un souhait de paternité ou de grossesse pendant la durée de l’étude (de la visite de screening jusqu’à 120 jours après l’arrêt des traitements),
    5. Patients participant à un autre essai clinique médicament et traités par un médicament à l’étude dans les 21 derniers jours,
    6. Participation antérieure à cet essai,
    7. Facteurs géographiques, sociaux ou psychologiques rendant le patient incapable de se soumettre au suivi et aux procédures de l’étude,
    8. Incapacité d’avaler,
    9. Antécédent d’allergie connu à un produit de composition chimique ou biologique similaire à l’un des produits utilisé dans l’étude,
    10. Maladie auto-immune active qui a nécessité un traitement systémique dans les deux dernières années (i.e., utilisation d’immunomodulateurs, corticostéroïdes ou agents immunosuppresseurs). Les traitements de substitution (eg. Thyroxine, insuline ou corticostéroïdes à dose physiologique pour une insuffisance adrénalienne ou pituitaire, etc…) ne sont pas considérés comme des traitements systémiques et sont autorisés.
    11. Patients diagnostiqués immunodéficient ou traités par stéroïdes systémiques ou toute autre thérapie immunosuppressive dans les 7 jours avant le début du traitement,
    12. Antécédent de fibrose pulmonaire idiopathique, de pneumopathie non-infectieuse nécessitant l’usage de stéroides, de pneumopathie en cours, de pneumopathie immuno-allergique, de pneumopathie organisée, ou pneumopathie active sur le scanner du bilan d’inclusion. Un antécédent de pneumopathie radique n’est pas un critère d’exclusion.
    13. Antécédent connu d’hépatite B (définie par la présence d’antigène de surface HBsAg positif) ou infection virale active par l’hépatite C (définie par la détection quantitaive d’ARN HCV).
    14. Virus de l’immunodéficience Humaine connu (HIV) infections (anticorps HIV1/2), Antécédent connu de tuberculose active (bacille de la tuberculose),
    15. Traitement anticoagulant : anti-vitamine K, inhibiteurs de la thrombine ou anti-Xa, antiagrégants plaquettaires (clopidogrel),
    16. Antécédent de greffe allogénique ou de transplantation d’organe,
    17. Infection active nécessitant un traitement systémique à l’entrée dans l’étude,
    18. QT corrigé (QTcF) > 500 ms dans les 28 jours précédant le traitement. Note: si le QTcF initial est > 500 ms, 2 ECG supplémentaires seront réalisés à 3 minutes d’intervalle. Si la moyenne des 3 QTcF est ≤ 500 ms, le patient est éligible en ce qui concerne ce critère,
    19. Traitement concomitants : inducteurs forts CYP3A4 (comme la phenytoine, la carbamazepine, la rifampicine, la rifabutine, rifapentine, phenobarbital, et St. John’s Wort). Les investigateurs sont invités à consulter le lien suivant pour la liste des médicaments concernés. http://medicine.iupui.edu/clinpharm/ddis/table.aspx. Les patients seront conseillés sur les risques d’interaction et sur la conduite à tenir en cas de prescription d’un nouveau traitement concomitant relevant de l’allopathie, de l’homéopathie ou de la phytothérapie.
    20. Le patient a présenté l’un des évènements suivants :
    - Hémorragie digestive cliniquement significative dans les 6 mois précédant le début du traitement
    - Hémoptysie significative (≥0.5 cuillère à café ou 2.5 ml) dans les 3 mois précédant le début du traitement
    - Tout autre signe évocateur d’hémorragie pulmonaire dans les 3 mois précédant le début du traitement
    - Présence radiologique de lésion cavitaire au niveau du parenchyme pulmonaire
    - Tumeur en contact ou envahissant un gros vaisseau
    - Tumeur envahissant le tube digestif (oesophage, estomac, intestin grêle, colon, rectum, anus) ou tumeur endo-trachéale ou endo-bronchique dans les 28 jours précédant le début du traitement.
    E.5 End points
    E.5.1Primary end point(s)
    • The primary efficacy endpoint for advanced undifferentiated pleomorphic sarcoma (stratum 1), advanced osteosarcoma (stratum 2) and advanced Ewing sarcoma (stratum 3) is 6-month non-progression (as per RECIST evaluation criteria v1.1).
    • Non-progression: complete response, partial response or stable disease more than 24 weeks as per RECIST evaluation criteria v1.1.
    • Objective response: complete response or partial response as per RECIST evaluation criteria v1.1.
    • Following RECIST v1.1 recommendations:
    o claimed responses (complete or partial response) will have to be confirmed at least 4 weeks later;
    o 6-month radiological data will be reviewed by an independent expert radiologist.
    o Primary efficacy analysis will be based on the central radiological review data.
    o Each patient will be assigned one of the following categories: Complete response, Partial response, Stable disease, Progression, not evaluated for response.
    • Le critère de jugement principal pour la strate des sarcomes pléomorphes indifférenciés des tissus mous avancés (strate 1), des ostéosarcomes avancés (strate 2) et des sarcomes d’Ewing avancés (strate 3) est la non-progression à 6 mois (RECIST v1.1).
    • Non-progression : réponse complète, réponse partielle ou maladie stable plus de 24 semaines selon les critères RECIST v1.1.
    • Réponse objective : réponse complète ou réponse partielle selon les critères RECIST v1.1.
    • Tel que recommandé par les critères RECIST v1.1:
    o Toutes les réponses devront être confirmées au moins 4 semaines plus tard ;
    o Les données radiologiques à 6 mois seront relues par un radiologue expert et indépendant.
    o L’analyse principale de l’efficacité sera basée sur la relecture radiologique centralisée.
    o La réponse de chaque patient sera classifiée selon les catégories suivantes (RECIST v1.1) : réponse complète, réponse partielle, maladie stable, progression, non évaluable pour la réponse.
    E.5.2Secondary end point(s)
    • Best overall response defined as per RECIST v1.1 criteria.
    • 1-year progression-free survival (PFS): 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.
    • 1-year overall survival (OS): OS is defined as the time from study treatment initiation to death (of any cause).
    • Growth modulation index (GMI), defined for each patient as the ratio of the PFS on the current treatment strategy to the PFS on the previous line of therapy (Von Hoff, 1998), in patients with documented progression at inclusion.
    • Toxicity will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0.
    • Immune-related response is defined according to iRECIST (Seymour 2017). Analysis will be based on data centrally reviewed by an expert radiologist.
    • Performance of pharmacodynamic (PD)/mechanism of action (MOA) biomarkers analysis as well as predictive biomarkers analysis (levels of angiogenic and immunologic biomarkers) in blood and tumor tissue at baseline and different study time points.
    o Blood samples will be mandatory collected at predefined timepoints for assessment of:
    o Serum/plasma cytokines levels (TNFγ, TNFα, TGFβ, IL2, 4, 6, 10), VEGF, HGF, sMET, sVEGFR2 (ELISA)
    o Treg, CD4+ CD8+ and DR lymphocytes subpopulations monitoring, CD8+/Treg ratio (flow cytometry)
    o Plasma levels of Kynurenine and Kynurenine to Tryptophan ratio (ELISA and LC/MS)
    o Availability of a < 3 months, non subsequently treated or fresh tumor samples, with frozen material available will be mandatory at inclusion for baseline, and a second sampling will be mandatorily collected during treatment at C2Day8 (+/- 3 days). Formalin-fixed, paraffin-embedded biopsy samples will be analysed for (but not limited to) CD8+ effectors, CD68 and 163 Macrophages and FOXP3+ cells infiltrates as well as PDL1, IDO1, CD31 (microvessel density), as well as MET and phosphoMET, Ki67 expression by IHC. Frozen samples will be analysed by (but not limited to) RNA sequencing in search for a predictive signature for response.
    • Meilleure réponse globale définie selon les critères RECIST v1.1.
    • Survie sans progression à 1 an (PFS): la PFS est définie par le délai entre la date d’initiation du traitement et la date du premier évènement suivant : progression (RECIST) ou décès (toute cause).
    • Survie globale à 1 an (OS): L’OS est définie par le délai entre la date d’initiation du traitement et la date du décès (toute cause).
    • Growth modulation index (GMI): le GMI est défini pour chaque patient, par le ratio de la PFS sous traitement à l’étude sur la PFS sous la ligne de traitement antérieure (Von Hoff, 1998), pour les patients présentant une maladie progressive et documentée à l’inclusion.
    • La réponse immunologique est définie selon les critères de Wolchok et al. (Clinical Cancer Research 2009). Les réponses immunologiques seront relues par un radiologue expert.
    • La toxicité/tolérance sera évaluée à partir de l’échelle de toxicité NCI CTC v5.0.
    • La réponse immunologique est définie selon les critères iRECIST de Seymour (2017). Les réponses immunologiques seront relues par un radiologue expert.
    • Recherche translationnelle : pharmacodynamie (PD)/mécanismes d’action (MOA) analyse de biomarqueurs prédictifs (niveau des marqueurs angiogéniques et immunologiques dans le sang et le tissu tumoral au baseline et à différents temps de suivi.
    o Echantillons sanguins collectés à des temps pré-définis pour évaluer :
    - Concentrations de cytokines dans le sérum/plasma (TNFγ, TNFα, TGFβ, IL2, 4, 6, 10), VEGF, HGF, sMET, Svegfr2 (ELISA)
    - Lymphocytes Treg, CD4+, CD8+, et ratio CD8+/Treg (cytométrie de flux)
    - Concentrations de Kynurenine et ratio Kynurenine/Tryptophane (ELISA and LC/MS)
    o Matériel tumoral archivé de moins de 3 mois et sans traitement depuis OU biopsies tumorales collectées au baseline et pendant traitement. Les blocs paraffine de biopsie fixés dans le formol seront analysés pour évaluer les marqueurs suivants (liste non exhaustive) : CD8+ effectors, CD68 et 163 Macrophages et FOXP3+ les infiltrats cellulaires tels que PDL1, IDO1, CD31, expression de MET et phosphoMET, Ki67 par IHC. Les tissus congelés seront analysés par RNA seq pour la recherche d’une signature prédictive de la réponse (liste non exhaustive).
    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 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 Yes
    E.8.1.7.1Other trial design description
    Schéma de Simon en 2 étapes
    2-stage optimal Simon’s design
    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 concerned10
    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 years4
    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: 101
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 18
    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 state119
    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 Decision2021-12-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-01
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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