APhase I Pharmacokinetic and Pharmacodynamic Study of TKI 258 , an Oral , Multitargeted ReceptorTyrosine Kinase Inhibitor in Patients with Advanced SolidTumors

To determine the maximum tolerated dose (MTD) dose-limiting toxicity, and pharmacokinetic and pharmacodynamic profile ofTKI258 (formerly CHIR-258).  A phase I dose escalating trial in patients with advanced solid tumors was performed. Treatment was initially as single daily doses on an intermittent 7-day on/7-day off schedule. Following a protocol amendment, a second schedule comprised, during cycle 1, 7-day on/7-day off treatment followed by14 days of continuous daily dosing; subsequent cycles comprised 28 days of daily dosing. Pharmacokinetics and evaluation of phosphorylated extracellular signal-regulated kinase (ERK) in peripheral blood mononuclear cells were done during the first 28 days of each schedule. Thirty-five patients were treated in four intermittent (25-100 mg/d) and three continuous (100-175mg/d) dosing cohorts. Observed drug-related toxicities were nausea and vomiting, fatigue, headache, anorexia, and diarrhea. Dose-limiting toxicities were grade 3 hypertension in one patient at 100 mg continuous dosing, grade 3 anorexia in a second patient at 175 mg, and grade 3 alkaline phosphatase elevation in a third patient at 175 mg. One patient had a partial response (melanoma) and two patients had stable disease >6 months.TKI258 pharmacokinetics were linear over the dose range of 25 to175 mg. Five of 14 evaluable patients had modulation of phosphorylated ERK levels. The MTD was defined as 125 mg/d. Evidence of antitumor activity in melanoma and gastrointestinal stromal tumors warrants further investigation, and other phase I studies are ongoing. Further pharmacodynamic evaluation is required in these studies to evaluate the biological effects ofTKI258. TKI258 is an oral multitargeted receptor tyrosine kinase (RTK) inhibitor. The development of RTK inhibitors for the treatment of cancer has provided significant therapeutic advances for a range of malignancies. In particular, drugs targeting the vascular endothelial growth factor receptors (VEGFR) have shown considerable promise (e.g., sunitinib and sorafenib for renal cancer; refs. 1, 2). TKI258 has shown direct activity against tumor cells and the formation and maintenance of blood vessels and stroma supporting tumors. TKI258 is a potent inhibitor of the class III, IV, and V RTKs, showing biochemical IC50 values <20 nmol/L for VEGFRs (VEGFR-1, VEGFR-2, and VEGFR-3); the platelet-derived growth factor receptor-h (PDGFR-h); fibroblast growth factor receptors 1, 2, and 3 (FGFR1,2,3); fetal liver tyrosine kinase receptor 3 (FLT-3); and KIT Ret, TrkA, and csf-1 RTKs (3). Although the principal targets of TKI258 are the VEGF RTKs, the unique inhibition profile of TKI258 differentiates it from several other RTK inhibitors; in particular, as it significantly inhibits the fibroblast growth factor receptors, TKI258 shows significant activity in a variety of tumor xenograft models in athymic mice, including acute myeloid leukemia, multiple myeloma, and colonand prostatederived models. Those xenografts using cell lines driven by activating mutations or ectopic expression of target RTKs were particularly sensitive to the effects of TKI258 (3). TKI258 shows a doseand exposure-dependent inhibition of target RTKs expressed in tumor xenografts and stromal components in several preclinical models. Inhibition of RTK phosphorylation was maintained for 24 h after a single dose of TKI258, with corresponding inhibition of downstream signaling pathways as measured by the inhibition of phosphorylation of extracellular signal-regulated kinase (ERK) and AKT.  Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom; Beatson Oncology Centre, University of Glasgow, Glasgow, United Kingdom; and Novartis Oncology, East Hanover, NewJersey Received 6/15/07; revised11/5/07; accepted12/11/07. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints: Johann S. de Bono, Section of Medicine, Royal Marsden Hospital and Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom. Phone: 44-20-8722-4029; Fax: 44-20-8642-7979; E-mail: johann.de-bono@icr.ac.uk. F2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-1466 www.aacrjournals.org Clin Cancer Res 2008;14(7) April 1, 2008 2075 Research. on May 29, 2017.  Studies with TKI258 in isolated human and rat peripheral blood mononuclear cells (PBMC) showed dosedependent inhibition of phosphorylated ERK (phospho-ERK) using both flow cytometry and Western blotting. Preliminary pharmacokinetic studies showed good oral bioavailability, with moderate-to-high plasma clearance and large volume of distribution (V ss). Plasma half-life was adequate for once daily dosing in tumor models, and plasma exposure increased proportionally with dose. Given the highly promising preclinical antitumor activity and safety data in animals, this phase I first-in-human study of oral TKI258 was undertaken to determine the maximum tolerated dose, doselimiting toxicities (DLT), and safety profile of TKI258, together with pharmacokinetic and pharmacodynamic analyses, when administered to patients with advanced solid malignancies. A secondary objective was to describe antitumor activity. Materials andMethods Eligible patients were recruited from two centers in the United Kingdom: The Royal Marsden Hospital/Institute of Cancer Research (Sutton) and The Beatson Oncology Centre (Glasgow). The study, sponsored by Novartis (Chiron Corp.), was approved by the Local Research Ethics Committees of both institutions and conducted in accordance with the principles of the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice. All patients gave written informed consent before any study-related procedures were done. Patient eligibility. Patients with histologic or cytologic confirmation of locally advanced or metastatic solid tumors who were refractory or resistant to conventional therapy or for which no standard therapy exists were eligible provided they met the following criteria: age of z18 years; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1; anticipated survival of z12 weeks; evidence of measurable or evaluable disease; adequate hematopoietic (absolute neutrophil count z1.5 10 L, platelet count z75 10 L, hemoglobin z8 g/dL), hepatic [bilirubin V1.5 upper limit of normal (ULN), alkaline phosphatase V5 ULN, aspartate aminotransferase V2.5 ULN (or V5 ULN in the presence of liver metastases), amylase (VULN)], and renal (serum creatinine V1.5 ULN) function; were >21 days since the last dose of antineoplastic therapy (prostate cancer patients could continue luteinizing hormone-releasing hormone analogue therapy); and a negative pregnancy test for females of childbearing potential. Exclusion criteria included the following: concurrent therapy with another investigational agent, concurrent active intracranial or epidural metastases, pregnancy or lactation, clinically significant cardiac disease, grade z2 compromised left ventricular ejection fraction (LVEF), diabetes mellitus requiring chronic medication, pericarditis or clinically significant pleural effusion in the previous 12 months, malabsorption, prior pancreatitis, prior intrahepatic or extrahepatic biliary obstruction Fig. 1. Treatment schema for intermittent and continuous dosing schedules ofTKI258. Shaded boxes,‘‘on drug’’days; unshaded boxes,‘‘off drug’’days. For the intermittent schedule, DLTwas defined as occurring in the first 28 d (cycle1). For the continuous schedule, DLTwas defined as occurring in the 7-d/7-d off intermittent lead-in period and the first 14 d of continuous dosing.  Clinical www.aacrjournals.org Clin Cancer Res 2008;14(7) April 1, 2008 2076 Research. on May 29, 2017.  Drug administration. TKI258 was supplied as a 1 or 5 g crystalline powder in a bottle. Sufficient water for irrigation was added to make a final concentration of 10 to 50 mg/mL. Seven to 16 individual bottles were dispensed at a time. For the initial 7 days of dosing, TKI258 was ingested either 1 h before a meal or 2 h following a meal; thereafter, ingestion was with food. Patients could add one to two tablespoons of water or clear fruit juice (except grapefruit juice) to the bottle to swallow any remaining content. The constituted solution was stored at 2jC to 8jC and used within 28 days. Appropriate supportive therapies were permitted.  Patients were assigned to receive escalating doses of TKI258 once daily in two schedules . Initially, all patients received TKI258, on an intermittent lead-in period, on days 1 to 7 followed by 7 days off drug. Thereafter, patients were treated in two sequential groups. In the first group, patients continued on an intermittent schedule every 28 days (one cycle). Doses of 25 to 200 mg were planned. Once initial drug safety and pharmacokinetic data had been acquired, the second group of patients received 7-day on/7-day off treatment followed by continuous daily dosing; doses of 100 to 235 mg were planned. At least three patients were treated at each dose