A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel PI3K inhibitor, XL765, administered orally to patients (pts) with advanced solid tumors

• DOI: 10.1200/jco.2008.26.15_suppl.3510
• Publication Date: 2017-02-24T07:33:44Z
• Authors: K. P. Papadopoulos; B. Markman; J. Tabernero; A. Patnaik; E. I. Heath; A. DeCillis; D. Laird; S. K. Aggarwal; L. Nguyen; P. M. LoRusso
• Keywords: Pharmacodynamics

3510 Background: XL765 is a selective dual oral inhibitor of Class I PI3K isoforms and mTOR. potent in vivo pathway signaling leading to tumor growth inhibition or shrinkage dose dependent manner multiple human xenograft models exhibiting dysregulated signaling. Methods: Pts with advanced solid malignancies are enrolled successive cohorts 3 receive orally bid for cycles 28 days. Cycle 1 safety data determine dose-limiting toxicities (DLT). Pharmacodynamic samples collected. Tumor response assessed by RECIST criteria every 8 weeks. Results: To date, total thirteen pts have been treated across four levels up 120 mg bid. There no DLTs. One grade 4 transaminitis possibly related (120 bid) has reported. Of the 9 into 3, 6 completed ≥3 treatment. patient (30 NSCLC stable disease after another testicular carcinoma that had progressed under chemotherapy regimes clinically significant reduction alfa-fetoprotein from 11,000 7,000 U/L radiological cycle. Plasma PK analyses indicated exposure increased less than dose-proportionally increasing (range: 15–120 bid). Median Tmax occurred at 1–3 hrs post-dose. Mean terminal plasma half life ranged 3–9 hours steady state, which was reached Dosing Day 8. No moderate drug accumulation evident following repeat daily dosing. Preliminary results suggest administration augments food-induced changes insulin an fashion. signs pharmacodynamic modulation mTOR hair bulbs as determined reductions phosphorylation AKT, AKT substrate PRAS40, 4E- BP1. Conclusions: In this Phase study, generally well tolerated doses The MTD not yet established escalation ongoing. demonstrates biologic activity, read-outs. Author Disclosure Employment Leadership Consultant Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Exelixis