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

Abstract

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/m2 intravenous) with 5-FU alone, or in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan, every 14 days. Safety, efficacy, and pharmacokinetics were assessed before and after four cycles (8 weeks) of treatment.

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 tmax was 10 min, and area under the plasma concentration-time curve from time 0 to 1 h increased linearly between 30 and 240 mg/m2. No accumulation was observed for [6R]-MTHF following repeated administration, and there were no major pharmacokinetic differences between cycle 1 and cycle 4 at any dose.

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.

Keywords: [6R]-5,10-methylentetrahydrofolate; arfolitixorin; chemotherapy; colorectal; fluorouracil; folate.

Conflict of interest statement

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.

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

Figures

Figure 1

Mechanism of action of arfolitixorin (stabilization of the ternary complex). 5-FU, 5-fluorouracil; DHF, dihydrofolate; DHFR, dihydrofolate reductase; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; FdUMP, flurodeoxyuridine monophosphate; MTHFR, methylenetetrahydrofolate; NADPH, nicotinamide adenine dinucleotide phosphate; SHMT, serine hydroxymethyltransferase; THF, tetrahydrofolate; TS, thymidylate synthase; UMP, uridine monophosphate.

Figure 2

Studydesign and dosing schedule.aThe dose of arfolitixorin 120 mg/m2 (given as two intravenous bolus injections 30 min apart) was selected as the dose for further investigation. 5-FU, 5-fluorouracil; DLT, dose-limiting toxicity; mCRC, metastatic colorectal cancer; SOC, standard of care.

Figure 3

Percentage change in tumor size at week 8 in the 16 patients who received arfolitixorin as first-line treatment (top), and in the 33 patients who received arfolitixorin as second-line treatment (bottom). (57 of 62 patients were assessable for tumor response with both pre- and post-baseline target lesion measurements. Each bar represents one patient).