A phase I dose-escalation study of an all-in-one 5-fluorouracil and leucovorin co-formulation administered after failure of standard treatment.
Authors: Brungs Daniel , Hill Jonathon , Aghmesheh Morteza , Ackland Stephen P. , Parker Suzanne , Jokela Rebecca Madeline , Garg Madhu Bala , Reuter Stephanie E. , Meola Tahlia R. , Ranson Marie , Ranson Richard David , Toouli Christian D. , Strange Natalie , Clingan Philip R. 
Published: January 2024

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Background: 5-fluorouracil (5-FU) and its biomodulator leucovorin (LV) are an efficacious treatment option for various solid tumours, and are considered the backbone of therapy for colorectal cancer. Standard administration schedules require sequential administration of the two agents due to their chemical incompatibility; given the importance of LV in modulating 5-FU activity, their simultaneous administration is expected to enhance anti-tumour efficacy. Deflexifol is an all-in-one injectable reformulation of 5-FU and LV at physiological pH. An initial phase I trial demonstrated the safety and efficacy of Deflexifol when administered as a bolus or infusion, with a maximum tolerated dose (MTD) of ≥25% more 5-FU than established for standard regimens. This subsequent phase I study sought to investigate Deflexifol administered as a combined bolus and infusion schedule. Methods: Patients with advanced malignancy who had failed standard treatment were administered Deflexifol as a bolus followed by a continuous 46-hr infusion. The infusional dose was escalated across four levels (2400 mg/m2 to 3800 mg/m2) in the absence of Dose Limiting Toxicity using a traditional 3+3 design; the bolus dose was fixed at the previously declared MTD of 525 mg/m2. The stated Deflexifol dose represents the dose of standard 5-FU delivered. Primary trial objectives were to determine the safety and tolerability of a bolus plus infusion regimen of Deflexifol, with a secondary objective to determine the pharmacokinetics and MTD. Efficacy was an exploratory objective. Results: Nineteen patients with mainly colorectal (n=13) and breast (n=4) cancers were enrolled and treated with Deflexifol. Approximately two-thirds of patients had previously received fluoropyrimidine treatment. Deflexifol was generally well tolerated, with the MTD declared as a 525 mg/m2 bolus plus 3400 mg/m2 infusion. Treatment-related toxicities were consistent with standard 5-FU/LV therapy; the most frequent Grade 1/2 adverse events were fatigue, mucositis, and diarrhea. Grade ≥3 adverse events were reported in 6/19 patients, including mucositis (2/19) and haematological toxicity (5/19). One treatment-related death occurred at the highest infusion dose level of 3800 mg/m2 due to haematological toxicity. Quantifiable 5-FU and LV concentrations were exhibited at all time-points. Disease control, including one partial response, was achieved in 9/13 evaluable patients. Conclusions: Deflexifol is safe and well tolerated at doses of 5-FU up to 40% higher than typically administered by the standard modified de Gramont regimen. 5-FU and LV co-exposure extended throughout the entire dosing period, substantially longer than reported for standard treatment. Disease control was achieved in 69% of patients. Clinical trial information: ACTRN12619001533189 .