Abstract
2022 Background: AGN 195183 is a novel retinoid that trans-activates retinoic acid receptor-α (RAR-α). In preclinical models, AGN 195183 caused less skin toxicity compared to RAR interactive agents lacking RAR-α specificity and demonstrated anti-tumor activity in breast cancer and leukemia models. We initiated a clinical trial of AGN 195183 in advanced solid tumor patients (pts) in order to establish toxicity and pharmacokinetic profiles and to establish the maximum tolerated dose (MTD). Methods: Fifteen pts with advanced solid tumors meeting standard phase I entry criteria were enrolled on study; mean age was 60 years (range 45–79). Pts took AGN 195183 (5 and 50 mg soft gelatin capsules) by mouth with or without food on a continuous daily dosing schedule. Pharmacokinetic (PK) blood samples were collected on the days 1 and 14 prior to dosing and at 0.5, 1, 1.5, 2, 3, 5, 8, and 24 hours post-dose and prior to and 1 hour post-dose on days 7, 21, and 28. Results: Five pts were treated at the starting dose level of 60 mg/m2/d; 2 pts had a dose limiting toxicity (DLT) including grade 3 elevation of alk phos (pt also had progressing liver metastases) and gr 3 mucositis. Drug was de-escalated to 30 mg/m2/d; 2 of 4 pts treated had gr 3 elevation of alkaline phosphatase. Further de-escalation to 15 mg/m2/d has been well tolerated by 6 pts for 17 treatment cycles, with no grade 3 or higher toxicity noted. Preliminary PK studies for 60 mg/m2/d dose level show the drug is absorbed rapidly and reached peak concentration at about one hour post-dose. The average terminal elimination half-life was 4.17 hours. Cmax ranged from 684 to 7660 ng/mL and AUC from 4140 to 31246 95183 ng-hr/mL in 3 pts. Conclusion: AGN 195183 is a novel retinoid that trans-activates retinoic acid receptor-α (RAR-α); it has been well tolerated on an oral daily dosing schedule of 15 mg/m2/d, which is the MTD and recommended Phase II dose. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Allergan Allergan Allergan
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