A phase Ib trial of LY2584702 tosylate, a p70 S6 inhibitor, in combination with erlotinib or everolimus in patients with solid tumours

作者：Hollebecque Antoine; Houede Nadine; Cohen Ezra E W; Massard Christophe; Italiano Antoine; Westwood Paul; Bumgardner William; Miller Joel; Brail Les H; Benhadji Karim A; Soria Jean Charles^*

来源：European Journal of Cancer, 2014, 50(5): 876-884.

DOI：10.1016/j.ejca.2013.12.006

• p70 S6 kinase inhibitor
• Erlotinib
• Everolimus
• LY2584702 tosylate

Background: LY2584702 tosylate (hereafter referred to as LY2584702) is an oral, selective ATP competitive inhibitor of p70 S6 kinase. Preclinical studies with LY2584702 demonstrated significant synergistic activity with erlotinib and everolimus. The primary objective was to determine a phase II dose and schedule. Secondary objectives included evaluation of safety, toxicity and pharmacokinetics of LY2584702 in combination with erlotinib or everolimus.
Methods: Patients with advanced solid tumours were treated with a total daily dose of 50-200 mg of LY2584702 in combination with erlotinib 150 mg once daily (Arm A) or everolimus 10 mg once daily (Arm B). Dose escalation was based on 3+3 design and used the Common Terminology Criteria for Adverse Events Version 4.0.
Results: Twenty-nine patients were enrolled, 17 in Arm A and 12 in Arm B. Dose limiting toxicities (DLTs) in cycle 1 were observed in Arm A in four patients and consisted of Grade 3 vomiting, hypophosphataemia, pulmonary embolism and decreased clotting factor V. No DLTs were observed in Arm B at cycle 1, and the most frequent treatment-emergent adverse events related to study drug were: fatigue, anorexia, diarrhoea, nausea and vomiting. Seven patients received >= 4 cycles (3 in A, 4 in B). Best overall response was stable disease. Exposure accumulation of LY2584702 occurred with BID (twice daily) dosing. Exposure of erlotinib increased when administered in combination with LY2584702.
Conclusion: LY2584702 was not well tolerated when administered with erlotinib, therefore this combination is not feasible. The combination with everolimus was better tolerated but yielded very limited clinical benefit.

• 出版日期2014-3