5FU/LV, Irinotecan, Temozolomide and Bevacizumab for MGMT Silenced, Microsatellite Stable Metastatic Colorectal Cancer.
Trial Parameters
Brief Summary
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/resistance to single chemotherapeutic drugs, the simultaneous delivery of all active chemotherapeutic agents might overcome resistance to single drugs. Temozolomide 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/MGMT 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. Moving 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. The 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.
Eligibility Criteria
(applies to phase 2 part) Inclusion criteria 1. Histologically confirmed metastatic adenocarcinoma of the colon and/or rectum. 2. Confirmed MGMT promoter methylation by PSQ (\> 5%) and absent MGMT expression by immunohistochemistry. 3. Locally assessed pMMR or MSS status. 4. Written informed consent obtained prior to any study procedures. 5. Availability of archival tumor tissue (primary tumor and metastases or at least one of the two) for confirmation of MGMT, MMR/MSI status and biomarker analyses. 6. Availability of blood sample for biomarker analysis. 7. Metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease. 8. At least one measurable lesion according to RECIST 1.1. 9. Age ≥ 18 and less or equal than 75 years. 10. ECOG PS ≤ 1 if patient \< 70 years old; ECOG PS 0 if patient 70-75 years old. 11. Life expectancy of at least 12 weeks. 12. Previous (neo)adjuvant fluoropyrimidine or fluoropyrimidine plus oxaliplatin chemotherapy allowed only if more