A phase I/II study of arfolitixorin and 5-fluorouracil in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan in metastatic colorectal cancer.

BACKGROUND

5-fluorouracil (5-FU) combined with a folate remains an essential treatment component for metastatic colorectal cancer (mCRC). Leucovorin is the folate most often used, but requires intracellular conversion to a reduced folate, and has high pharmacokinetic variability and limited bioavailability in patients with low folate pathway gene expression. Arfolitixorin is an immediately active form of folate, [6R]-5,10-methylenetetrahydrofolate ([6R]-MTHF), and may improve outcomes.

PATIENTS AND METHODS

This open-label, multicenter, phase I/II study in patients with mCRC (NCT02244632) assessed the tolerability and efficacy of first- or second-line arfolitixorin (30, 60, 120, or 240 mg/m

RESULTS

In 105 treated patients, investigators reported 583 adverse events (AEs) in 86 patients (81.9%), and 256 AEs (43.9%) were potentially related to arfolitixorin and 5-FU. Dose adjustments were required in 16 patients (15.2%). At 8 weeks, 9 out of 57 patients assessed for efficacy achieved an objective response (15.8%), and all 9 achieved a partial response. Six of these nine patients had received arfolitixorin as a first-line treatment. A further 33 patients (57.9%) achieved stable disease. Pharmacokinetics were assessed in 35 patients. The average t

CONCLUSIONS

Arfolitixorin is a well-tolerated moderator of 5-FU activity. It is suitable for further investigation in mCRC and has the potential to improve treatment outcomes in patients with low folate pathway gene expression. Arfolitixorin can easily be incorporated into current standard of care, requiring minimal changes to chemotherapy regimens.

Informations de copyright

Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Disclosure PK has received payment/honoraria from BMS, MSD, and Ipsen, and has participated on a Data Safety Monitoring Board or Advisory Board for Roche. HT has an unconditional grant from Isofol Medical AB for a separate controlled clinical trial, and has relations with an owner of Isofol stock. LS and RT are employees of Isofol Medical AB and hold stocks/shares. CP has received support for this clinical trial from Isofol Medical AB; research grants from BMS, ELPEN Pharma GmbH, and Roche; consulting fees from MSD and Roche; payment/honoraria from Amgen, AstraZeneca, Genesis Pharmaceuticals, Merck, MSD, Novartis, and Roche; and has participated on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Merck, MSD, Novartis, and Roche. All other authors have declared no conflicts of interest.