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Plummer R.,Northern Center for Cancer Care | Swaisland H.,Therakin Consulting | Leunen K.,UZ Leuven | Van Herpen C.M.L.,Radboud University Nijmegen | And 11 more authors.
Cancer Chemotherapy and Pharmacology

Background: The oral PARP inhibitor olaparib has shown efficacy in patients with BRCA-mutated cancer. This Phase I, open-label, three-part study (Parts A-C) in patients with advanced solid tumours evaluated the effect of food on the pharmacokinetics (PK) of olaparib when administered in tablet formulation. Methods: PK data were obtained in Part A using a two-treatment period crossover design; single-dose olaparib 300 mg (two 150 mg tablets) was administered in two prandial states: fasted and fed. In Part B, patients received olaparib tablets (300 mg bid) for 5 days under fasting conditions; in Part C, patients were allowed continued access to olaparib. Safety was assessed throughout, with data reported for Parts A and B. Results: A total of 60 and 56 patients were evaluable for safety and PK analyses, respectively; 57 patients entered Part B. Rate of olaparib absorption was slower in the presence of food (t max delayed by 2.5 h), resulting in a statistically significant ~21 % decrease in peak plasma exposure (C max) [ratio of geometric means (90 % CI), 0.79 (0.72, 0.86)] but only a marginal increase in olaparib absorption (AUC0-∞) [ratio of geometric means (90 % CI), 1.08 (1.01, 1.16)]. The point estimate and 90 % CI for the AUC0-∞ treatment ratio were within pre-defined bioequivalence limits (0.80-1.25). Adverse event data were consistent with the known safety profile of olaparib. Conclusions: Results of this study showed that a high-fat meal decreases the rate of absorption and peak exposure to olaparib 300 mg tablets, although in the absence of an effect on the extent of olaparib absorption. © 2015 Springer-Verlag Berlin Heidelberg. Source

Molife L.R.,Royal Marsden Institute of Cancer Research | Molife L.R.,Drug Development Unit | Dean E.J.,University of Manchester | Blanco-Codesido M.,Royal Marsden Institute of Cancer Research | And 10 more authors.
Clinical Cancer Research

Purpose : Receptor tyrosine kinases c-Met and Ron transduce signals regulating cell migration and matrix invasion. This phase I dose-escalation trial tested golvatinib, a highly potent, small-molecule, ATP-competitive inhibitor of c-Met and multiple members of the Eph receptor family plus c-Kit and Ron. @copy;2014 American Association for Cancer Research.Experimental Design: Patients with advanced solid tumors received golvatinib orally, once daily, continuously. Using a "33" design, dosing started at 100 mg once daily, escalating to the maximum tolerated dose ( MTD) defined by dose-limiting toxicities. Pharmacokinetic, pharmacodynamic, and preliminary antitumor activity was assessed during dose escalation and in a MTD expansion cohort.Results: Thirty-four patients were treated at six dose levels. The MTD was determined as 400 mg once daily. Three dose-limiting toxicities were observed: grade 3 increased g -glutamyltransferase and alkaline phosphatase (200 mg), repeated grade 2 fatigue, and grade 3 fatigue (50.0%). Frequent treatment-related adverse events (with incidence >10%) included diarrhea (58.8%), nausea (50%), vomiting (44.1%), fatigue (41.2%), decreased appetite (32.4%), elevated alanine aminotransferase (32.4%), elevated aspartate aminotransferase (20.6%), dry skin (11.8%), and dysgeusia (11.8%). Best overall response was stable disease (median duration 85 days, range 85-237). Pharmacokinetics demonstrated high variability, although maximum plasma concentration and area under the plasma concentration-time curve increased with dose. Soluble urokinase-type plasminogen activator receptor, VEGFR2, c-Met, and angiopoietin-2 levels increased after dose. Posttreatment decrease in either p-c-Met or p-ERK was observed in 3 of 4 paired biopsies at MTD.Conclusions: Golvatinib at the MTD of 400 mg once daily was well tolerated with pharmacodynamic evidence of c-Met target modulation. Source

Molife L.R.,Royal Marsden Institute of Cancer Research | Alam S.,Royal Marsden Institute of Cancer Research | Olmos D.,Royal Marsden Institute of Cancer Research | Puglisi M.,Royal Marsden Institute of Cancer Research | And 7 more authors.
Annals of Oncology

Background: This study defined the risk of serious toxicity in phase I trials of molecularly targeted agents (MTA). Patients and methods: A retrospective analysis of toxicity data from patients treated in phase I trials of MTAs was carried out to define the rate of treatment-related grade 3/4 toxic effects, deaths and risk factors associated with grade 3 or more toxicity. Results: Data from 687 patients [median age, 59.1 years (range 12.5-85.5)] treated in 36 trials were analysed. Two hundred and eleven patients were of Eastern Cooperative Oncology Group performance status (PS) zero, 432 of PS one, 38 of PS two and 6 unknown. The rate of grade 3 and 4 events was 14.1% (n = 97) and 1.9% (n = 13), respectively. Twenty-four percent of events were gastrointestinal, 22% constitutional and 20% metabolic. PS two was associated with a higher risk of toxicity [odds ratio (OR), 2.6; 95% confidence interval (CI) 1.1-6.1; P = 0.032] as was receiving >100% of maximum tolerated dose or maximum administered dose (OR 2.5; CI 1.6-3.9; P < 0.001). Mortality rate was 0.43% (n = 3). Conclusions: Therapy with novel MTAs in phase I trials is associated with a moderate risk of significant toxicity. This appears less than in phase I studies involving cytotoxic agents, particularly in relation to grade 4 toxicity. The risk of death is low. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source

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