A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies

Background
The kinase activity of mTOR is mediated through two distinct multiprotein complexes: mTORC1 and mTORC2. While targeting mTORC1 with rapalogs has shown some therapeutic effect, it often triggers compensatory feedback mechanisms, notably the activation of AKT and ERK pathways. This feedback can potentially be suppressed by concurrently inhibiting mTORC2. A first-in-human clinical trial was conducted to evaluate the tolerability, pharmacokinetics, and pharmacodynamics of OSI-027, a dual mTORC1/mTORC2 inhibitor.

Methods
The study involved dose escalation across three different dosing schedules: three consecutive days per week (Schedule 1, S1), once weekly (Schedule 2, S2), and daily dosing (Schedule 3, S3). Escalation continued until dose-limiting toxicities (DLTs) were identified. Based on tolerability and pharmacodynamic responses, expansion cohorts were initiated, which included patients who underwent paired tumor biopsies.

Results
A total of 128 patients with advanced malignancies were enrolled in the study. The primary DLTs included fatigue, renal dysfunction, and cardiac events. OSI-027 demonstrated dose-proportional pharmacokinetics, with peak plasma concentrations (Tmax) occurring within 4 hours and an approximate half-life of 14 hours. Expansion cohorts were launched for S1 and S2 dosing schedules, as the maximum tolerated dose (MTD) for S3 was deemed suboptimal. While pharmacodynamic effects were evident in peripheral blood mononuclear cells at doses starting from 30 mg, effective target modulation in tumor biopsies required 120 mg once daily—an intolerable dose due to associated renal toxicity. No objective responses per RECIST criteria were observed; however, six patients (5%) experienced stable disease lasting more than six months.

Conclusions
OSI-027 demonstrated dose-dependent inhibition of both mTORC1 and mTORC2 in patients with advanced tumors. However, achieving sustained biological effects in tumor tissues required doses that exceeded tolerability thresholds under S1 and S3 schedules, limiting the clinical utility of OSI-027 at effective concentrations.