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5FU/LV, Irinotecan, Temozolomide and Bevacizumab for MGMT Silenced, Microsatellite Stable Metastatic Colorectal Cancer.

NCT04689347 · Status: RECRUITING · Phase: PHASE1/PHASE2 · Type: INTERVENTIONAL · Enrollment: 27

Last updated 2026-01-12

No results posted yet for this study

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.

Conditions

Interventions

DRUG

Bevacizumab

Bevacizumab 5 mg/kg intravenous infusion every 2 weeks

DRUG

Irinotecan

irinotecan 165 mg/sqm intravenous infusion every 2 weeks

DRUG

Leucovorin

leucovorin 200 mg/sqm intravenous infusion every 2 weeks

DRUG

5Fluorouracil

48-hours continuous intravenous infusion of 5-fluorouracil (5-FU) 3200 mg/sqm every 2 weeks

DRUG

Temozolomide

Oral temozolomide with progressive dose escalation at inter-patient level over days 1-5 every 28 days. (75 mg/sqm; 100 mg/sqm; 125 mg/sqm or 150 mg/sqm)

Sponsors & Collaborators

  • Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

    lead OTHER

Principal Investigators

  • Filippo Pietrantonio, MD · Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Study Design

Allocation
NA
Purpose
TREATMENT
Masking
NONE
Model
SEQUENTIAL

Eligibility

Min Age
18 Years
Max Age
75 Years
Sex
ALL
Healthy Volunteers
No

Timeline & Regulatory

Start
2021-01-01
Primary Completion
2026-04-30
Completion
2027-01-31

Countries

  • Italy

Study Locations

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Entities

Drugs
Diseases

Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT04689347 on ClinicalTrials.gov