A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765 (SAR245409), a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced malignancies.

3030 Background: XL765 is a potent and selective inhibitor of class I PI3K isoforms, TORC1, and TORC2. XL765 has shown dose-dependent target modulation and tumor growth inhibition or shrinkage in multiple human xenografts. Methods: Pts receive XL765 twice daily (bid) or daily (qd) for 28-day cycles. Dose escalation follows a standard 3 + 3 design. PK and pharmacodynamic biomarker analyses are performed. Tumor response is assessed by RECIST every 8 weeks. A cohort of lymphoma pts will be enrolled to explore the potential utility of combined inhibition of PI3K and TORC1/2 in this disease setting. Results: 79 pts have been dosed with XL765; 52 pts on a bid regimen (30-240 mg/day) and 27 pts on a qd regimen (70-100 mg/day). On the bid schedule, 25 subjects have been treated at the established maximum tolerated dose (MTD) of 50 mg bid. The maximum administered dose (MAD) is 120 mg bid. On the qd schedule, the MAD is 100 mg and the preliminary MTD is 90 mg. The most common related adverse events (> 10% of pts) ...