Ignite Creation Date:
2025-12-24 @ 6:29 PM
Ignite Modification Date:
2025-12-28 @ 2:11 AM
Study NCT ID:
NCT00142168
Status:
TERMINATED
Last Update Posted:
2016-04-21
First Post:
2005-09-01
Is NOT Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
CC-5013 (Lenalidomide) and Rituximab in Waldenstrom's Macroglobulinemia
Sponsor:
Organization:
Raw JSON
{'hasResults': True, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'conditionBrowseModule': {'meshes': [{'id': 'D008258', 'term': 'Waldenstrom Macroglobulinemia'}], 'ancestors': [{'id': 'D054219', 'term': 'Neoplasms, Plasma Cell'}, {'id': 'D009370', 'term': 'Neoplasms by Histologic Type'}, {'id': 'D009369', 'term': 'Neoplasms'}, {'id': 'D020141', 'term': 'Hemostatic Disorders'}, {'id': 'D014652', 'term': 'Vascular Diseases'}, {'id': 'D002318', 'term': 'Cardiovascular Diseases'}, {'id': 'D010265', 'term': 'Paraproteinemias'}, {'id': 'D001796', 'term': 'Blood Protein Disorders'}, {'id': 'D006402', 'term': 'Hematologic Diseases'}, {'id': 'D006425', 'term': 'Hemic and Lymphatic Diseases'}, {'id': 'D006474', 'term': 'Hemorrhagic Disorders'}, {'id': 'D008232', 'term': 'Lymphoproliferative Disorders'}, {'id': 'D008206', 'term': 'Lymphatic Diseases'}, {'id': 'D007160', 'term': 'Immunoproliferative Disorders'}, {'id': 'D007154', 'term': 'Immune System Diseases'}]}, 'interventionBrowseModule': {'meshes': [{'id': 'D000077269', 'term': 'Lenalidomide'}, {'id': 'D000069283', 'term': 'Rituximab'}], 'ancestors': [{'id': 'D010797', 'term': 'Phthalimides'}, {'id': 'D010795', 'term': 'Phthalic Acids'}, {'id': 'D000146', 'term': 'Acids, Carbocyclic'}, {'id': 'D002264', 'term': 'Carboxylic Acids'}, {'id': 'D009930', 'term': 'Organic Chemicals'}, {'id': 'D010881', 'term': 'Piperidones'}, {'id': 'D010880', 'term': 'Piperidines'}, {'id': 'D006573', 'term': 'Heterocyclic Compounds, 1-Ring'}, {'id': 'D006571', 'term': 'Heterocyclic Compounds'}, {'id': 'D054833', 'term': 'Isoindoles'}, {'id': 'D006574', 'term': 'Heterocyclic Compounds, 2-Ring'}, {'id': 'D000072471', 'term': 'Heterocyclic Compounds, Fused-Ring'}, {'id': 'D058846', 'term': 'Antibodies, Monoclonal, Murine-Derived'}, {'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'}]}}, 'resultsSection': {'moreInfoModule': {'pointOfContact': {'email': 'steven_treon@dfci.harvard.edu', 'phone': '617 632 2681', 'title': 'Steven P. Treon MD PhD', 'organization': 'DFCI'}, 'certainAgreement': {'piSponsorEmployee': False, 'restrictiveAgreement': False}, 'limitationsAndCaveats': {'description': 'Due to toxicity, study was terminated.'}}, 'adverseEventsModule': {'eventGroups': [{'id': 'EG000', 'title': 'Lenalidomide and Rituximab', 'description': 'Intended therapy consisted of 48 weeks of lenalidomide (25 mg/d for 3 weeks and then 1 week off) along with rituximab (375 mg/m(2)/wk) dosed on weeks 2 to 5 and 13 to 16.', 'otherNumAtRisk': 16, 'otherNumAffected': 8, 'seriousNumAtRisk': 16, 'seriousNumAffected': 11}], 'otherEvents': [{'term': 'Anemia', 'notes': '1 patient grade 3', 'stats': [{'groupId': 'EG000', 'numAtRisk': 16, 'numEvents': 8, 'numAffected': 8}], 'organSystem': 'Blood and lymphatic system disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT'}], 'seriousEvents': [{'term': 'Neutropenia', 'notes': '5 patients developed grade 3 neutropenia', 'stats': [{'groupId': 'EG000', 'numAtRisk': 16, 'numEvents': 5, 'numAffected': 5}], 'organSystem': 'Blood and lymphatic system disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT'}, {'term': 'Anemia', 'notes': '1 patient, grade 3', 'stats': [{'groupId': 'EG000', 'numAtRisk': 16, 'numEvents': 1, 'numAffected': 1}], 'organSystem': 'Blood and lymphatic system disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT'}, {'term': 'arrythmia', 'notes': '1 patient, grade 3', 'stats': [{'groupId': 'EG000', 'numAtRisk': 16, 'numEvents': 1, 'numAffected': 1}], 'organSystem': 'Cardiac disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT'}, {'term': 'chest pain', 'notes': '1 patient, grade 3', 'stats': [{'groupId': 'EG000', 'numAtRisk': 16, 'numEvents': 1, 'numAffected': 1}], 'organSystem': 'Cardiac disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT'}, {'term': 'pulmonitis', 'notes': '1 patient, grade 3', 'stats': [{'groupId': 'EG000', 'numAtRisk': 16, 'numEvents': 1, 'numAffected': 1}], 'organSystem': 'Respiratory, thoracic and mediastinal disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT'}, {'term': 'Thrombocytopenia', 'notes': '1 patient, grade 3', 'stats': [{'groupId': 'EG000', 'numAtRisk': 16, 'numEvents': 1, 'numAffected': 1}], 'organSystem': 'Blood and lymphatic system disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT'}, {'term': 'pleural effusion', 'notes': '1 patient, grade 3', 'stats': [{'groupId': 'EG000', 'numAtRisk': 16, 'numEvents': 1, 'numAffected': 1}], 'organSystem': 'Respiratory, thoracic and mediastinal disorders', 'assessmentType': 'SYSTEMATIC_ASSESSMENT'}], 'frequencyThreshold': '5'}, 'outcomeMeasuresModule': {'outcomeMeasures': [{'type': 'PRIMARY', 'title': 'Time to Progression', 'denoms': [{'units': 'Participants', 'counts': [{'value': '16', 'groupId': 'OG000'}]}], 'groups': [{'id': 'OG000', 'title': 'Lenalidomide and Rituximab', 'description': 'Intended therapy consisted of 48 weeks of lenalidomide (25 mg/d for 3 weeks and then 1 week off) along with rituximab (375 mg/m(2)/wk) dosed on weeks 2 to 5 and 13 to 16.'}], 'classes': [{'categories': [{'measurements': [{'value': '17.1', 'groupId': 'OG000', 'lowerLimit': '2', 'upperLimit': '34.3'}]}]}], 'paramType': 'MEDIAN', 'timeFrame': '34.3 months', 'description': 'Time to progression is measured as the length in time in months from starting therapy until progression, defined as 25% increase in serum IgM from nadir.', 'unitOfMeasure': 'months', 'dispersionType': 'Full Range', 'reportingStatus': 'POSTED', 'populationDescription': 'All enrolled patients'}, {'type': 'PRIMARY', 'title': 'Overall Response', 'denoms': [{'units': 'Participants', 'counts': [{'value': '12', 'groupId': 'OG000'}]}], 'groups': [{'id': 'OG000', 'title': 'Lenalidomide and Rituximab', 'description': 'Intended therapy consisted of 48 weeks of lenalidomide (25 mg/d for 3 weeks and then 1 week off) along with rituximab (375 mg/m(2)/wk) dosed on weeks 2 to 5 and 13 to 16.'}], 'classes': [{'categories': [{'measurements': [{'value': '8', 'groupId': 'OG000'}]}]}], 'paramType': 'NUMBER', 'timeFrame': '34.3 months', 'description': 'Overall response is the total number of participants who respond to therapy. Patients achieving a complete response (CR) will be defined as having achieved resolution of all symptoms, normalization of their serum IgM levels with complete disappearance of their IgM paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly during any point while in this study and normal bone marrow biopsy. Patients achieving a partial response (PR) and a minor response (MR) will be defined as achieving a \\> 50% and \\> 25% reduction in serum IgM levels, respectively, during any point while in this study. Patients with stable disease (SD) will be defined as having \\< 25% change in serum IgM levels, in the absence of new or increasing adenopathy or splenomegaly and/or other progressive signs or symptoms of WMduring any point while in this study.', 'unitOfMeasure': 'participants', 'reportingStatus': 'POSTED', 'populationDescription': 'Evaluable patients. 4 participants were withdrawn for adverse events and were unevaluable.'}, {'type': 'SECONDARY', 'title': 'Major Response Rate', 'denoms': [{'units': 'Participants', 'counts': [{'value': '12', 'groupId': 'OG000'}]}], 'groups': [{'id': 'OG000', 'title': 'Lenalidomide and Rituximab', 'description': 'Intended therapy consisted of 48 weeks of lenalidomide (25 mg/d for 3 weeks and then 1 week off) along with rituximab (375 mg/m(2)/wk) dosed on weeks 2 to 5 and 13 to 16.'}], 'classes': [{'categories': [{'measurements': [{'value': '4', 'groupId': 'OG000'}]}]}], 'paramType': 'NUMBER', 'timeFrame': '34.3 months', 'description': 'Major response rate is the number of participants who achieve at a PR or better. A PR or better will be defined as achieving a \\>50% reduction in serum IgM levels.', 'unitOfMeasure': 'participants', 'reportingStatus': 'POSTED', 'populationDescription': 'Evaluable patients. 4 participants were withdrawn for adverse events and were unevaluable.'}, {'type': 'SECONDARY', 'title': 'Minor Response Rate', 'denoms': [{'units': 'Participants', 'counts': [{'value': '12', 'groupId': 'OG000'}]}], 'groups': [{'id': 'OG000', 'title': 'Lenalidomide and Rituximab', 'description': 'Intended therapy consisted of 48 weeks of lenalidomide (25 mg/d for 3 weeks and then 1 week off) along with rituximab (375 mg/m(2)/wk) dosed on weeks 2 to 5 and 13 to 16.'}], 'classes': [{'categories': [{'measurements': [{'value': '4', 'groupId': 'OG000'}]}]}], 'paramType': 'NUMBER', 'timeFrame': '34.3 months', 'description': 'A minor response is defined as having achieved \\>25% but less than 50% reduction in serum IgM levels.', 'unitOfMeasure': 'participants', 'reportingStatus': 'POSTED', 'populationDescription': 'Evaluable patients. 4 participants were withdrawn for adverse events and were unevaluable.'}]}, 'participantFlowModule': {'groups': [{'id': 'FG000', 'title': 'Lenalidomide and Rituximab', 'description': 'Intended therapy consisted of 48 weeks of lenalidomide (25 mg/d for 3 weeks and then 1 week off) along with rituximab (375 mg/m(2)/wk) dosed on weeks 2 to 5 and 13 to 16.'}], 'periods': [{'title': 'Overall Study', 'milestones': [{'type': 'STARTED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '16'}]}, {'type': 'COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '16'}]}, {'type': 'NOT COMPLETED', 'achievements': [{'groupId': 'FG000', 'numSubjects': '0'}]}]}], 'recruitmentDetails': 'Outpatient clinic at DFCI', 'preAssignmentDetails': 'Symptomatic WM patients requiring therapy'}, 'baselineCharacteristicsModule': {'denoms': [{'units': 'Participants', 'counts': [{'value': '16', 'groupId': 'BG000'}]}], 'groups': [{'id': 'BG000', 'title': 'Lenalidomide and Rituximab', 'description': 'Intended therapy consisted of 48 weeks of lenalidomide (25 mg/d for 3 weeks and then 1 week off) along with rituximab (375 mg/m(2)/wk) dosed on weeks 2 to 5 and 13 to 16.'}], 'measures': [{'title': 'Age, Categorical', 'classes': [{'categories': [{'title': '<=18 years', 'measurements': [{'value': '0', 'groupId': 'BG000'}]}, {'title': 'Between 18 and 65 years', 'measurements': [{'value': '10', 'groupId': 'BG000'}]}, {'title': '>=65 years', 'measurements': [{'value': '6', 'groupId': 'BG000'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'unitOfMeasure': 'Participants'}, {'title': 'Age, Continuous', 'classes': [{'categories': [{'measurements': [{'value': '59', 'spread': '9', 'groupId': 'BG000'}]}]}], 'paramType': 'MEAN', 'unitOfMeasure': 'years', 'dispersionType': 'STANDARD_DEVIATION'}, {'title': 'Sex: Female, Male', 'classes': [{'categories': [{'title': 'Female', 'measurements': [{'value': '4', 'groupId': 'BG000'}]}, {'title': 'Male', 'measurements': [{'value': '12', 'groupId': 'BG000'}]}]}], 'paramType': 'COUNT_OF_PARTICIPANTS', 'unitOfMeasure': 'Participants'}, {'title': 'Region of Enrollment', 'classes': [{'title': 'United States', 'categories': [{'measurements': [{'value': '16', 'groupId': 'BG000'}]}]}], 'paramType': 'NUMBER', 'unitOfMeasure': 'participants'}]}}, 'protocolSection': {'designModule': {'phases': ['PHASE2'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'NA', 'maskingInfo': {'masking': 'NONE'}, 'primaryPurpose': 'TREATMENT', 'interventionModel': 'SINGLE_GROUP'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 16}}, 'statusModule': {'whyStopped': 'Toxicity', 'overallStatus': 'TERMINATED', 'startDateStruct': {'date': '2004-09'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2016-03', 'completionDateStruct': {'date': '2008-04', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2016-03-23', 'studyFirstSubmitDate': '2005-09-01', 'resultsFirstSubmitDate': '2012-12-19', 'studyFirstSubmitQcDate': '2005-09-01', 'lastUpdatePostDateStruct': {'date': '2016-04-21', 'type': 'ESTIMATED'}, 'resultsFirstSubmitQcDate': '2015-11-11', 'studyFirstPostDateStruct': {'date': '2005-09-02', 'type': 'ESTIMATED'}, 'resultsFirstPostDateStruct': {'date': '2015-12-16', 'type': 'ESTIMATED'}, 'primaryCompletionDateStruct': {'date': '2006-05', 'type': 'ACTUAL'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Time to Progression', 'timeFrame': '34.3 months', 'description': 'Time to progression is measured as the length in time in months from starting therapy until progression, defined as 25% increase in serum IgM from nadir.'}, {'measure': 'Overall Response', 'timeFrame': '34.3 months', 'description': 'Overall response is the total number of participants who respond to therapy. Patients achieving a complete response (CR) will be defined as having achieved resolution of all symptoms, normalization of their serum IgM levels with complete disappearance of their IgM paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly during any point while in this study and normal bone marrow biopsy. Patients achieving a partial response (PR) and a minor response (MR) will be defined as achieving a \\> 50% and \\> 25% reduction in serum IgM levels, respectively, during any point while in this study. Patients with stable disease (SD) will be defined as having \\< 25% change in serum IgM levels, in the absence of new or increasing adenopathy or splenomegaly and/or other progressive signs or symptoms of WMduring any point while in this study.'}], 'secondaryOutcomes': [{'measure': 'Major Response Rate', 'timeFrame': '34.3 months', 'description': 'Major response rate is the number of participants who achieve at a PR or better. A PR or better will be defined as achieving a \\>50% reduction in serum IgM levels.'}, {'measure': 'Minor Response Rate', 'timeFrame': '34.3 months', 'description': 'A minor response is defined as having achieved \\>25% but less than 50% reduction in serum IgM levels.'}]}, 'oversightModule': {'oversightHasDmc': True}, 'conditionsModule': {'keywords': ['CC-5103 (lenalidomide)', 'rituximab', "Waldenstrom's macroglobulinemia"], 'conditions': ["Waldenstrom's Macroglobulinemia"]}, 'referencesModule': {'references': [{'pmid': '19118065', 'type': 'RESULT', 'citation': "Treon SP, Soumerai JD, Branagan AR, Hunter ZR, Patterson CJ, Ioakimidis L, Chu L, Musto P, Baron AD, Nunnink JC, Kash JJ, Terjanian TO, Hyman PM, Nawfel EL, Sharon DJ, Munshi NC, Anderson KC. Lenalidomide and rituximab in Waldenstrom's macroglobulinemia. Clin Cancer Res. 2009 Jan 1;15(1):355-60. doi: 10.1158/1078-0432.CCR-08-0862."}]}, 'descriptionModule': {'briefSummary': "The purpose of this study is to determine the number of patients with Waldenstrom's macroglobulinemia that will benefit from treatment with CC-5103 (lenalidomide) and rituximab, what the side effects are and how long the benefit will last.", 'detailedDescription': "* The study drug CC-5103 (lenalidomide) will be administered orally once daily for 21 days followed by 7 days of no CC-5103 (lenalidomide) (this will be one 28 day treatment cycle). This cycle will repeat itself every 28 days as long as the patient is tolerating the medication and there is no disease progression.\n* Starting on the second week, patients will begin treatment with rituximab intravenously once a week for 4 weeks (week 2-5). Prior to each treatment, patients will receive medications to prevent or reduce the side effects of rituximab (benadryl, tylenol and possible decadron). During the infusion, the patients' blood pressure and pulse will be monitored frequently and the rate of infusion may decrease depending upon the side effects. Blood work will also be performed each week.\n* On week 12 the disease status will be evaluated. A physical exam, blood test, CT scan and bone marrow biopsy may be repeated if necessary to fully evaluate the disease. If the disease has gone away completely, some tests may be repeated again to confirm this.\n* If the disease has gotten worse after 12 weeks, then the patient will be removed from the study.\n* If the disease is stable or getting better, the patient will continue with therapy. During weeks 13-16 rituximab infusions will be repeated and CC-5103 will continue to be taken daily for 21 days followed by 7 days of rest. This 28 day cycle may be repeated until the patient has completed 48 weeks (12 months) of treatment as long as the side effects are acceptable and the disease does not progress.\n* All patients will undergo an off-study evaluation that includes a physical exam, blood work, CT scans and bone marrow biopsy. If the patient completes 78 weeks of therapy and the disease does not get worse, they will be evaluated every 12 weeks to determine the status of their disease for up to 2 years."}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['ADULT', 'OLDER_ADULT'], 'maximumAge': '80 Years', 'minimumAge': '18 Years', 'healthyVolunteers': False, 'eligibilityCriteria': "Inclusion Criteria:\n\n* Clinicopathological diagnosis of Waldenstrom's macroglobulinemia using consensus panel criteria\n* Age 18 years or older\n* CD20 positive based on any previous bone marrow immunohistochemistry or flow cytometric analysis\n* All previous cancer therapy, including radiation, hormonal therapy and surgery, must have been discontinued at least 4 weeks prior to treatment in this study\n* Measurable disease, defined as presence of immunoglobulin M paraprotein with a minimum IgM level of equal to or greater than 2 times the upper limit of normal.\n* ECOG performance status of 0-2\n* Absolute neutrophil count ≥ 100,000,000/L\n* Platelet count ≥ 50,000,000,000/L\n* Hemoglobin \\> 8 g/dL\n* Serum creatinine \\< 2.5 mg/dL\n* Total bilirubin \\< 1.5 mg/dL\n* AST and ALT \\< 2.5 x ULN\n* Disease free of prior malignancies fir 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast\n\nExclusion Criteria:\n\n* Any serious medical condition, laboratory abnormality, or psychiatric illness\n* Pregnant or lactating women\n* Prior therapy with rituximab or CC-5103\n* Known hypersensitivity to thalidomide\n* Development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.\n* Concurrent use of other anti-cancer agents or treatments"}, 'identificationModule': {'nctId': 'NCT00142168', 'briefTitle': "CC-5013 (Lenalidomide) and Rituximab in Waldenstrom's Macroglobulinemia", 'organization': {'class': 'OTHER', 'fullName': 'Dana-Farber Cancer Institute'}, 'officialTitle': "Phase II Study of CC-5103 and Rituximab in Waldenstrom's Macroglobulinemia", 'orgStudyIdInfo': {'id': '04-158'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'EXPERIMENTAL', 'label': 'CC-5103 (Lenalidomide) and Rituximab', 'description': 'Intended therapy consisted of 48 weeks of CC-5103 (lenalidomide)(25 mg/d for 3 weeks and then 1 week off) along with rituximab (375 mg/m(2)/wk) dosed on weeks 2 to 5 and 13 to 16.', 'interventionNames': ['Drug: CC-5103 (lenalidomide)', 'Drug: Rituximab']}], 'interventions': [{'name': 'CC-5103 (lenalidomide)', 'type': 'DRUG', 'otherNames': ['lenalidomide', 'Revlimid'], 'description': 'Taken orally once a day for 21 days followed by 7 days of no CC-5103 (lenalidomide)', 'armGroupLabels': ['CC-5103 (Lenalidomide) and Rituximab']}, {'name': 'Rituximab', 'type': 'DRUG', 'otherNames': ['Rituxan'], 'description': 'Begins on week 2 of treatment and is given intravenously once a week for 4 weeks', 'armGroupLabels': ['CC-5103 (Lenalidomide) and Rituximab']}]}, 'contactsLocationsModule': {'locations': [{'zip': '02115', 'city': 'Boston', 'state': 'Massachusetts', 'country': 'United States', 'facility': 'Dana-Farber Cancer Institute', 'geoPoint': {'lat': 42.35843, 'lon': -71.05977}}, {'zip': '02215', 'city': 'Boston', 'state': 'Massachusetts', 'country': 'United States', 'facility': 'Beth Israel Deaconess Medical Center', 'geoPoint': {'lat': 42.35843, 'lon': -71.05977}}], 'overallOfficials': [{'name': 'Steven Treon, MD, MA, PhD', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'Dana-Farber Cancer Insitute'}]}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Dana-Farber Cancer Institute', 'class': 'OTHER'}, 'collaborators': [{'name': 'Beth Israel Deaconess Medical Center', 'class': 'OTHER'}, {'name': "Brigham and Women's Hospital", 'class': 'OTHER'}, {'name': 'Celgene Corporation', 'class': 'INDUSTRY'}, {'name': 'Genentech, Inc.', 'class': 'INDUSTRY'}], 'responsibleParty': {'type': 'PRINCIPAL_INVESTIGATOR', 'investigatorTitle': 'Principal Investigator', 'investigatorFullName': 'Steven P. Treon, MD, PhD', 'investigatorAffiliation': 'Dana-Farber Cancer Institute'}}}}