Abstract CT511: A phase 1 trial of AMP945, a potent and selective focal adhesion kinase inhibitor, in healthy volunteers

Abstract

Abstract Background: Focal Adhesion Kinase (FAK) plays a key role in tumor cell growth, particularly immunosuppression, cancer cell invasion and metastasis and also contributes to multiple mechanisms underlying fibrosis. AMP945 is a selective oral inhibitor of FAK. Following a favorable pre-clinical evaluation, we report the results of a Phase 1, randomized, double-blinded, placebo-controlled single ascending dose (SAD) and multiple ascending dose (MAD) trial of AMP945. Methods: For the SAD portion, four cohorts of eight healthy volunteers aged between 18 and 56 years received either single doses of AMP945 (n=6/cohort) of 15, 30, 60, or 125 mg per oral or matching placebo (n=2/cohort) per oral. For the MAD portion, three cohorts of eight healthy volunteers received either AMP945 (n=6/cohort) at 25, 50, or 100 mg once daily (QD) per oral or matching placebo (n=2/cohort) per oral QD on each of 7 consecutive days. Blood plasma samples were collected for pharmacokinetic (PK) analyses pre-dose at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 36, and 48 h post-dose in SAD cohorts, and at the same time points up to 24 h post-dose on Days 1 and 7 in the MAD cohorts. Target engagement through FAK activity (phosphorylation; p-FAK) was assessed in skin biopsies taken before and after dosing in the 125 mg AMP945 (SAD) and 25, 50, 100 mg AMP945 (MAD) cohorts. Safety and tolerability were assessed according to incidence, nature and severity of adverse events (AEs). Results: AMP945 was well tolerated at all doses studied. There was no increase in the incidence or severity of AEs with increasing doses and no treatment-related changes in laboratory parameters. AEs were mainly mild and deemed not related or unlikely related to AMP945 by the Investigator with headache, backpain and pyrexia being the most commonly observed events. After single doses of AMP945 the mean time to maximum plasma concentration ranged from 1 to 6 h post-dose. Maximum plasma concentration and area under the curve increased proportionally with dose. Mean Cmax values ranged from 55.4 to 407 ng/mL and AUC0-inf ranged from 1,086 to 10,567 h.ng/mL respectively. The mean half-life of AMP945 ranged from 15.7 to 23 h supporting the feasibility of QD dosing. The mean apparent volume of distribution ranged from 328 to 463 L, indicating wide tissue distribution. In skin biopsies, p-FAK levels following doses of AMP945 were reduced in a dose-dependent manner: there was a significant (linear) relationship observed between the decrease in p-FAK from baseline and AMP945 AUC0-inf following dosing with 25, 50, 100 and 125 mg of AMP945. Conclusions: AMP945, a selective FAK inhibitor, was well tolerated across SAD (15 to 125 mg) and MAD (25 to 100 mg) cohorts in healthy volunteers. AMP945 PK and pharmacodynamic data demonstrate wide tissue distribution and target engagement. These data support continued development of AMP945 in patients with solid tumors and fibrotic diseases in which FAK inhibition could be beneficial. Citation Format: John Lambert, Christopher J. Burns, Mark Devlin, Nicole Kruger, Jason Lickliter, Mark Sullivan, Warwick Tong. A phase 1 trial of AMP945, a potent and selective focal adhesion kinase inhibitor, in healthy volunteers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT511.