OncoMatch/Clinical Trials/NCT04689347
5FU/LV, Irinotecan, Temozolomide and Bevacizumab for MGMT Silenced, Microsatellite Stable Metastatic Colorectal Cancer.
Is NCT04689347 recruiting? Yes, currently enrolling (May 2026). This Phase 1/2 trial studies multiple treatments for metastatic colorectal cancer.
Treatment: Bevacizumab · Irinotecan · Leucovorin · 5Fluorouracil · Temozolomide — 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.
Check if I qualifyExtracted eligibility criteria
Cancer type
Colorectal Cancer
Biomarker criteria
Required: MGMT promoter methylation (>5% by PSQ)
Confirmed MGMT promoter methylation by PSQ (> 5%)
Required: MGMT absent expression (absent by immunohistochemistry)
absent MGMT expression by immunohistochemistry
Required: MMR proficient
Locally assessed pMMR or MSS status
Required: MSI stable
Locally assessed pMMR or MSS status
Excluded: DPYD c.1905+1G>A
Presence of one of the following: DPYD2a (c.1905+1G>A)
Excluded: DPYD c.1679T>G
Presence of one of the following: DPYD13 (c.1679 T>G)
Excluded: DPYD D949V (c.2846A>T)
Presence of one of the following: DPYD D949V (c.2846 A>T)
Excluded: DPYD c.1129-5923C>G
Presence of one of the following: DPYD IVS10 (c.1129-5923 C>G)
Excluded: UGT1A1 1(TA)6/36(TA)5 (homozygous)
Presence of one of the following UGT1A1 1(TA)6/UGT1A1 36(TA)5 (homozygous genotype)
Excluded: UGT1A1 28(TA)7/37(TA)8 (homozygous)
Presence of one of the following UGT1A1 28(TA)7/UGT1A1 37(TA)8 (homozygous genotype)
Disease stage
Metastatic disease required
metastatic colorectal cancer; at least one measurable lesion according to RECIST 1.1
Performance status
ECOG 0–1(Restricted strenuous activity)
Prior therapy
Cannot have received: chemotherapy
Exception: 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.
Metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease.
Cannot have received: radiation therapy
Radiotherapy to any site within 4 weeks before the study.
Cannot have received: investigational drug
Treatment with any investigational drug within 30 days prior to enrollment or 2 investigational agent half-lives (whichever is longer).
Lab requirements
Blood counts
Neutrophils ≥1.5 x 10^9/L, Platelets ≥100 x 10^9/L, Hemoglobin ≥ 9 g/dl
Kidney function
Creatinine clearance ≥ 50 mL/min or serum creatinine ≤1.5 x UNL
Liver function
Total bilirubin ≤1.5 x UNL, AST (SGOT) and/or ALT (SGPT) ≤ 2.5 x UNL (or <5 x UNL in the case of liver metastases), alkaline phosphatase ≤ 2.5 x UNL (or <5 x UNL in case of liver metastases)
Neutrophils ≥1.5 x 10^9/L, Platelets ≥100 x 10^9/L, Hemoglobin ≥ 9 g/dl. Total bilirubin ≤1.5 x UNL, AST (SGOT) and/or ALT (SGPT) ≤ 2.5 x UNL (or <5 x UNL in the case of liver metastases), alkaline phosphatase ≤ 2.5 x UNL (or <5 x UNL in case of liver metastases). Creatinine clearance ≥ 50 mL/min or serum creatinine ≤1.5 x UNL.
Structured fields extracted by AI. May contain errors — verify against the official protocol.
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