Pharmacodynamics of OSI-027, a dual mTORC1/mTORC2 inhibitor, in tumor and surrogate tissues: Results from the expansion phase of a first-in-man study.

Background: The kinase activity of the mammalian target of rapamycin (mTOR) involves 2 multiprotein complexes, mTORC1 and mTORC2, regulating distinct signaling pathways. We conducted a first-in-human study of OSI-027, an orally bio-available inhibitor of both mTORC1 and mTORC2, with the aim of evaluating its safety, pharmacokinetics (PK), maximum tolerated dose (MTD) and pharmacodynamics (PD). We present final results, focusing on expansion cohorts for biomarker assessments at different dose levels. Material and Methods: Three dose-escalation arms evaluated different schedules (S) of administration; S1: once daily for 3 of every 7 days (qd 3/7d), S2: once weekly (qwk) or S3: continuous qd, in 21-day cycles. Dose limiting toxicities (DLT) were assessed in cycle 1 (CTCAE v3). Safety and PK were studied after single and multiple dosing. Expansion cohorts for biomarker assessment were initiated at different dose levels based on safety data, collecting PBMC samples and paired pre/post-treatment tumor and skin biopsies. Results: 123 patients (pts) were treated. Overall, DLTs (n=11) were fatigue (4), elevated serum creatinine (2), cardiomyopathy (1), decreased left ventricular ejection fraction (1), hyperglycemia (1), rash (1) and bone pain (1). S3 was discontinued (MTD 35mg qd) due to renal toxicity. Based on safety data, expansion cohorts were initiated to assess PD at 90mg qd 3/7d, 120mg qd 3/7d (MTD for S1) and 240mg qwk (maximum administered dose on S2 due to high number of capsules required; MTD for S2 not reached). Cmax and AUC were dose-linear. PD inhibition in PBMC was associated with OSI-027 exposure; results of tumor and skin biopsies are presented in table 1. Stable disease (RECIST 1.0) after 24 weeks was observed in 5 pts. Conclusions: OSI-027 modulates mTORC1/mTORC2 in a dose-dependent manner. PD in skin samples did not predict PD in tumor. While 90mg qd 3/7d inhibited target in PBMC and skin, 120mg qd 3/7d was required to achieve substantial effect in tumor but this dose was not well tolerated: 1/3 of pts required dose-reductions due to adverse events. ![Figure][1] Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B187. Citation Format: Joaquin Mateo, Patrick Schoffski, David Olmos, Herlinde Dumez, Victor Moreno, Fei Jie, Srinivasu Poondru, Nancy L. Samberg, Jan M. Van Tornout, Stanley B. Kaye, Patricia M. LoRusso. Pharmacodynamics of OSI-027, a dual mTORC1/mTORC2 inhibitor, in tumor and surrogate tissues: Results from the expansion phase of a first-in-man study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B187. [1]: pending:yes