A phase I safety and pharmacokinetic (PK) study of PI3K/TORC1/TORC2 inhibitor XL765 (SAR245409) in combination with erlotinib (E) in patients (pts) with advanced solid tumors.

3015 Background: The PI3K pathway is frequently dysregulated in cancer cells and has been implicated as a mechanism of resistance to EGFR inhibitors. XL765 is an oral, selective inhibitor of Class I PI3Ks, TORC1, and TORC2. In preclinical studies, XL765 has demonstrated dose-dependent target modulation in tumor xenograft models. Methods: Pts with advanced solid tumors are enrolled in successive cohorts to receive escalating doses of XL765 in combination with E. After the preliminary MTD has been defined, 9-12 additional pts with NSCLC will be enrolled. Cycles consist of 28 days of XL765 qd or bid and E qd. Pts enrolled into the dose escalation cohorts have a 14-day E monotherapy run-in with PK sampling. Tumor response is evaluated every 8 weeks. Results: 21 pts with advanced solid tumors have been enrolled at four dose levels of XL765 (30, 50, and 70 mg qd and 20 mg bid) in combination with 100 mg E. Thirteen of the 14 NSCLC pts enrolled had prior treatment with E. No dose limiting toxicities have been reported. The most common (≥ 10%) treatment-related adverse events (AEs) were skin and subcutaneous tissue disorders (including rash) and diarrhea. Grade 3 AEs related to study treatment were observed in 1 pt: nausea, vomiting, anorexia and AST increased. No grade 4 events were reported. Based on comparison with historical single agent data, no major PK interaction between XL765 and E has been observed. In skin and tumor biopsies, substantial post-dose reductions were evident in phosphorylation of AKT, 4EBP1, ERK, and EGFR. For example, reductions in pAKT-T308 (57%), p4EBP1 (60%), pERK (61%), and pEGFR (38%) were evident in tumor biopsies from a NSCLC adenocarcinoma pt previously treated with E after administration of 30 mg qd XL765/100 mg E for 21 days. Four NSCLC pts with prior E (3 had progressed on E) have been on study for 16 to 45+ weeks. Conclusions: XL765 in combination with E is generally well tolerated at daily doses up to 50 mg XL765/100 mg E with no apparent PK interaction, and results in robust inhibition of PI3K and EGFR signaling in skin and tumor tissue. The MTD has not yet been determined. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Exelixis, Gatekeeper AVEO, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, MedImmune, Millennium, Novartis, OSI Pharmaceuticals, Pfizer, Roche, Schering-Plough, Syndax Pharmaceuticals Exelixis, Gatekeeper Exelixis, Novartis, Pfizer Genzyme