Ignite Creation Date:
2025-12-24 @ 9:46 PM
Ignite Modification Date:
2026-01-03 @ 9:01 PM
Study NCT ID:
NCT03220932
Status:
UNKNOWN
Last Update Posted:
2019-11-01
First Post:
2017-05-11
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Cytoreductive Surgery and HIPEC in First or Secondary Platinum-resistant Recurrent Ovarian Epithelial Cancer
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'conditionBrowseModule': {'meshes': [{'id': 'D000077216', 'term': 'Carcinoma, Ovarian Epithelial'}], 'ancestors': [{'id': 'D002277', 'term': 'Carcinoma'}, {'id': 'D009375', 'term': 'Neoplasms, Glandular and Epithelial'}, {'id': 'D009370', 'term': 'Neoplasms by Histologic Type'}, {'id': 'D009369', 'term': 'Neoplasms'}, {'id': 'D010051', 'term': 'Ovarian Neoplasms'}, {'id': 'D004701', 'term': 'Endocrine Gland Neoplasms'}, {'id': 'D009371', 'term': 'Neoplasms by Site'}, {'id': 'D010049', 'term': 'Ovarian Diseases'}, {'id': 'D000291', 'term': 'Adnexal Diseases'}, {'id': 'D005831', 'term': 'Genital Diseases, Female'}, {'id': 'D052776', 'term': 'Female Urogenital Diseases'}, {'id': 'D005261', 'term': 'Female Urogenital Diseases and Pregnancy Complications'}, {'id': 'D000091642', 'term': 'Urogenital Diseases'}, {'id': 'D005833', 'term': 'Genital Neoplasms, Female'}, {'id': 'D014565', 'term': 'Urogenital Neoplasms'}, {'id': 'D000091662', 'term': 'Genital Diseases'}, {'id': 'D004700', 'term': 'Endocrine System Diseases'}, {'id': 'D006058', 'term': 'Gonadal Disorders'}]}, 'interventionBrowseModule': {'meshes': [{'id': 'D000084262', 'term': 'Hyperthermic Intraperitoneal Chemotherapy'}, {'id': 'D004358', 'term': 'Drug Therapy'}, {'id': 'D000068258', 'term': 'Bevacizumab'}], 'ancestors': [{'id': 'D017024', 'term': 'Chemotherapy, Adjuvant'}, {'id': 'D003131', 'term': 'Combined Modality Therapy'}, {'id': 'D013812', 'term': 'Therapeutics'}, {'id': 'D006979', 'term': 'Hyperthermia, Induced'}, {'id': 'D061067', 'term': 'Antibodies, Monoclonal, Humanized'}, {'id': 'D000911', 'term': 'Antibodies, Monoclonal'}, {'id': 'D000906', 'term': 'Antibodies'}, {'id': 'D007136', 'term': 'Immunoglobulins'}, {'id': 'D007162', 'term': 'Immunoproteins'}, {'id': 'D001798', 'term': 'Blood Proteins'}, {'id': 'D011506', 'term': 'Proteins'}, {'id': 'D000602', 'term': 'Amino Acids, Peptides, and Proteins'}, {'id': 'D012712', 'term': 'Serum Globulins'}, {'id': 'D005916', 'term': 'Globulins'}]}}, 'protocolSection': {'designModule': {'phases': ['PHASE3'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'RANDOMIZED', 'maskingInfo': {'masking': 'NONE'}, 'primaryPurpose': 'TREATMENT', 'interventionModel': 'PARALLEL'}, 'enrollmentInfo': {'type': 'ESTIMATED', 'count': 132}}, 'statusModule': {'overallStatus': 'UNKNOWN', 'lastKnownStatus': 'NOT_YET_RECRUITING', 'startDateStruct': {'date': '2019-11-30', 'type': 'ESTIMATED'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2019-10', 'completionDateStruct': {'date': '2022-11-30', 'type': 'ESTIMATED'}, 'lastUpdateSubmitDate': '2019-10-31', 'studyFirstSubmitDate': '2017-05-11', 'studyFirstSubmitQcDate': '2017-07-17', 'lastUpdatePostDateStruct': {'date': '2019-11-01', 'type': 'ACTUAL'}, 'studyFirstPostDateStruct': {'date': '2017-07-18', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2022-11-30', 'type': 'ESTIMATED'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Progression free survival', 'timeFrame': 'Change from baseline to 36 months', 'description': 'Progression will be based on RECIST V1.1 criteria performed on thoraco-abdominopelvic tomodensitometry (TDM ) assessed every 3 months. There is a follow-up period of 36 months.'}], 'secondaryOutcomes': [{'measure': 'Overall survival', 'timeFrame': 'From the randomization to the death or 36 months end of follow-up', 'description': 'There is a follow-up period of 36 months.'}, {'measure': 'Potential treatment-related mortality', 'timeFrame': 'During the first 60 postoperative days', 'description': 'Reported only in the experimental arm (cytoreductive surgery + HIPEC)'}, {'measure': 'Potential treatment-related morbidity', 'timeFrame': 'During the first 60 postoperative days', 'description': 'Adverse events (AE) during the follow-up period: safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, and vital signs. AEs will be described using MedDRA terms (version 18.0) and graded according to Common Terminology Criteria for Adverse Events (CTCAE version 5.0). These will be collected for all randomized patients.'}, {'measure': 'Quality of life assessment', 'timeFrame': 'Baseline to 36 months end of follow-up', 'description': 'Quality of Life will be assessed using the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) for all randomized patients.'}]}, 'oversightModule': {'oversightHasDmc': True, 'isFdaRegulatedDrug': False, 'isFdaRegulatedDevice': False}, 'conditionsModule': {'keywords': ['Epithelial Ovarian Cancer - Platinum-resistant - Cytoreductive surgery - HIPEC - Quality of Life'], 'conditions': ['Ovarian Epithelial Cancer']}, 'descriptionModule': {'briefSummary': 'With 4,600 new cases in France in 2012, ovarian cancer is the seventh most common cancer in women and the fourth cause of mortality by cancer. Despite a high response rate to initial treatment, most patients will relapse within 2 years. No standard treatment has yet been established for patients with recurrent ovarian cancer.\n\nMost patients with such recurrences are currently treated with new combinations of systemic chemotherapy. A repeated laparotomy with complete cytoreduction is also an option that several authors have used to obtain median survival rates of more than 30 months.\n\nTwenty five percent of patients experiencing relapse present with platinum-resistant recurrence, occurring less than 6 months after chemotherapy completion. Recently, Pujade et al. showed that adding bevacizumab to chemotherapy significantly improves progression-free survival (PFS) in this subgroup of patients with poor prognoses (16.6 months versus 13.3 months in women treated with chemotherapy alone). Three case control studies have compared systemic chemotherapy and CRS (Cytoreduction Surgery) alone versus CRS plus HIPEC in patients with recurrent disease. They showed significantly improved results with the addition of HIPEC. In the French registry that included 474 patients with recurrence and peritoneal carcinomatosis, the median PFS was 13.8 months for platinum-resistant patients and 13 months for platinum-sensitive patients. Our hypothesis is that surgery would reduce the tumor burden and consequently the number of platinum-resistant tumor clones and that HIPEC would control the microscopic residual disease by increasing the tumor cell cytotoxicity.\n\nWe assume that adding a locoregional treatment to an "Aurelia-like" systemic treatment would improve the PFS. We aim to assess the benefit of adding surgery and HIPEC to the treatment of first or second platinum-resistant recurrence compared to chemotherapy + bevacizumab.'}, 'eligibilityModule': {'sex': 'FEMALE', 'stdAges': ['ADULT', 'OLDER_ADULT'], 'maximumAge': '75 Years', 'minimumAge': '18 Years', 'healthyVolunteers': False, 'eligibilityCriteria': "Inclusion Criteria:\n\n* Histologically confirmed platinum-resistant Epithelial Ovarian Carcinoma (EOC)(clinical recurrence or persistence within 6 months of last treatment);\n* White blood cells \\>3,500/mm3, neutrophils ≥1,500/mm3, platelets ≥100,000/mm3;\n* Good renal function: serum creatinine values \\<1.5 mg/dl, creatinine clearance \\>60 ml/min;\n* Performance Status ≤2, Karnofsky Index ≥70%;\n* Serum bilirubin ≤1.5 x Upper limit of normal (UNL) 2 mg/dl;\n* Prior ovarian surgery before starting study treatment;\n* Covered by a Healthcare System, where applicable, and/or in compliance with the recommendations of the national laws in force relating to biomedical research;\n* Signed written informed consent obtained prior to any study-specific screening procedures.\n\nExclusion Criteria:\n\n* Platinum-refractory EOC (i.e progression under platinum containing chemotherapy);\n* Any prior malignancy not considered in complete remission for at least 2 years;\n* Pregnancy or breastfeeding;\n* Untreated central nervous system disease or symptomatic central nervous system metastasis, history or evidence of thrombotic or hemorrhagic disorders within 6 months before first study treatment;\n* Uncontrolled hypertension or active clinically significant cardiovascular disease;\n* Females of childbearing age not using medically accepted contraceptive measures, as judged by the investigator;\n* Contraindication to any drug contained in the chemotherapy regimen;\n* Known contraindication to cisplatin\n* Medical, geographical, sociological, psychological or legal conditions that would prevent the patient from completing the study or signing the informed consent;\n* Any significant disease which, in the investigator's opinion, excludes the patient from the study;\n* Under any administrative or legal supervision."}, 'identificationModule': {'nctId': 'NCT03220932', 'acronym': 'HIPOVA-01', 'briefTitle': 'Cytoreductive Surgery and HIPEC in First or Secondary Platinum-resistant Recurrent Ovarian Epithelial Cancer', 'organization': {'class': 'OTHER', 'fullName': 'Hospices Civils de Lyon'}, 'officialTitle': 'Assessment of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in First or Secondary Platinum-resistant Recurrent Ovarian Epithelial Cancer', 'orgStudyIdInfo': {'id': '69HCL17_0342'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'EXPERIMENTAL', 'label': 'Cytoreductive surgery combined with HIPEC', 'description': 'All patients will start with three cycles of CT-BEV 15 mg/kg, and will then be randomly. Then one cycle of monochemotherapy without bevacizumab is administered and followed by an interval CRS and HIPEC with postoperative chemotherapy and bevacizumab (CT-BEV - 15 mg/kg once every 3 weeks) until disease progression', 'interventionNames': ['Procedure: Cytoreductive surgery combined with HIPEC']}, {'type': 'ACTIVE_COMPARATOR', 'label': 'Aurelia arm', 'description': 'Chemotherapy and bevacizumab (CT-BEV) once every 3 weeks from enrollment until disease progression', 'interventionNames': ['Drug: Chemotherapy and bevacizumab (CT-BEV)']}], 'interventions': [{'name': 'Cytoreductive surgery combined with HIPEC', 'type': 'PROCEDURE', 'description': 'Cytoreductive surgery combined with HIPEC (Cisplatin 70 mg/m2).', 'armGroupLabels': ['Cytoreductive surgery combined with HIPEC']}, {'name': 'Chemotherapy and bevacizumab (CT-BEV)', 'type': 'DRUG', 'description': 'Chemotherapy and bevacizumab (CT-BEV) 15 mg/kg once every 3 weeks from enrollment until disease progression (RECIST 1.1)', 'armGroupLabels': ['Aurelia arm']}]}, 'contactsLocationsModule': {'locations': [{'zip': '25030', 'city': 'Besançon', 'country': 'France', 'contacts': [{'name': 'Brice PAQUETTE, MD', 'role': 'CONTACT', 'email': 'bpaquette@chu-besancon.fr', 'phone': '381 668 970', 'phoneExt': '+33'}, {'name': 'Brice PAQUETTE, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Centre Hospitalier Universitaire Jean Minjoz', 'geoPoint': {'lat': 47.24878, 'lon': 6.01815}}, {'zip': '25030', 'city': 'Besançon', 'country': 'France', 'contacts': [{'name': 'Fernando BAZAN, MD', 'role': 'CONTACT', 'email': 'fbazan@chu-besancon.fr', 'phone': '381 479 999', 'phoneExt': '+33'}, {'name': 'Fernando BAZAN, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Centre Hospitalier Universitaire Jean Minjoz', 'geoPoint': {'lat': 47.24878, 'lon': 6.01815}}, {'zip': '59000', 'city': 'Lille', 'country': 'France', 'contacts': [{'name': 'Fabrice NARDUCCI, MD', 'role': 'CONTACT', 'email': 'F-Narducci@o-lambret.fr', 'phone': '32 0295 944', 'phoneExt': '+33'}, {'name': 'Fabrice NARDUCCI, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Centre Oscar Lambret', 'geoPoint': {'lat': 50.63391, 'lon': 3.05512}}, {'zip': '59067', 'city': 'Lille', 'country': 'France', 'contacts': [{'name': 'Clarisse EVENO, MD', 'role': 'CONTACT', 'email': 'clarisse.eveno@chru-lille.fr', 'phone': '320 445 962', 'phoneExt': '+33'}, {'name': 'Clarisse EVENO, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'CHRU Claude Huriez', 'geoPoint': {'lat': 50.63391, 'lon': 3.05512}}, {'zip': '69008', 'city': 'Lyon', 'country': 'France', 'contacts': [{'name': 'Pierre MEEUS, MD', 'role': 'CONTACT', 'email': 'pierre.meeus@lyon.unicancer.fr', 'phone': '478 782 637', 'phoneExt': '+33'}, {'name': 'Pierre MEEUS, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Centre Léon Bérard', 'geoPoint': {'lat': 45.74906, 'lon': 4.84789}}, {'zip': '69008', 'city': 'Lyon', 'country': 'France', 'contacts': [{'name': 'Isabelle RAY-COQUARD, MD', 'role': 'CONTACT', 'email': 'isabelle.ray-coquard@lyon.unicancer.fr', 'phone': '478 782 888', 'phoneExt': '+33'}, {'name': 'Isabelle RAY-COQUARD, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Centre Léon Bérard', 'geoPoint': {'lat': 45.74906, 'lon': 4.84789}}, {'zip': '34298', 'city': 'Montpellier', 'country': 'France', 'contacts': [{'name': 'Pierre-Emmanuel COLOMBO, MD', 'role': 'CONTACT', 'email': 'Pierre-Emmanuel.Colombo@icm.unicancer.fr', 'phone': '467 618 501', 'phoneExt': '+33'}, {'name': 'Pierre-Emmanuel COLOMBO, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Institut du Cancer de Montpellier', 'geoPoint': {'lat': 43.61093, 'lon': 3.87635}}, {'zip': '34298', 'city': 'Montpellier', 'country': 'France', 'contacts': [{'name': "Véronique D'HONDT, MD", 'role': 'CONTACT', 'email': 'Veronique.Dhondt@icm.unicancer.fr', 'phone': '467 613 151', 'phoneExt': '+33'}, {'name': "Véronique D'HONDT, MD", 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Institut du Cancer de Montpellier', 'geoPoint': {'lat': 43.61093, 'lon': 3.87635}}, {'zip': '06200', 'city': 'Nice', 'country': 'France', 'contacts': [{'name': 'Jérôme DELOTTE, MD', 'role': 'CONTACT', 'email': 'delotte.j@chu-nice.fr', 'phone': '492 035 948', 'phoneExt': '+33'}, {'name': 'Jérôme DELOTTE, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': "Centre Hospitalier Universitaire L'Archet II", 'geoPoint': {'lat': 43.70313, 'lon': 7.26608}}, {'zip': '06200', 'city': 'Nice', 'country': 'France', 'contacts': [{'name': 'Jean Marc BEREDER, MD', 'role': 'CONTACT', 'email': 'bereder.jm@chu-nice.fr', 'phone': '4 92 03 64 86', 'phoneExt': '+33'}, {'name': 'Jean Marc BEREDER, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': "Centre Hospitalier Universitaire L'Archet II", 'geoPoint': {'lat': 43.70313, 'lon': 7.26608}}, {'zip': '06200', 'city': 'Nice', 'country': 'France', 'contacts': [{'name': 'Delphine OUVRIER, MD', 'role': 'CONTACT', 'email': 'ouvrier.d@chu-nice.fr', 'phone': '492 037 777', 'phoneExt': '+33'}, {'name': 'Delphine OUVRIER, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': "Centre Hospitalier Universitaire L'Archet II", 'geoPoint': {'lat': 43.70313, 'lon': 7.26608}}, {'zip': '75015', 'city': 'Paris', 'country': 'France', 'contacts': [{'name': 'Fabrice LECURU, MD', 'role': 'CONTACT', 'email': 'fabrice.lecuru@egp.aphp.fr', 'phone': '156 093 567', 'phoneExt': '+33'}, {'name': 'Fabrice LECURU, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Hôpital Européen Georges Pompidou - APHP', 'geoPoint': {'lat': 48.85341, 'lon': 2.3488}}, {'zip': '69495', 'city': 'Pierre-Bénite', 'country': 'France', 'contacts': [{'name': 'Benoit YOU, MD', 'role': 'CONTACT', 'email': 'benoit.you@chu-lyon.fr', 'phone': '478 864 318', 'phoneExt': '+33'}, {'name': 'Benoit YOU, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Centre Hospitalier Lyon Sud', 'geoPoint': {'lat': 45.70359, 'lon': 4.82424}}, {'city': 'Pierre-Bénite', 'country': 'France', 'contacts': [{'name': 'Naoual BAKRIN, MD', 'role': 'CONTACT', 'email': 'naoual.bakrin@chu-lyon.fr', 'phone': '478 862 371', 'phoneExt': '+33'}, {'name': 'Naoual BAKRIN, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Centre Hospitalier Lyon Sud', 'geoPoint': {'lat': 45.70359, 'lon': 4.82424}}, {'zip': '86021', 'city': 'Poitiers', 'country': 'France', 'contacts': [{'name': 'Nadia RABAN, MD', 'role': 'CONTACT', 'email': 'nadia.raban@chu-poitiers.fr', 'phone': '549 444 444', 'phoneExt': '+33'}, {'name': 'Nadia RABAN, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Centre Hospitalier Universitaire de Poitiers', 'geoPoint': {'lat': 46.58261, 'lon': 0.34348}}, {'zip': '42270', 'city': 'Saint-Priest-en-Jarez', 'country': 'France', 'contacts': [{'name': 'Karine ABBOUD, MD', 'role': 'CONTACT', 'email': 'karine.abboud@chu-st-etienne.fr', 'phone': '477 828 337', 'phoneExt': '+33'}, {'name': 'Karine ABBOUD, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Centre Hospitalier Universitaire de St Etienne', 'geoPoint': {'lat': 45.4739, 'lon': 4.37678}}, {'zip': '42270', 'city': 'Saint-Priest-en-Jarez', 'country': 'France', 'contacts': [{'name': 'Céline CHAULEUR, MD', 'role': 'CONTACT', 'email': 'celine.chauleur@chu-st-etienne.fr', 'phone': '477 828 287', 'phoneExt': '+33'}, {'name': 'Céline CHAULEUR, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Centre Hospitalier Universitaire de St Etienne', 'geoPoint': {'lat': 45.4739, 'lon': 4.37678}}, {'zip': '42270', 'city': 'Saint-Priest-en-Jarez', 'country': 'France', 'contacts': [{'name': 'Romain RIVOIRARD, MD', 'role': 'CONTACT', 'email': 'romain.rivoirard@icloire.fr', 'phone': '477 917 134', 'phoneExt': '+33'}, {'name': 'Romain RIVOIRARD, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Institut de Cancérologie de la Loire', 'geoPoint': {'lat': 45.4739, 'lon': 4.37678}}, {'zip': '67200', 'city': 'Strasbourg', 'country': 'France', 'contacts': [{'name': 'Cécile BRIGAND, MD', 'role': 'CONTACT', 'email': 'cecile.brigand@chru-strasbourg.fr', 'phone': '388 127 226', 'phoneExt': '+33'}, {'name': 'Cécile BRIGAND, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Centre Hospitalier Universitaire Hautepierre', 'geoPoint': {'lat': 48.58392, 'lon': 7.74553}}, {'zip': '67200', 'city': 'Strasbourg', 'country': 'France', 'contacts': [{'name': 'Emmanuel KURTZ, MD', 'role': 'CONTACT', 'email': 'j-emmanuel.kurtz@chru-strasbourg.fr', 'phone': '388 128 436', 'phoneExt': '+33'}, {'name': 'Emmanuel KURTZ, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Centre Hospitalier Universitaire Hautepierre', 'geoPoint': {'lat': 48.58392, 'lon': 7.74553}}, {'zip': '67200', 'city': 'Strasbourg', 'country': 'France', 'contacts': [{'name': 'Chérif AKLADIOS, MD', 'role': 'CONTACT', 'email': 'Cherif.youssef.azer@chru-strasbourg.fr', 'phone': '388 127 492', 'phoneExt': '+33'}, {'name': 'Chérif AKLADIOS, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Centre Hospitalier Universitaire Hautepierre', 'geoPoint': {'lat': 48.58392, 'lon': 7.74553}}, {'zip': '54519', 'city': 'Vandœuvre-lès-Nancy', 'country': 'France', 'contacts': [{'name': 'Frédéric MARCHAL, MD', 'role': 'CONTACT', 'email': 'f.marchal@nancy.unicancer.fr', 'phone': '383 598 451', 'phoneExt': '+33'}, {'name': 'Frédéric MARCHAL, MD', 'role': 'PRINCIPAL_INVESTIGATOR'}], 'facility': 'Institut de Cancérologie de Lorraine - Alexis Vautrin', 'geoPoint': {'lat': 48.66115, 'lon': 6.17114}}], 'centralContacts': [{'name': 'Naoual BARKIN, MD,PhD', 'role': 'CONTACT', 'email': 'naoual.bakrin@chu-lyon.fr', 'phone': '4 78 86 23 71', 'phoneExt': '+33'}, {'name': 'Laurent VILLENEUVE', 'role': 'CONTACT', 'email': 'laurent.villeneuve@chu-lyon.fr', 'phone': '78 86 45 36', 'phoneExt': '+33'}]}, 'ipdSharingStatementModule': {'ipdSharing': 'NO'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Hospices Civils de Lyon', 'class': 'OTHER'}, 'responsibleParty': {'type': 'SPONSOR'}}}}