5FU/LV, Irinotecan, Temozolomide and Bevacizumab for MGMT Silenced, Microsatellite Stable Metastatic Colorectal Cancer.
Status:
Recruiting
Trial end date:
2023-01-01
Target enrollment:
Participant gender:
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.
Phase:
Phase 1
Details
Lead Sponsor:
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano