Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245409 (XL765), a Novel, Orally Administered PI3K/mTOR Inhibitor in Patients with Advanced Solid Tumors

Abstract

Purpose: This phase I, first-in-human study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SAR245409, an inhibitor of pan-Class I phosphoinositide 3-kinase (PI3K) and mTOR, administered orally once or twice daily in patients with advanced solid tumors.Experimental Design: Eighty-three patients received SAR245409. Doses ranged from 15 to 120 mg twice daily, and 70 to 100 mg once daily. A 3þ3 dose-escalation design was used to determine the MTD. Patients were evaluated for adverse events and response. Assessments included pharmacokinetic, pharmacodynamic impact of SAR245409 on PI3K pathway signaling in hair sheath cells, skin and tumor, and characterization of tumor molecular alterations.Results: The MTDs were 50 mg twice daily and 90 mg once daily. The most frequent treatment-related adverse events were nausea (36.1%), diarrhea (21.7%), vomiting (19.3%), and decreased appetite (16.9%). The most frequent treatment-related grade 3/4 adverse events were increases in alanine aminotransferase (6.0%) and aspartate aminotransferase (4.8%). SAR245409 had a relatively short plasma half-life (2.96-7.52 hours). At MTDs, once-and twice-daily regimens yielded similar mean steady-state plasma exposure. A reduction in PI3K and mTORC1/mTORC2 pathway signaling was observed in serial hair sheath cells, skin, and tumor samples. Best response was stable disease in 48% of evaluable patients; seven patients had minor tumor regression. Twelve patients with stable disease were treated for !16 weeks. No trend was observed correlating tumor molecular alteration with antitumor activity.Conclusion: SAR245409 had a manageable safety profile, demonstrated reduced PI3K and mTORC1/ mTORC2 pathway signaling and was associated with clinically relevant stable disease. Clin Cancer Res; 20(9); 2445-56. Ó2014 AACR.

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

“…Earlyphase studies with the pan-PI3K inhibitor SAR245408 (relapsed/refractory CLL and lymphoma) and PI3K/ mTOR inhibitor SAR245409 (relapsed/refractory lymphoma) are ongoing, but early data suggest modest efficacy, compared with GS-1101 (47,48). Additional clinical data are needed to compare the safety and efficacy of pan-PI3K/mTOR inhibitors and p110d-specific inhibitors in hematologic malignancies.…”

GD2 ganglioside specific antibody treatment downregulates PI3K/Akt/mTOR signaling network in human neuroblastoma cell lines

“…Moreover, BEZ235 and the lysosomotropic agent chloroquine synergize to trigger apoptosis in neuroblastoma cells via mitochondrial-lysosomal cross-talk (48). SAR245409 (also known as XL765), another PI3K/mTOR inhibitor, was shown to inhibit proliferation and induce apoptosis in various tumor cell lines (49), in mouse xenograft models (50) and in patients with advanced solid tumors (51,52). Perifosine, a pan-Akt inhibitor of PIP 3 binding, possesses antitumor growth effect alone or in combination with chemotherapy in neuroblastoma (53).…”

Metformin and mTOR Inhibitors: Allies against Ovarian and Breast Cancers

“…This molecular knowledge has stimulated the development of news inhibitors termed dual PI3K-mTOR inhibitors that include NVP-BEZ235, XL765, BGT226, PI-103, PF-04691502, PKI-587 and GDC-0980 [142][143][144][145][146][147][148]. Comparing with the other types of PI3K pathway inhibitors, dual PI3KmTOR inhibitors have the possible advantage of inhibiting all PI3K catalytic isoforms, mTORC1 and mTORC2 [6].…”