Phase I Dose-Escalation Trial of an Innovative Chemotherapy Regimen Combining a Fractionated Dose of Irinotecan Plus Bevacizumab, Oxaliplatin, 5-Fluorouracil, and Folinic Acid (bFOLFIRINOX-3) in Chemorefractory Metastatic Colorectal Cancer

Abstract

The care of metastatic colorectal cancers is based on combination chemotherapies including 5-fluorouracil, oxaliplatin, irinotecan, and monoclonal antibodies targeting the epidermal growth factor receptor or vascular endothelial growth factor. The regimen is determined based on the patient's molecular biology and general condition. Irinotecan bifractionation showed efficacy in chemorefractory patients in a previous study, FOLFIRI-3, but a desynchronized triplet has never been tested. The aim of bFOLFIRINOX-3 is to determine the safety, tolerance, and efficacy of a new regimen (FOLFIRINOX-3 bevacizumab) in chemorefractory patients. The aim of this study was to evaluate the safety and efficacy of FOLFIRINOX-3 bevacizumab in chemorefractory metastatic colorectal cancer (mCRC). A standard phase I, "3 + 3" design study was performed. The standard protocol comprised simplified FOLFOX 4 (folinic acid 400 mg/m²), 5-fluorouracil (a 400 mg/m² bolus followed by 2400 mg/m² for 46 h), oxaliplatin (85 mg/m²) and irinotecan (administered before and after 5-fluorouracil infusion), plus bevacizumab (5 mg/kg). In a "3 + 3" design, three different doses of irinotecan were tested: 60, 70 and 90 mg/m². The primary endpoint was the maximum tolerable dose (MTD) of irinotecan. The secondary endpoints included the objective response (at 8 and 16 weeks) according to the RECIST 1.1 criteria and progression free survival. Thirteen patients were enrolled, and twelve patients were finally evaluated for dose-limiting toxicity (DLT). The dose level defined was 70 mg/m² irinotecan. A total of three DLTs were observed (grade 3 diarrhea): two DLTs at the 90 mg/m² dose level and one at the 70 mg/m² dose level. The most frequently described adverse events were asthenia (93%), diarrhea (77%), nausea (62%) and peripheral sensory neuropathy (46%). The most frequent biological event was thrombopenia (54%). Regarding efficacy, among the 11 evaluable patients, no progression was observed at 8 weeks, and the partial response rate was 18.2%. At 16 weeks, a partial response rate of 27.3% was observed, and five patients had a stable disease. The new regimen of bFOLFIRINOX-3 with irinotecan at 70 mg/m² was well tolerated. In chemorefractory patients, this protocol shows a high response rate.

Keywords: 5-fluorouracil; bevacizumab; chemotherapy metastatic colorectal cancer; irinotecan; oxaliplatin.

Figure 1

FOLFIRINOX 3–bevacizumab regimen. A treatment cycle consisted of 14 days of treatment. A maximum of 12 cycles was administered.

Figure 2

Waterfall plot of the disease evaluation in bFOLFIRINOX 3 measuring the maximum percentage change from the baseline for the target lesions for the 11 evaluable patients (two patients could not be evaluated for response) after 8 and 16 weeks. (A) Waterfall plot of the best change over the baseline at 8 weeks. (B) Waterfall plot of the best change over the baseline at 16 weeks. In one patient (*), the response was not evaluable because of their death before the next evaluation. In one patient (**), the evaluation according RECIST 1.1 showed an overall decrease but was classed as progressive disease due to the development of new lesions.

Figure 3

Kaplan–Meier curve of the Progression-Free Survival (PFS) for all of the enrolled patients who received bFOLFIRINOX.