First-in-human phase I study of infusional and bolus schedules of Deflexifol, a novel 5-fluorouracil and leucovorin formulation, after failure of standard treatment

Background: 5‐Fluorouracil (5‐FU) is administered with leucovorin (LV) to enhance clinical activity. However, simultaneous administration is not feasible due to their chemical incompatibility, so conditions for the maximum possible beneficial interaction cannot be met. To overcome this, we developed a novel all‐in‐one, pH neutral stable solution of 5‐FU plus LV with β‐cyclodextrin (termed Deflexifol) and assessed its safety and tolerability in a first‐in‐human phase I trial. Methods: Patients with advanced solid malignancy received Deflexifol as weekly bolus (375–575 mg/m2) or two‐weekly 46 h infusion (1200–3600 mg/m2) for six cycles in a 3+3 dose escalation design. Adverse events, pharmacokinetics and tumor response rates were assessed by standard methods. Results: Forty patients were treated (19 bolus, 21 infusional, median age 67) with no grade 4 adverse events reported. Dose‐limiting toxicities of grade 3 diarrhea and myelosuppression were reported for the bolus schedule at 575 mg/m2 (maximum tolerated dose 525 mg/m2), whereas none were reported for the infusional schedule. The recommended phase II infusional dose was declared as 3,000 mg/m2, >25% that of 5‐FU used in standard‐of‐care regimens. Pharmacokinetic analyses showed evidence of inter‐patient variability, with no evidence of saturation in clearance, and a trend to linear increase in AUC with dose. Disease control rate was 64% despite most patients having failed previous 5‐FU regimens. Conclusion: Deflexifol is safer and effective in bolus and infusion schedules at higher doses than that permitted by separate infusion of 5‐FU and LV. A phase II study evaluating Deflexifol is planned.