Abstract C197: A phase 1 safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with erlotinib in patients with advanced solid tumors

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Abstract Background: The PI3K pathway is frequently dysregulated in cancer cells and has been implicated as a mediator of resistance to EGFR inhibitors. In preclinical xenograft models, the oral selective Class I PI3K inhibitor XL147 augments the anti-tumor efficacy of EGFR inhibitors, including erlotinib. Methods: Patients (pts) with advanced solid tumors are enrolled in successive cohorts of 3 to receive escalating doses of XL147 in combination with erlotinib. Erlotinib is dosed qd, and XL147 is dosed once daily on Days 1–21 of each 28-day cycle. Dose limiting toxicities (DLTs) are determined using Cycle 1 safety data. Tumor response is evaluated every 8 weeks. Results: As of 01 Aug2009, 18 pts with advanced solid tumors have been enrolled: NSCLC (7), CRC (5), HCC, HNSCC, biliary tract, carcinoid, ethmoid, and esophageal cancer (1 each). Pts have been treated at 6 dose levels up to 400 mg XL147/150 mg erlotinib. No DLTs or study treatment-related SAEs have been reported. The MTD has not yet been established. The most frequently reported related AEs were rash (40%), fatigue (30%), diarrhea, nausea, and vomiting (each 20%). Two events of Grade 3 thrombosis (both unrelated) were reported. Based on preliminary data, the PK of XL147 in combination with erlotinib is consistent with that observed for XL147 given alone (Exelixis Study XL147-001). Likewise, XL147 does not appear to alter the PK of erlotinib as the PK parameters of erlotinib are similar to published single agent values. Modulation of PI3K pathway and EGFR signaling by XL147/erlotinib has been demonstrated in PBMCs by reductions in phosphorylation of AKT, the AKT substrates PRAS40 and GSK3 , and ERK. In skin and tumor biopsies, robust post-dose reductions were evident in phosphorylation of AKT, the mTOR substrate 4EBP1, ERK, and EGFR. For example, in tumor biopsies from a subject with an ethmoid tumor (400 mg XL147/150 mg erlotinib), reductions in pAKT-T308 (43%), p4EBP1 (44%), pERK (43%), and pEGFR (40%) were evident at Day 15 post-dose, with a corresponding reduction in Ki67 (47%) and induction of apoptosis (2.7-fold). One EGFR inhibitor-naïve NSCLC pt (no EGFR mutations detected in archival tumor sample, 200 mg XL147/150 mg erlotinib) had a confirmed PR with a 59% reduction in the sum of target lesions. Nine pts continued on study ≥ 12 weeks, including 2 pts who remained on study ≥ 24 weeks. Conclusions: The combination of XL147 and erlotinib is generally well tolerated at doses up to 400 mg XL147/150 mg erlotinib, with no apparent drug-drug PK interaction or emergent toxicities, and results in robust simultaneous inhibition of PI3K and EGFR signaling. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C197.