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

Sponsor
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Study ID
NCT04689347
Phase
PHASE1/PHASE2
Status
Recruiting
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Conditions

  • Metastatic Colorectal Cancer

Eligibility Criteria

Sex
ALL
Age
18 Years - 75 Years
Healthy Volunteers
Not accepted

Interventions

  • Bevacizumab — DRUG
    Bevacizumab 5 mg/kg intravenous infusion every 2 weeks
  • Irinotecan — DRUG
    irinotecan 165 mg/sqm intravenous infusion every 2 weeks
  • Leucovorin — DRUG
    leucovorin 200 mg/sqm intravenous infusion every 2 weeks
  • 5Fluorouracil — DRUG
    48-hours continuous intravenous infusion of 5-fluorouracil (5-FU) 3200 mg/sqm every 2 weeks
  • Temozolomide — DRUG
    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)

Study Details

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.

Key Dates

Start date
Jan 1, 2021
Status verified
Sep 2025
Primary completion
Apr 30, 2026
Completion
Jan 31, 2027

Study Design

Enrollment
27 participants (estimated)
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT

Arms

  • Experimental: FLIRT-bevacizumab
    Bevacizumab intravenous infusion (IV), irinotecan IV, leucovorin (LV) IV, 48-hours continuous intravenous infusion of 5-fluorouracil (5-FU), given every 14 days, in combination with oral (PO) temozolomide with progressive dose escalation at inter-patient level over days 1-5 every 28 days. The treatment will consist of an induction period of four 28-day cycles of FLIRT- bevacizumab followed by maintenance regimen of 5-FU/LV-bevacizumab administered every 14 days in combination with PO temozolomide according to dose level over days 1-5 every 28 days in patients without progressive disease at the end of the induction period. In the phase 2 patient will receive the same treatment of the phase 1b with temozolomide at the RP2D (150 mg/sqm)

Primary Outcome Measure

(Phase 1b) safety and to determine the recommended phase 2 dose of the combination of FLIRT- bevacizumab in patients with MGMT silenced and MSS mCRC, previously untreated for advanced disease. (Phase 2) efficacy of FLIRT/bev [ Time Frame: 24 months ]

Central Contacts

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