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

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

  • ESMO Open. 2022 Oct;7(5):100589. doi: 10.1016/j.esmoop.2022.100589.
G Carlsson 1,  A Koumarianou 2,  T K Guren 3,  J Haux 4,  P Katsaounis 5,  N Kentepozidis 6,  P Pfeiffer 7,  M Brændengen 3,  D Mavroudis 8,  H Taflin 9,  L Skintemo 10,  R Tell 10,  C Papadimitriou 11
Affiliations

Affiliations

  • 1 Department of Surgery, University of Gothenburg, Sahlgrenska University Hospital/Östra Institute of Clinical Sciences, Gothenburg, Sweden. Electronic address: [email protected].
  • 2 Hematology Oncology Unit, Fourth Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
  • 3 Department of Oncology, Oslo University Hospital, Oslo, Norway.
  • 4 Department of Surgery, Skaraborg Hospital, Skövde, Sweden.
  • 5 Oncology Department, Metropolitan General Hospital, Athens, Greece.
  • 6 Department of Medical Oncology, 251 General Air Force Hospital, Athens, Greece.
  • 7 Experimental Research in Medical Cancer Therapy, Odense University Hospital, Odense, Denmark.
  • 8 Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Crete, Greece.
  • 9 Department of Transplant Surgery, The Institute of Clinical Sciences, The Sahlgrenska Academy At University of Gothenburg, Gothenburg, Sweden.
  • 10 Isofol Medical AB, Gothenburg, Sweden.
  • 11 Oncology Unit, 'Aretaieion' University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
PMID: 36183444 DOI: 10.1016/j.esmoop.2022.100589
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.

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