PMID- 36183444 OWN - NLM STAT- MEDLINE DCOM- 20221026 LR - 20221103 IS - 2059-7029 (Electronic) IS - 2059-7029 (Linking) VI - 7 IP - 5 DP - 2022 Oct TI - A phase I/II study of arfolitixorin and 5-fluorouracil in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan in metastatic colorectal cancer. PG - 100589 LID - S2059-7029(22)00219-8 [pii] LID - 10.1016/j.esmoop.2022.100589 [doi] LID - 100589 AB - 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(2) 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 t(max) was 10 min, and area under the plasma concentration-time curve from time 0 to 1 h increased linearly between 30 and 240 mg/m(2). 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. CI - Copyright (c) 2022 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Carlsson, G AU - Carlsson G AD - Department of Surgery, University of Gothenburg, Sahlgrenska University Hospital/Ostra Institute of Clinical Sciences, Gothenburg, Sweden. Electronic address: goran.u.carlsson@vgregion.se. FAU - Koumarianou, A AU - Koumarianou A AD - Hematology Oncology Unit, Fourth Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece. FAU - Guren, T K AU - Guren TK AD - Department of Oncology, Oslo University Hospital, Oslo, Norway. FAU - Haux, J AU - Haux J AD - Department of Surgery, Skaraborg Hospital, Skovde, Sweden. FAU - Katsaounis, P AU - Katsaounis P AD - Oncology Department, Metropolitan General Hospital, Athens, Greece. FAU - Kentepozidis, N AU - Kentepozidis N AD - Department of Medical Oncology, 251 General Air Force Hospital, Athens, Greece. FAU - Pfeiffer, P AU - Pfeiffer P AD - Experimental Research in Medical Cancer Therapy, Odense University Hospital, Odense, Denmark. FAU - Braendengen, M AU - Braendengen M AD - Department of Oncology, Oslo University Hospital, Oslo, Norway. FAU - Mavroudis, D AU - Mavroudis D AD - Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Crete, Greece. FAU - Taflin, H AU - Taflin H AD - Department of Transplant Surgery, The Institute of Clinical Sciences, The Sahlgrenska Academy At University of Gothenburg, Gothenburg, Sweden. FAU - Skintemo, L AU - Skintemo L AD - Isofol Medical AB, Gothenburg, Sweden. FAU - Tell, R AU - Tell R AD - Isofol Medical AB, Gothenburg, Sweden. FAU - Papadimitriou, C AU - Papadimitriou C AD - Oncology Unit, 'Aretaieion' University Hospital, National and Kapodistrian University of Athens, Athens, Greece. LA - eng SI - ClinicalTrials.gov/NCT02244632 PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20220929 PL - England TA - ESMO Open JT - ESMO open JID - 101690685 RN - 2S9ZZM9Q9V (Bevacizumab) RN - U3P01618RT (Fluorouracil) RN - 7673326042 (Irinotecan) RN - Q573I9DVLP (Leucovorin) RN - 04ZR38536J (Oxaliplatin) SB - IM MH - Humans MH - *Antineoplastic Combined Chemotherapy Protocols/adverse effects MH - Bevacizumab/therapeutic use MH - *Colorectal Neoplasms/drug therapy/pathology MH - Fluorouracil/therapeutic use MH - Irinotecan/therapeutic use MH - Leucovorin/therapeutic use MH - Oxaliplatin/therapeutic use PMC - PMC9588906 OTO - NOTNLM OT - [6R]-5,10-methylentetrahydrofolate OT - arfolitixorin OT - chemotherapy OT - colorectal OT - fluorouracil OT - folate COIS- 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. EDAT- 2022/10/03 06:00 MHDA- 2022/10/25 06:00 PMCR- 2022/09/29 CRDT- 2022/10/02 18:05 PHST- 2022/05/19 00:00 [received] PHST- 2022/08/18 00:00 [revised] PHST- 2022/08/21 00:00 [accepted] PHST- 2022/10/03 06:00 [pubmed] PHST- 2022/10/25 06:00 [medline] PHST- 2022/10/02 18:05 [entrez] PHST- 2022/09/29 00:00 [pmc-release] AID - S2059-7029(22)00219-8 [pii] AID - 100589 [pii] AID - 10.1016/j.esmoop.2022.100589 [doi] PST - ppublish SO - ESMO Open. 2022 Oct;7(5):100589. doi: 10.1016/j.esmoop.2022.100589. Epub 2022 Sep 29.