Safety and efficacy of eniluracil + capecitabine (6422 + Cap) in phase 1b trial.

e15152 Background: In comparison to the prior studies with eniluracil (6422) and 5-FU, 6422 + Cap uses a novel schedule of a single dose of 6422 followed the next 7 days with capecitabine (Cap) at a dose approximately one-tenth that of present monotherapy Cap (Mono-Cap). 6422 irreversibly inhibits dihydropyrimidine dehydrogenase (DPD), the enzyme that metabolizes 5-FU to catabolites which cause side effects while providing no therapeutic benefit. Inhibition of DPD not only eliminates these catabolites but also exposes cancer cells to more 5-FU and more cancer killing 5-FU anabolites. The objectives of this Phase 1B study in gastrointestinal cancer patients were to: evaluate the safety and efficacy, evaluate exposure to Cap, 5-FU, and FBAL (major catabolite of 5-FU), determine the Maximum Tolerated Dose (MTD), and determine the Recommended Phase 2 Dose Range (RP2DR) for the optimal dosage regimen studies. Methods: The 3+3 design trial included patient cohorts who received ascending Cap doses given 7 days on/7 days off preceded 16-24 hours by a single dose of 6422 before the start of every Cap cycle. 5-FU and FBAL exposure (AUC) were calculated. All patients were refractory or intolerant to available cancer therapies. Radiological tumor response evaluation (RECIST 1.1) was performed every 8 weeks. Results: PK Results: 18 patients were enrolled in 4 dose levels from 75 mg qd to 225 mg BID of Cap. All 6422 + Cap BID dosing had 5-FU AUC exposure greater than reported for Mono-Cap. The AUC for the 150 mg BID and 225 mg BID cohorts were approximately 5-10 times the previously reported AUC for the typical 2,250 mg BID Mono-Cap treatment. The 5-FU T1/2 of approximately 3 hrs for these two cohorts was also much longer than 0.84 hrs reported for Mono-Cap. Efficacy-Safety Results: 36.4% (4/11) of the patients in the 150 mg BID and 225 mg BID cohorts had grade 3-4 adverse events (AEs) (eg, neutropenia) associated with anabolites, similar to the incidence reported for Mono-Cap. The extremely low FBAL catabolite formation/exposure across all 6422 + cap doses resulted in only 1 out of 18 patients (5.6%) having mild Grade 1 HFS, a much lower incidence and severity than Mono-Cap. For the 13 RECIST evaluable patients, partial response (PR) was 15.4% (2/13) and stable disease (SD) was 46.2% (6/13). The median Progression-Free Survival (PFS) for the evaluable patients was 93 days (ranging from 53 to 332 days). For all 18 patients, PR was 11.1% (2/18 – the 2 PR patients in the highest Cap dose) and SD was 33.3% (6/18). Conclusions: Although 5-FU exposure was up to 5-10x greater than for Mono-Cap, AEs from 5-FU catabolites were minimal while anabolite associated AEs for the highest dose cohorts were similar to those reported for Mono-Cap. In these evaluable refractory or intolerant cancer patients, 6422 + Cap efficacy occurred with a PR of 15.4%, SD of 46.2%, and median PFS of 93 days. The MTD was 225 mg BID and RP2DR was 75 mg BID to 225 mg BID. Clinical trial information: NCT04861987 .