Actively Recruiting
5FU/LV, Irinotecan, Temozolomide and Bevacizumab for MGMT Silenced, Microsatellite Stable Metastatic Colorectal Cancer.
Led by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano · Updated on 2026-01-12
27
Participants Needed
3
Research Sites
317 weeks
Total Duration
On this page
AI-Summary
What this Trial Is About
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.
CONDITIONS
Official Title
5FU/LV, Irinotecan, Temozolomide and Bevacizumab for MGMT Silenced, Microsatellite Stable Metastatic Colorectal Cancer.
Who Can Participate
Eligibility Criteria
You may qualify if you...
- Histologically confirmed metastatic adenocarcinoma of the colon and/or rectum.
- Confirmed MGMT promoter methylation by pyrosequencing (>5%) and absent MGMT expression by immunohistochemistry.
- Locally assessed proficient mismatch repair (pMMR) or microsatellite stable (MSS) status.
- Written informed consent obtained before any study procedures.
- Availability of archival tumor tissue for confirmation of MGMT and MMR/MSI status and biomarker analyses.
- Availability of blood sample for biomarker analysis.
- No prior chemotherapy for metastatic colorectal cancer.
- At least one measurable lesion according to RECIST 1.1.
- Age between 18 and 75 years.
- ECOG performance status ≤1 if under 70 years old; ECOG 0 if aged 70-75 years.
- Life expectancy of at least 12 weeks.
- Prior (neo)adjuvant fluoropyrimidine or fluoropyrimidine plus oxaliplatin chemotherapy allowed if more than 6 months elapsed since end of therapy and disease relapse.
- Neutrophils ≥1.5 x 10^9/L, platelets ≥100 x 10^9/L, hemoglobin ≥9 g/dl.
- Total bilirubin ≤1.5 times upper normal limit; AST and/or ALT ≤2.5 times upper normal limit (or <5 times with liver metastases); alkaline phosphatase ≤2.5 times upper normal limit (or <5 times with liver metastases).
- Creatinine clearance ≥50 mL/min or serum creatinine ≤1.5 times upper normal limit.
- Women of childbearing potential must have a negative pregnancy test at baseline.
- Male and female participants of childbearing potential must agree to use adequate contraception during the study and for 6 months after last treatment.
- Willingness and ability to comply with the study protocol.
- Willingness and ability to provide adequate tumor samples for molecular screening.
You will not qualify if you...
- Need for treatments that contraindicate study medications or interfere with planned treatment.
- Metastatic disease considered R0 resectable upfront or after induction therapy.
- Radiotherapy within 4 weeks before study start.
- Presence of specific DPYD gene variants.
- Presence of homozygous UGT1A1 genotypes (e.g., 28(TA)7/37(TA)8).
- Untreated brain metastases or spinal cord compression (dose escalation phase); known brain metastases (dose expansion phase).
- History or evidence of untreated central nervous system disease.
- Active uncontrolled infections or other illnesses that contraindicate chemotherapy.
- Evidence of bleeding disorders or coagulopathy.
- Uncontrolled hypertension or history of hypertensive crises.
- Significant cardiovascular disease within 6 months before enrollment.
- Significant vascular disease within 6 months before enrollment.
- Previous venous thromboembolism of grade 4 or higher.
- History of abdominal fistula, gastrointestinal perforation, abscess, or active gastrointestinal bleeding within 6 months prior to treatment.
- Treatment with investigational drugs within 30 days or two half-lives prior to enrollment.
- Other malignancies within last 3 years except certain localized skin or cervical cancers.
- Lack of upper gastrointestinal tract integrity or inability to take oral medication.
- Known hypersensitivity to trial drugs or their components.
- Use of concomitant drugs contraindicated with trial medications.
- Pregnancy or breastfeeding.
AI-Screening
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Trial Site Locations
Total: 3 locations
1
Fondazione IRCCS Istituto Nazionale dei Tumori
Milan, Milan, Italy, 20133
Actively Recruiting
2
Istituto Oncologico Veneto IRCCS
Padova, PD, Italy, 35128
Actively Recruiting
3
Ospedale Santa Chiara
Pisa, PI, Italy, 56126
Actively Recruiting
Research Team
F
Filippo Pietrantonio, MD
CONTACT
F
Federica Morano, MD
CONTACT
How is the study designed?
Study Type
INTERVENTIONAL
Masking
NONE
Allocation
NA
Model
SEQUENTIAL
Primary Purpose
TREATMENT
Number of Arms
1
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