A Phase I Study of GGTI-2418 (Geranylgeranyl Transferase I Inhibitor) in Patients with Advanced Solid Tumors

Background Geranylgeranyltransferase I (GGTase I) catalyzes geranylgeranylation, a modification required for the function of many oncogenic RAS-related proteins. GGTI-2418 is a peptidomimetic small molecule inhibitor of GGTase I. Objective The aim of this study was to establish the maximum tolerated dose of GGTI-2418 in patients with advanced solid tumors. Patients and Methods This was a phase I, open-label, dose-escalation study conducted in two US centers (University of Pennsylvania and Indiana University) in adults with treatment-refractory advanced solid tumors. An accelerated dose-escalation schema was used across eight dose levels, from 120 to 2060 mg/m(2), administered on days 1-5 of each 21-day cycle. Results Fourteen patients were enrolled in the dose-escalation cohort. No dose-limiting toxicities were observed, and 2060 mg/m(2) was determined to be the maximum tolerated dose. The only potential drug-related grade 3 or 4 toxicities were elevated bilirubin and alkaline phosphatase in a single patient with concurrent malignant biliary obstruction. No objective responses were observed. Four of thirteen evaluable patients had stable disease for up to 6.7 months. The study was terminated prior to dose expansion based on a sponsor decision. Pharmacokinetic analysis demonstrated a mean terminal half-life of 1.1 h. Conclusions GGTI2418 was safe and tolerable at all tested dose levels with some evidence of disease stability. Due to rapid elimination, dosing of GGTI2418 in this study may have been inadequate to achieve optimal inhibition of its target, GGTase I.