A phase I trial of LY2584702 tosylate, a p70 S6 kinase inhibitor, in patients with advanced solid tumours

• Published in: European journal of cancer (1990) 2014-03, Vol.50 (5), p.867-875
• Main Authors: Tolcher, Anthony, Goldman, Jonathan, Patnaik, Amita, Papadopoulos, Kyriakos P, Westwood, Paul, Kelly, Claudia S, Bumgardner, William, Sams, Lillian, Geeganage, Sandaruwan, Wang, Tao, Capen, Andrew R, Huang, Jianping, Joseph, Sajan, Miller, Joel, Benhadji, Karim A, Brail, Les H, Rosen, Lee S
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Area Under Curve; Biological and medical sciences; Cancer; Cholesterol - metabolism; Drug Administration Schedule; Fatigue - chemically induced; Female; Hematology, Oncology and Palliative Medicine; Humans; LY2584702 tosylate; Male; Medical sciences; Metabolic Clearance Rate; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nausea - chemically induced; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; p70 S6 kinase (p70S6K); Pharmacology. Drug treatments; Phosphorylation - drug effects; PI3 kinase; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Pyrazoles - adverse effects; Pyrazoles - pharmacokinetics; Pyrazoles - therapeutic use; Pyrimidines - adverse effects; Pyrimidines - pharmacokinetics; Pyrimidines - therapeutic use; Ribosomal Protein S6 Kinases, 70-kDa - antagonists & inhibitors; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Skin - metabolism; Time Factors; Treatment Outcome; Tumors; Vomiting - chemically induced
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2013.11.039

Abstract Background LY2584702 tosylate (hereafter referred to as LY2584702) is a potent, highly selective adenosine triphosphate (ATP) competitive inhibitor against p70 S6 kinase, a downstream component of the phosphatidylinositol-3-kinase signalling pathway which regulates cell proliferation and survival. LY2584702 exhibited anti-tumour activity in preclinical analysis. Methods Patients with advanced solid tumours were treated with LY2584702 orally on a 28-day cycle until the criteria for maximum tolerated dose (MTD) were met. Skin biopsies were collected for pharmacodynamic analysis, and levels of phospho-S6 protein were examined. The primary objective was to determine a phase II dose and schedule with secondary objectives of observing safety and tolerability. Dose escalation was based upon Common Terminology Criteria for Adverse Events Version 3.0. Results Thirty-four patients were enrolled onto this phase I study and treated with LY2584702 on a QD (once-daily) or BID (twice-daily) dosing schedule. Part A dose escalation ( n = 22) began with 300 mg BID ( n = 2). Due to toxicity, this was scaled back to doses of 25 mg ( n = 3), 50 mg ( n = 8), 100 mg ( n = 3), and 200 mg ( n = 6) QD. Part B dose escalation ( n = 12) included 50 mg ( n = 3), 75 mg ( n = 3), and 100 mg ( n = 6) BID. Seven patients experienced dose-limiting toxicity (DLT). All DLTs were Grade 3 and included vomiting, increased lipase, nausea, hypophosphataemia, fatigue and pancreatitis. Conclusion The MTD was determined to be 75 mg BID or 100 mg QD. No responses were observed at these levels. Pharmacokinetic analysis revealed substantial variability in exposure and determined that LY2584702 treatment was not dose proportional with increasing dose.