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

Abstract

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