Abstract CT103: Next generation capecitabine (NGC-Cap) in phase 1b trial significantly increases 5-FU exposure while improving safety profile compared to capecitabine
Authors: Young David , Bigora Sian , Nyberg Mary , Parks Kayla , Mahipar Amit , Boland Patrick , Feldman Eric , Hochster Howard 
Published: April 2024

Abstract
Background: Capecitabine (Cape) at the recommended dose of 1,000 - 1,250 mg/m2 bid has been shown to frequently cause clinically meaningful side effects such as myelosuppression and hand-foot syndrome (HFS), both of which may require dose modification, interruption, or discontinuation. HFS is caused by 5-FU catabolites while myelosuppression is caused by 5-FU anabolites. NGC-Cap combines ethynyl-uracil (PCS6422), an irreversible inhibitor of the DPD catabolism enzyme, and Cape.
Methods: The Phase 1b trial is a 3+3 design with up to 5 ascending Cape doses from 75 mg qd to 300 mg bid. Cape is given 7 days on/7 days off every 14 days with a single dose of PCS6422 given 16-24 hours before the start of every cycle. The 5-FU AUC(0-9 hrs), Cmax, and T1/2 were calculated on Day 1 when DPD inhibition is at its maximum. New cohorts are opened following a review of the safety data by a cohort review committee after the second cycle. Blood samples are obtained for PK analysis of PCS6422, Cape, and Cape metabolites (e.g., 5-FU, FBAL). All patients have cancer refractory or intolerant to existing available therapies. Radiological tumor response evaluation (RECIST 1.1) is performed every 8 weeks.
Results: 18 patients were enrolled in the first 4 dose levels of Cape in NGC-Cap. The 5-FU AUC (geometric mean, CV%) for the 150 and 225 mg bid NGC-Cap cohorts were 3,802 (23%) and 6,311 (37%) ng-hr/ml, respectively. These AUCs were approximately 5-10 times the AUC(0-inf) of 698 (33%) previously reported for a larger dose of approximately 2,250 mg of monotherapy Cape (Mono-Cape) (Reigner 1998). Similarly, the 5-FU Cmaxs (geometric mean, CV%) for these 2 cohorts were greater at 694 (22%) and 1,056 (28%) ng/ml than the Cmax of Mono-Cape at 310 (50%). The 5-FU T1/2 (arithmetic mean, CV%) of 3.54 (18%) and 5.72 (51%) hrs for these two NGC-Cap cohorts were also much longer than the 0.84 (25%) hrs for Mono-Cape. Although 150 and 225 bid NGC-Cap cohorts produced greater Cmax and AUC levels than Mono-Cape, the side effect profile from anabolites for the 150 cohort was better than Mono-Cape while the profile for the 225 cohort was similar to Mono-Cape. The extremely low FBAL catabolite formation and exposure (AUC of &lt; 250 vs 31,400 for Mono-Cape) across all NGC-Cap doses also resulted in only 1 patient having Grade 1 HFS.
Conclusion: The Phase 1b trial has already revealed some of the potential benefits of NGC-Cap over Mono-Cap. 1.NGC-Cap can provide a greater 5-FU exposure based on AUC and Cmax with a better or similar side effect profile.2.Side effects from the 5-FU catabolites are minimal and less severe for NGC-Cap.3.Side effects from 5-FU anabolites are dependent on 5-FU exposure with less exposure leading to fewer side effects that may also be less severe.4.NGC-Cap is to be further evaluated in a Phase 2 trial with the expectation that NGC-Cap will provide a better efficacy and safety profile than Cape.
Citation Format: David Young, Sian Bigora, Mary Nyberg, Kayla Parks, Amit Mahipar, Patrick Boland, Eric Feldman, Howard Hochster. Next generation capecitabine (NGC-Cap) in phase 1b trial significantly increases 5-FU exposure while improving safety profile compared to capecitabine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT103.