Modufolin (arfolitixorin)

The study failed to demonstrate clinical benefit of arfolitixorin (120 mg/m2) over leucovorin. However, it provides some useful insights from the first-line treatment setting, including the effect of gene expression on outcomes.

P3, N=490, Completed, Isofol Medical AB | Active, not recruiting --> Completed

Funding: Isofol Medical AB Background: One of the target enzymes of 5-fluorouracil (5-FU)-based therapies is thymidylate synthase (TS) encoded by the TYMS gene...In this context, it has previously been shown in the ISO-CC-005 clinical study that TYMS gene expression can be predictive of response to 5-FU + folate analogue Arfolitixorin...MYC activation, a known transcriptional regulator of TYMS, has been identified as a potentially relevant common upstream controller of a group of genes involved in 5-FU + folate analogue efficacy . Here we have also observed a similar relationship to OS between TYMS and inferred MYC activity in Stage IV CRC . MYC family activity (and activated protein forms), genes of the MYCN signature, or the identified immune cell proportions are all potential biomarker candidates to explore as factors in 5-FU + folate analogue efficacy.

Background - 5-fluorouracil (5-FU) in combination with the folate leucovorin (LV) has formed the backbone of chemotherapy for advanced colorectal cancer for several decades...We previously reported that high tumoral expression of genes involved in folate transport, polyglutamation, and metabolism was associated with decreased risk of recurrent disease in patients with stage III colorectal cancer treated with 5-FU + LV (FLV) alone, or in combination with oxaliplatin (FLOX) according to the Nordic bolus regimen. The aim of the present study was to determine the association between expression of the folate-associated genes ABCC3, MTHFD2, SLC19A1, SLC25A32, SLC46A1, and TYMS and outcome of patients with metastatic colorectal cancer subjected to palliative chemotherapy.Patients and Methods - A total of 290 patients treated with FLV (n = 113), FLOX (n = 102) or FLV + irinotecan (FLIRI, n = 75) were included...Multivariate models showed that low TYMS and high SLC25A32 expression in subgroup 1 and high ABCC3 expression in subgroup 2 correlated significantly with better PFS (Hazard Ratio (HR) = 0.75 (95% CI = 0.57-1.0), HR = 2.21 (95% CI = 1.37-3.6), and HR = 1.34 (95% CI = 1.08 -1.7), respectively).Conclusion - Expression of TYMS, the target enzyme of 5-FU, was strongly associated with clinical benefit in the whole group, whereas expression of TYMS and the folate transporters SLC25A32, and ABCC3 was associated with PFS in the subgroups (stage I-III and stage IV), respectively. The prospective global phase III study AGENT is presently conducted on patients with advanced colorectal cancer, to determine whether expression of these genes can predict response to 5-FU-based chemotherapy that includes LV or the novel folate arfolitixorin.