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  • Carlsson, Göran,1951Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery (author)

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

  • Article/chapterEnglish2022

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  • Elsevier BV,2022

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  • LIBRIS-ID:oai:gup.ub.gu.se/320099
  • https://gup.ub.gu.se/publication/320099URI
  • https://doi.org/10.1016/j.esmoop.2022.100589DOI

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  • Language:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

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  • 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 concentrationetime 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.

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  • Koumarianou, A. (author)
  • Guren, T. K. (author)
  • Haux, J. (author)
  • Katsaounis, P. (author)
  • Kentepozidis, N. (author)
  • Pfeiffer, P. (author)
  • Braendengen, M. (author)
  • Mavroudis, D. (author)
  • Taflin, HelenaGothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery(Swepub:gu)xtafhe (author)
  • Skintemo, L. (author)
  • Tell, R. (author)
  • Papadimitriou, C. (author)
  • Göteborgs universitetInstitutionen för kliniska vetenskaper, Avdelningen för kirurgi (creator_code:org_t)

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  • In:ESMO Open: Elsevier BV7:52059-7029

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