Purpose: GSK2126458 (GSK458) is a potent inhibitor of PI3K (α, β, γ, and δ), with preclinical studies demonstrating broad antitumor activity. We performed a first-in-human phase I study in patients with advanced solid tumors. Materials and Methods: Patients received oral GSK458 once or twice daily in a dose-escalation design to define the maximum tolerated dose (MTD). Expansion cohorts evaluated pharmacodynamics, pharmacokinetics, and clinical activity in histologically and molecularly defined cohorts. Results: One hundred and seventy patients received doses ranging from 0.1 to 3 mg once or twice daily. Dose-limiting toxicities (grade 3 diarrhea, n = 4; fatigue and rash, n = 1) occurred in 5 patients (n = 3 at 3 mg/day). The MTD was 2.5 mg/day (MTD with twice daily dosing undefined). The most common grade ≥3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). Pharmacokinetic analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458. Durable objective responses (ORs) were observed across multiple tumor types (sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer). Responses were not associated with PIK3CA mutations (OR rate: 5% wild-type vs. 6% mutant). Conclusions: Although the MTD of GSK458 was 2.5 mg once daily, twice-daily dosing may increase duration of target inhibition. Fasting insulin and glucose levels served as pharmacodynamic markers of drug exposure. Select patients achieved durable responses; however, PIK3CA mutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K. Clin Cancer Res; 22(8); 1932–9. ©2015 AACR.

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AZD3514 has moderate anti-tumour activity in pts with advanced CRPC but with significant levels of nausea and vomiting. However, anti-tumour activity as judged by significant PSA declines, objective responses and durable disease stabilisations, provides the rationale for future development of SARD compounds.

The family of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) plays a critical role in cell proliferation and survival. A variety of genetic alterations (e.g. amplifications, mutations, and translocations) of these receptors and ligands have been found in diverse types of tumors. NVP-BGJ398 is a potent, selective, and orally bioavailable inhibitor of the FGFR tyrosine kinases. It inhibits the proliferation of various FGFR-dependent cell lines at nano-molar concentrations including breast and lung cancers harboring FGFR1 amplification, FGFR2-amplified gastric cancer cell lines and FGFR3-mutated bladder cancers. Objectives of the study: The purpose of this phase I-First In Human dose-escalation study is to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RPTD) of NVP-BGJ398 when administered orally to adult patients with advanced solid tumors. Secondary objectives include safety, tolerability, pharmacokinetics and preliminary anti-tumor activity in FGFR-dependent cancer. Methods: Patients received BGJ398 daily in a 28-day cycle in escalating dose cohorts starting from 5mg once daily. After cohort 3, patients had to have FGFR1 or FGFR2 amplification or FGFR3 mutation. Dose limiting toxicities (DLTs) were pre-defined and included both severe events and those resulting in significant dosing delays. Preliminary data: 26 patients have been treated, including 10 patients with FGFR1-amplified breast and 3 patients with FGFR1-amplified squamous cell lung cancer. The dose was escalated from 5 mg to 150 mg over 7 dose cohorts. One DLT of delayed dose occurred following a grade 3 AST/ALT event at 100 mg. Adverse events (AE) were generally grade 1-2. The most frequently observed AEs were diarrhea (37%) fatigue (37%) and nausea (32%) Hyperphosphatemia was observed, with increasing frequency at higher doses of NVP-BGJ398, and could be managed with phosphate binders and diuretics. One lung cancer patient with an FGFR1/CEP8 ratio of 2.6 by FISH analysis responded to 100 mg of NVP-BGJ398 with a 33% reduction in target lesions by CT scan at 8 weeks, confirmed at 12 weeks, and a substantial SUV decrease on PET. These observations provide early evidence that inhibition of the FGFR pathway is effective in patients with FGFR dependent cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-122. doi:1538-7445.AM2012-LB-122