Plasma deoxyuridine as a surrogate marker for toxicity and early clinical response in patients with metastatic colorectal cancer after 5-FU-based therapy in combination with arfolitixorin

Abstract

Purpose The aim was to explore the correlation between increasing doses of [6R]-5,10-methylenetetrahydrofolate (arfolitixorin) and plasma concentrations of deoxyuridine (dUr) in patients with metastatic colorectal cancer (mCRC), subjected to 5-fluorouracil (5-FU)-based chemotherapy. The aim was further to investigate the possibility to predict toxicity and clinical response during treatment using gender, age, and plasma dUr as explanatory variables. Methods Thirty-three patients from the ISO-CC-005 phase I/IIa study, which investigated safety and tolerability of arfolitixorin at four dose levels, were included. Toxicity and clinical response were evaluated after 4 cycles of chemotherapy. Plasma dUr was quantified before (0 h) and 24 h after 5-FU administration at the first (C1) and fourth (C4) cycle using LC–MS/MS. Fit modelling was used to predict toxicity and clinical response. Results The dUr levels increased with increasing arfolitixorin dose. Females had higher total and haematological toxicity scores (p = 0.0004 and 0.0089, respectively), and needed dose reduction more often than males (p = 0.012). Fit modeling showed that gender and the dUr levels at C1-0 h and C4-24 h predicted total toxicity (p = 0.0011), whereas dUr C4-0 h alone was associated with gastrointestinal toxicity (p = 0.026). Haematological toxicity was predicted by gender and age (p = 0.0071). The haematological toxicity score in combination with the dUr levels at C1-24 h and C4-24 h predicted early clinical response (p = 0.018). Conclusion The dUr level before and during administration of 5-FU and arfolitixorin was predictive for toxicity and early clinical response and could be a potential surrogate marker for thymidylate synthase inhibition in patients with mCRC. Trial registration NCT02244632, first posted on ClinicalTrials.gov on September 19, 2014

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

“…Plasma concentrations of the biologically active molecule ([6R]-MTHF) and its metabolites (THF and methyl-THF) increased linearly with the dose increase of arfolitixorin from 30 to 240 mg/m 2 , indicating that higher plasma levels are reached with higher doses. On the basis of existing evidence associating folate plasma concentrations with early treatment response, 27 a higher dose of arfolitixorin may elicit a greater treatment response than lower doses.…”

“…This decision was also supported by a published subset analysis of 33 patients, who were initially enrolled into the PK analysis set of this trial. 27 The analysis found that levels of plasma deoxyuridine, a surrogate marker for toxicity and early clinical response, were significantly higher 24 h into cycle 1 with arfolitixorin 120 mg/m 2 than with 30 or 60 mg/m 2 . 27 This suggests that arfolitixorin 120 mg/m 2 elicits an earlier clinical response than with the lower doses of 30 and 60 mg/m 2 , and the findings of this study indicate that this dose has a manageable safety and tolerability profile.…”

“… 23 Arfolitixorin is metabolized to methyl-tetrahydrofolate (methyl-THF), which donates a methyl group in the remethylation of homocysteine to methionine, 24 and THF, an active form of folic acid. 25 Earlier studies of arfolitixorin 26 , 27 have indicated that arfolitixorin has a promising pharmacological profile, and have laid the foundation for its more comprehensive evaluation in mCRC. This phase I/IIa multicenter study investigated clinical and pharmacokinetic (PK) outcomes for escalating doses of arfolitixorin combined with 5-FU, either alone or in combination with other agents, and aimed to determine a suitable dose for further investigation.…”

A Randomized Phase III Study of Arfolitixorin versus Leucovorin with 5-Fluorouracil, Oxaliplatin, and Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer: The AGENT Trial

“…A subanalysis of that study also indicated that plasma deoxyuridine (a surrogate marker of cytotoxicity and early clinical response) was significantly higher with increasing dose of arfolitixorin ( P = 0.023; ref. 23 ). Consequently, this was the dose evaluated in this phase III study.…”

Magnolol and 5-fluorouracil synergy inhibition of metastasis of cervical cancer cells by targeting PI3K/AKT/mTOR and EMT pathways

“…5-Fluorouracil (5-FU) is an anti-metabolic antitumor drug, which can inhibit thymine nucleotide synthetase and interfere with DNA synthesis ( Taflin et al, 2021 ). It exerts significant antitumor effect in a variety of tumors ( Akalovich et al, 2021 , Proietti et al, 2021 ).…”