Plasma deoxyuridine levels in metastatic colorectal cancer (mCRC) patients and clinical response after 5FU based therapy in combination with arfolitixorin.

Abstract

185 Background: 5-Fluorouracil (5FU) is one of the most commonly used cancer drugs. FdUMP is a metabolite from 5FU which inhibits thymidylate synthase (TS). TS inhibition causes a rise in the intracellular pool of the natural TS substrate dUMP leading to increased global levels of deoxyuridine (dUR). In order to increase TS inhibition, 5FU is combined with folates, usually leucovorin (LV). However, LV needs enzymatic conversion to become active. The LV conversion capacity differs between patients, with the consequence that many patients will have a reduced effect of 5FU-based treatment. Arfolitixorin is a biologically active folate, 5,10-methylenetetrahydrofolate, which doesn´t need enzymatic conversion; hence it could potentially be more efficacious. Methods: ISO-CC-005 is a phase I/II safety and tolerability study in mCRC patients receiving 5FU/arfolitixorin alone or in combination with irinotecan or oxaliplatin ± bevacizumab. Efficacy was evaluated as Overall Response Rate (ORR) after 4 cycles of chemotherapy. A LC-MS/MS method was developed for quantification of plasma dUr and 5FU. Blood samples were collected before and 24 h after 5FU administration at the first (C1) and fourth (C4) treatment cycle (n = 33). The C4/C1 ratio for dUr and 5FU, respectively, were calculated.The clinical response, which is an ordered categorical data, was modelled using nominal logistic regression using the ratio C4/C1 and the absolute values C1 and C4 as explanatory variables. Results: A positive correlation between dUr and 5FU levels was seen (r = 0.89, p = 0.0011) at C4. The C4/C1 ratio for dUr and 5FU in plasma correlated positively (r = 0.95, p = 0.0001). A positive correlation was also found between arfolitixorin dose and plasma levels of dUr (r = 0.44, p = 0.016) at C1, but not at C4. In the model test, the C4/C1 dUr ratio, as well as the individual dUr levels at C1 and C4, had a highly significant effect on ORR (p = 0.0075). Conclusions: The results demonstrate that the arfolitixorin dose has an impact on plasma levels of dUr and also on clinical response. dUr could potentially be an early surrogate marker for TS inhibition in mCRC patients treated with 5FU/arfolitixorin. Clinical trial information: NCT02244632.