[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"health-study-detail:100415416":3},{"organization":4,"armGroups":7,"interventions":18,"overallOfficials":41,"centralContacts":45,"locations":54,"responsibleParty":101,"collaborators":24,"id":103,"slug":104,"hasResults":105,"nctId":106,"briefTitle":107,"officialTitle":108,"acronym":24,"eligibilityCriteria":109,"healthyVolunteers":105,"sex":110,"minAge":111,"maxAge":112,"enrollmentInfo":113,"targetDuration":24,"studyType":116,"phases":117,"briefSummary":120,"conditions":121,"keywords":123,"overallStatus":57,"whyStopped":24,"lastUpdateSubmitDate":129,"lastUpdatePostDateStruct":130,"startDateStruct":133,"completionDateStruct":135,"leadSponsor":137,"locationsCount":138},{"fullName":5,"class":6},"Fondazione IRCCS Istituto Nazionale dei Tumori, Milano","OTHER",[8],{"label":9,"type":10,"description":11,"interventionNames":12},"FLIRT-bevacizumab","EXPERIMENTAL","Bevacizumab intravenous infusion (IV), irinotecan IV, leucovorin (LV) IV, 48-hours continuous intravenous infusion of 5-fluorouracil (5-FU), given every 14 days, in combination with oral (PO) temozolomide with progressive dose escalation at inter-patient level over days 1-5 every 28 days.\n\nThe treatment will consist of an induction period of four 28-day cycles of FLIRT- bevacizumab followed by maintenance regimen of 5-FU\u002FLV-bevacizumab administered every 14 days in combination with PO temozolomide according to dose level over days 1-5 every 28 days in patients without progressive disease at the end of the induction period.\n\nIn the phase 2 patient will receive the same treatment of the phase 1b with temozolomide at the RP2D (150 mg\u002Fsqm)",[13,14,15,16,17],"Drug: Bevacizumab","Drug: Irinotecan","Drug: Leucovorin","Drug: 5Fluorouracil","Drug: Temozolomide",[19,25,29,33,37],{"type":20,"name":21,"description":22,"armGroupLabels":23,"otherNames":24},"DRUG","Bevacizumab","Bevacizumab 5 mg\u002Fkg intravenous infusion every 2 weeks",[9],null,{"type":20,"name":26,"description":27,"armGroupLabels":28,"otherNames":24},"Irinotecan","irinotecan 165 mg\u002Fsqm intravenous infusion every 2 weeks",[9],{"type":20,"name":30,"description":31,"armGroupLabels":32,"otherNames":24},"Leucovorin","leucovorin 200 mg\u002Fsqm intravenous infusion every 2 weeks",[9],{"type":20,"name":34,"description":35,"armGroupLabels":36,"otherNames":24},"5Fluorouracil","48-hours continuous intravenous infusion of 5-fluorouracil (5-FU) 3200 mg\u002Fsqm every 2 weeks",[9],{"type":20,"name":38,"description":39,"armGroupLabels":40,"otherNames":24},"Temozolomide","Oral temozolomide with progressive dose escalation at inter-patient level over days 1-5 every 28 days. (75 mg\u002Fsqm; 100 mg\u002Fsqm; 125 mg\u002Fsqm or 150 mg\u002Fsqm)",[9],[42],{"name":43,"affiliation":5,"role":44},"Filippo Pietrantonio, MD","PRINCIPAL_INVESTIGATOR",[46,50],{"name":43,"role":47,"phone":48,"phoneExt":24,"email":49},"CONTACT","+390223903807","filippo.pietrantonio@istitutotumori.mi.it",{"name":51,"role":47,"phone":52,"phoneExt":24,"email":53},"Federica Morano, MD","+390223903842","federica.morano@istitutotumori.mi.it",[55,71,86],{"facility":56,"status":57,"city":58,"state":58,"zip":59,"country":60,"countryCode":61,"cosmosGeoPoint":62,"geoPoint":67,"contacts":68},"Fondazione IRCCS Istituto Nazionale dei Tumori","RECRUITING","Milan","20133","Italy","IT",{"type":63,"coordinates":64},"Point",[65,66],9.18951,45.46427,{"lat":66,"lon":65},[69,70],{"name":43,"role":47,"phone":48,"phoneExt":24,"email":49},{"name":51,"role":47,"phone":52,"phoneExt":24,"email":53},{"facility":72,"status":57,"city":73,"state":74,"zip":75,"country":60,"countryCode":61,"cosmosGeoPoint":76,"geoPoint":80,"contacts":81},"Istituto Oncologico Veneto IRCCS","Padova","PD","35128",{"type":63,"coordinates":77},[78,79],11.14261,44.38225,{"lat":79,"lon":78},[82],{"name":83,"role":47,"phone":84,"phoneExt":24,"email":85},"Rossana Intini, MD","049 821 1111","rossana.intini@iov.veneto.it",{"facility":87,"status":57,"city":88,"state":89,"zip":90,"country":60,"countryCode":61,"cosmosGeoPoint":91,"geoPoint":95,"contacts":96},"Ospedale Santa Chiara","Pisa","PI","56126",{"type":63,"coordinates":92},[93,94],10.4036,43.70853,{"lat":94,"lon":93},[97],{"name":98,"role":47,"phone":99,"phoneExt":24,"email":100},"Chiara Cremolini, MD","050.992111","chiaracremolini@gmail.com",{"type":102,"investigatorFullName":24,"investigatorTitle":24,"investigatorAffiliation":24,"oldNameTitle":24,"oldOrganization":24},"SPONSOR","100415416","phase-1-5fulv-irinotecan-temozolomide-and-bevacizumab-for-mgmt-silenced-microsatellite-stable-metastatic-colorectal-cancer-100415416",false,"NCT04689347","5FU\u002FLV, Irinotecan, Temozolomide and Bevacizumab for MGMT Silenced, Microsatellite Stable Metastatic Colorectal Cancer.","Phase 1b\u002F2 Trial of 5-fluorouracil, Leucovorin, Irinotecan in Combination With Temozolomide (FLIRT) and Bevacizumab for the First-line Treatment of Patients With MGMT Silenced, Microsatellite Stable Metastatic Colorectal Cancer.","(applies to phase 2 part)\n\nInclusion criteria\n\n1. Histologically confirmed metastatic adenocarcinoma of the colon and\u002For rectum.\n2. Confirmed MGMT promoter methylation by PSQ (\\> 5%) and absent MGMT expression by immunohistochemistry.\n3. Locally assessed pMMR or MSS status.\n4. Written informed consent obtained prior to any study procedures.\n5. Availability of archival tumor tissue (primary tumor and metastases or at least one of the two) for confirmation of MGMT, MMR\u002FMSI status and biomarker analyses.\n6. Availability of blood sample for biomarker analysis.\n7. Metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease.\n8. At least one measurable lesion according to RECIST 1.1.\n9. Age ≥ 18 and less or equal than 75 years.\n10. ECOG PS ≤ 1 if patient \\\u003C 70 years old; ECOG PS 0 if patient 70-75 years old.\n11. Life expectancy of at least 12 weeks.\n12. Previous (neo)adjuvant fluoropyrimidine or fluoropyrimidine plus oxaliplatin chemotherapy allowed only if more than 6 months elapsed between the end of (neo)adjuvant therapy and first evidence of disease relapse.\n13. Neutrophils ≥1.5 x 109\u002FL, Platelets ≥100 x 109\u002FL, Hemoglobin ≥ 9 g\u002Fdl.\n14. Total bilirubin ≤1.5 fold the upper-normal limits (UNL), AST (SGOT) and\u002For ALT (SGPT) ≤ 2.5 x UNL (or \\\u003C5 x UNL in the case of liver metastases), alkaline phosphatase ≤ 2.5 x UNL (or \\\u003C5 x UNL in case of liver metastases).\n15. Creatinine clearance ≥ 50 mL\u002Fmin or serum creatinine ≤1.5 x UNL.\n16. Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of amenorrhea, a single FSH measurement is insufficient.\n17. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must be willing to use adequate contraception as approved be the Investigator (barrier contraceptive measure or oral contraception) as outlined in Section 7.6, starting with the screening visit and through 6 months after the last treatment dose. Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.\n18. Will and ability to comply with the protocol.\n19. Is willing and able to provide an adequate archival tumor sample (FFPE) available for molecular screening and exploratory analyses. If the tumor block is not available, a minimum of 25 3-micron unstained sections on charged slides of tumor will be required.\n\nExclusion criteria\n\n1. Requirement for treatment with any medicinal product that contraindicates the use of any of the study medications, may interfere with the planned treatment, affects patient compliance or puts the patient at high risk for treatment-related complications.\n2. Metastatic disease deemed R0 resectable upfront or after induction therapy by means of multidisciplinary team assessment.\n3. Radiotherapy to any site within 4 weeks before the study.\n4. Presence of one of the following: DPYD2a (c.1905+1G\\>A); DPYD13 (c.1679 T\\>G); DPYD D949V (c.2846 A\\>T); DPYD IVS10 (c.1129-5923 C\\>G).\n5. Presence of one of the following UGT1A1 1(TA)6\u002FUGT1A1 36(TA)5; UGT1A1 28(TA)7\u002FUGT1A1 37(TA)8 (homozygous genotype).\n6. In the dose escalation phase, untreated brain metastases or spinal cord compression or primary brain tumors; in the dose expansion phase, known history of brain metastases.\n7. History or evidence upon physical examination of central nervous system disease unless adequately treated.8. Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration.\n\n9\\. Evidence of bleeding diathesis or coagulopathy. 10. Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy.\n\n11\\. Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication.\n\n12\\. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment.\n\n13\\. Any previous venous thromboembolism ≥ NCI CTCAE Grade 4. 14. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to the first study treatment.\n\n15\\. Treatment with any investigational drug within 30 days prior to enrollment or 2 investigational agent half-lives (whichever is longer).\n\n16\\. Other co-existing malignancies or malignancies diagnosed within the last 3 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ.\n\n17\\. Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.\n\n18\\. Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.\n\n19\\. Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.\n\n20\\. Pregnant or lactating women.","ALL","18 Years","75 Years",{"count":114,"type":115},27,"ESTIMATED","INTERVENTIONAL",[118,119],"PHASE1","PHASE2","An upfront-intensified treatment combining all the three active cytotoxic agents in metastatic colorectal cancer (mCRC) including fluoropyrimidines, oxaliplatin, irinotecan (FOLFOXIRI) plus antiangiogenic blockade with bevacizumab significantly improved survival. No biomarkers are available for predicting sensitivity\u002Fresistance to single chemotherapeutic drugs, the simultaneous delivery of all active chemotherapeutic agents might overcome resistance to single drugs.\n\nTemozolomide has modest but non-negligible activity (about 10%) in chemo-refractory patients with MGMT methylated mCRC. The response rate to temozolomide-based therapy in pretreated patients is increased to up to 20% when restricting the focus on those with MGMT IHC-negative\u002FMGMT methylated and MSS cancers. Clinical and preclinical synergy has been reported for combination of temozolomide with irinotecan and fluoropyrimidines. Temozolomide could be regarded as a \"targeted\" chemotherapy for patients with MSS and MGMT silenced tumors. In this subgroup of patients, an intensified triplet upfront regimen including temozolomide, fluoropyrimidines, irinotecan, associated with bevacizumab, could be a novel combination in molecularly super-selected mCRC patients.\n\nMoving from this, the investigators designed this open-label, monocentric, phase 1b study evaluating the safety of the combination regimen 5-fluorouracil, leucovorin, irinotecan, temozolomide and bevacizumab in patients with MGMT silenced and MSS mCRC.\n\nThe study will consist in a dose-escalation assessment of the safety of the treatment in subjects with previously untreated MGMT silenced, MSS mCRC. A 3 + 3 design will be used to assess the maximum tolerated dose (MTD) or maximum tested dose of the combination FLIRT-bevacizumab. Upon completion of the phase 1b part, the phase 2 part of the study will start.",[122],"Metastatic Colorectal Cancer",[38,124,125,126,127,128],"MGMT","microsatellite stable","First-line","Phase 1","Colorectal cancer","2026-01-08",{"date":131,"type":132},"2026-01-12","ACTUAL",{"date":134,"type":132},"2021-01-01",{"date":136,"type":115},"2027-01-31",{"name":5,"class":6},3]