Phase 1b/2 study of arfolitixorin in combination with 5-fluorouracil (5FU), oxaliplatin, and bevacizumab as first-line therapy for metastatic colorectal cancer (mCRC)

Background: Arfolitixorin ([6R]-5,10-methylene-tetrahydrofolate) is a direct-acting folate in development that may enhance treatment outcomes in patients with mCRC by bypassing the multi-step metabolic activation required by leucovorin (LV), the most commonly used folate agent. In a Phase 3 study with bevacizumab (NCT03750786), ARFOX (arfolitixorin, 5FU, oxaliplatin) demonstrated efficacy comparable to standard mFOLFOX6 (LV, 5FU, oxaliplatin), but did not achieve the primary endpoint of superiority, potentially due to a suboptimal arfolitixorin dose for a cellular response. Recent preclinical studies have indeed shown a clear dose-response relationship, with increased arfolitixorin activity at higher doses. This new Phase 1b/2 study (ClinicalTrials.gov: NCT06922383; EU Clinical Trials: 2024-516802-43-00) is therefore investigating the safety and maximum tolerated dose (MTD) of arfolitixorin at doses ≥120 mg/m² within the ARFOX and bevacizumab regimen, with the aim of later assessing efficacy. Trial design: The study comprises a single-center Phase 1b dose-finding stage (N=~20; ~1-3 patients/dose level, max 6 patients/dose) and a randomized Phase 2 dose-optimization stage at ~3 sites in Germany (N=~40). Adult patients with RAS mutant mCRC eligible for first-line 5-FU, oxaliplatin, and bevacizumab undergo baseline assessments within 28 days prior to initiating treatment. Imaging (CT or MRI) is performed after 6 and 12 weeks, and every 12 weeks thereafter as long as on study treatment. All eligible patients receive ARFOX and bevacizumab every 14 days (+7 days) until disease progression or clinical deterioration according to the investigator's judgment. In Phase 1b, arfolitixorin dosing begins at 120 mg/m², escalating to 200, 300, 400, and up to 500 mg/m², administered until the MTD is identified by the Safety Review Committee, with dose adjustments made at their discretion. In Phase 2, patients will be randomized (1:1) to one of two arfolitixorin dose levels: the MTD identified in Phase 1b and a dose one level below the MTD. Key endpoints of the Phase 1b/2 study include safety, tolerability, efficacy outcomes (objective response rate, progression-free survival, and overall survival), and pharmacokinetics. The Phase 2 protocol is currently being amended to include a new standard-of-care arm, which will also entail an increase in target patient enrolment. Further details will be made available following finalization of protocol updates. Patient enrolment is ongoing as of December 2025.