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.
Histologically confirmed metastatic adenocarcinoma of the colon and/or rectum.
Confirmed MGMT promoter methylation by PSQ (> 5%) and absent MGMT expression by immunohistochemistry.
Locally assessed pMMR or MSS status.
Written informed consent obtained prior to any study procedures.
Requirement for treatment with any medicinal product that contraindicates the use of any of the study medications, may interfere with the planned treatment, affects patient compliance or puts the patient at high risk for treatment-related complications.
Metastatic disease deemed R0 resectable upfront or after induction therapy by means of multidisciplinary team assessment.
Radiotherapy to any site within 4 weeks before the study.
Presence of one of the following: DPYD2a (c.1905+1G>A); DPYD13 (c.1679 T>G); DPYD D949V (c.2846 A>T); DPYD IVS10 (c.1129-5923 C>G).
Sequential
Bevacizumab
DrugBevacizumab 5 mg/kg intravenous infusion every 2 weeks
Irinotecan
Drugirinotecan 165 mg/sqm intravenous infusion every 2 weeks
Leucovorin
Drugleucovorin 200 mg/sqm intravenous infusion every 2 weeks
5Fluorouracil
Drug48-hours continuous intravenous infusion of 5-fluorouracil (5-FU) 3200 mg/sqm every 2 weeks
Temozolomide
DrugOral 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)
(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
(phase 1b) The RD to be tested in a future phase 2 trial will be one dose level below the MTD or the maximum tested dose if MTD will not be reached. he MTD will be defined as the dose level at which ≥2/3 or ≥2/6 subjects experience a dose-limiting toxicity. At least 6 patients should be treated at the RD during the dose escalation. (phase 2) an overall sample size of 27 patients achieves an 80% power to detect the probability to increase 9-month PFS rate to 55% with a one-sided α level of 0.1 by the combination of temozolomide at the RP2D in combination with irinotecan, 5-fluorouracil and bevacizumab. The null hypothesis will be rejected if at least 14 patients are free of disease progression at 9 months.
ORR obtained by FLIRT bevacizumab
To assess ORR per RECIST version 1.1
Quality of life as assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
EORTC QLQ-C30 administered every 8 weeks
Quality of life as assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal Cancer 29 (EORTC QLQ-CR29)
EORTC QLQ-CR29 administered every 8 weeks
Quality of life as assessed using the Euro Quality of Life 5 Dimensions Questionnaire (EQ-5D-5L)
EQ-5D-5L administered every 8 weeks
OS of FLIRT bevacizumab (phase 2) - secondary endpoint for phase 2
OS is defined as the time from enrolment to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive.
Evaluate tumor biomarkers in archival tumor tissue
Quantification of the percentage of MGMT methylation by digital PCR methylBEAMing will be performed in archival tumor tissue. Mutational load will be assessed in archival tumor tissues by means of whole exome sequencing.
Evaluate plasma biomarkers in longitudinal blood samples (plasma and PBMCs)
Digital PCR for MGMT methylation status will be performed in cell-free circulating DNA (cfDNA). Mutational load will be assessed in cfDNA by means of whole exome sequencing.
PFS of FLIRT bevacizumab (phase 1b)
FS is defined as the time from enrolment to the first documentation of objective disease progression determined by investigator assessment or death due to any cause, whichever occurs first. PFS will be censored on the date of the last evaluable on study tumour assessment documenting absence of progressive disease for patients who are alive, on study and progression free at the time of the analysis. Alive patients having no tumour assessments after baseline will have time to event censored on the date of enrolment
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