Fixed-Dose Eniluracil Under Investigation in Advanced Refractory Gastrointestinal Cancers

Fixed-dose eniluracil (PCS6422) is being evaluated with escalating doses of capecitabine in patients with advanced, refractory gastrointestinal (GI) cancers, or in advanced GI cancers who are intolerant to fluoropyrimidine chemotherapy, as part of an open-label, phase 1b dose-escalation trial (NCT04861987), according to Processa Pharmaceuticals, Inc., the developer of the agent.¹

Investigators will study the safety and pharmacokinetics of PCS6422 in the trial, in which the first patient was dosed with the treatment on August 4, 2021. Investigators expect to enroll 30 patients on the study.

“We believe that the irreversible inhibitor effects of PCS6422 on the dihydropyrimidine dehydrogenase enzyme may significantly improve exposure to the cancer killing [5-fluorouacil] metabolites while reducing the 5-FU metabolites, like α-fluoro-β-alanine, related to dose limiting side effects such as hand foot syndrome,” said Sian Bigora, PharmD, chief development officer of Processa. “The dosing of the first patient in our phase 1b trial represents an important step to explore PCS6422’s potential as a disease modifying therapy for capecitabine.”

Bigora noted that interim results of the trial are expected by the end of 2021, with maximum-tolerated dose and biomarker data for the combination anticipated in 2022.

PCS6422 is defined as an oral, potent, selective, irreversible inhibitor of dihydropyrimidine dehydrogenase (DPD), which is an enzyme that metabolizes 5-fluorouracil (5-FU) to inactive metabolites, including α-fluoro-β-alanine (F-Bal).² F-Bal is linked with the development of neurotoxicity and hand-foot syndrome related to 5-FU, as well as decrease in 5-FU–related clinical activity.

Through PCS6422’s DPD inhibition, researchers theorize that 5-FU exposure may be increased, while reducing F-Bal–related adverse events (AEs) that occur with 5-FU. Preclinical data suggest that pretreatment with PCS6422 enhanced the clinical efficacy of capecitabine in colorectal cancer models.

Further, in 2 multicenter phase 3 trials of PCS6422 that was given in 10-fold excess to 5-FU, the dosage was found to be suboptimal, nor was PCS6422 given early enough in the treatment to irreversibly affect DPD. Results also showed that the control arm of 5-FU and leucovorin performed a greater antitumor benefit vs the standard regimen with the addition of PCS6422.^3,4

However, researchers noted that these findings support clinically dosing of PCS6422 several hours before 5-FU, to permit clearance before 5-FU administration.

On August 23, 2020, Processa Pharmaceuticals and Elion Oncology, Inc., entered into a license agreement to develop, manufacture, and commercialize PCS6422 on a global scale.

In the phase 1 trial, investigators are enrolling patients with advanced, relapsed/refractory GI cancers or those who are not intolerant to fluoropyrimidine chemotherapy.⁵ PCS6422 is given at a fixed dose in combination with various doses of capecitabine in 14-day cycles.

The coprimary end points are treatment-emergent AEs and maximum plasma concentration of both PCS6422 and capecitabine. AEs of special interest is a secondary end point.

To be eligible for enrollment, patients must also have measurable disease via RECIST v1.1 criteria; have not received intravenous 5-FU or oral 5-FU analogs within 4 weeks of study enrollment; has an ECOG performance status of 0 to 2; has adequate renal, liver, and bone marrow function; and a life expectancy of at least 12 weeks.

Those who cannot take oral medication, have an history of clinically significant abnormal 12 lead electrocardiogram results, current brain metastasis, prolonged QTc of greater than 480 msec at screening, history of prolonged QTc, and other clinically significant cardiac disease, among other criteria, are excluded from trial enrollment.

“The Processa strategy is to design and develop our pipeline of drugs to improve a patient’s benefit-risk profile compared to existing therapy,” said David Young, PharmD, PhD, chief executive officer of Processa. “PCS6422 is a prime example of the drugs in our pipeline and being able to enroll our first patient into this study is the first of many steps that we expect to achieve over the next 6-18 months.”

References

1. Processa Announces First Patient Dosed in PCS6422 Study in Gastrointestinal Cancer. News release. Processa Pharmaceuticals, Inc. August 4, 2021. Accessed August 24, 2021. https://bit.ly/3zskAih
2. PCS6422. Processa Pharmaceuticals. Accessed August 24, 2021. https://bit.ly/3BbftTJ
3. Schilsky RL, Levin J, West WH, et al. Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. J Clin Oncol. 2002;20(6):1519-1526. doi:10.1200/JCO.2002.20.6.1519
4. Van Cutsem E, Sorensen J, Cassidy J, et al. International phase III study of oral eniluracil (EU) plus 5-fluorouracil (5-FU) versus intravenous (IV) 5-FU plus leucovorin (LV) in the treatment of advanced colorectal cancer (ACC). Proc Am Soc Clin Oncol. 2021;20:131a.
5. A Study of the Safety and PK of PCS6422 (Eniluracil) With Capecitabine in Patients With Advanced, Refractory GI Tract Tumors. ClinicalTrials.gov. Last Updated July 20, 2021. Accessed August 24, 2021. https://clinicaltrials.gov/ct2/show/NCT04861987.