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Pharmacokinetics of Novel Anticancer Drugs and Dynamics of Circulating Tumor Cells in Early Clinical Studies

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Pharmacokinetics of Novel Anticancer Drugs and Dynamics of Circulating Tumor Cells in Early Clinical Studies Pharmacokinetics of novel anticancer drugs and dynamics of circulating tumor cells in early clinical studies L.A. Devriese 2011 ISBN: 978-94-91211-94-2 Cover design: Eke Westra www.westudio.nl “Schets voor Regenboog”, Maria Roosen (2004) Layout: Bob Kielstra. Ipskamp Drukkers BV, Enschede Printed by: Ipskamp Drukkers BV © 2011 by L.A. Devriese No part of this thesis may be reproduced or transmitted, in any form or by any means without prior permission of the author. Pharmacokinetics of novel anticancer drugs and dynamics of circulating tumor cells in early clinical studies Farmacokinetiek van nieuwe anti-kanker middelen en dynamiek van circulerende tumor cellen in vroeg-klinische studies (met een samenvatting in het Nederlands) PROEfscHRifT ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op woensdag 30 november 2011 des middags te 2.30 uur door Lotje Antonetta Devriese geboren op 20 september 1977 te Velsen Promotoren: Prof.dr. J.H.M. Schellens Prof.dr. E.E. Voest The research described in this thesis was performed at the Division of Experimental Therapy and the Department of Clinical Pharmacology of the Netherlands Cancer Institute – Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands The publication of this thesis was financially supported by: Abbott B.V., Hoofddorp; Amgen B.V., Breda; Astellas Pharma B.V., Leiderdorp; Boehringer Ingelheim B.V., Alkmaar; Eli Lilly Nederland B.V., Houten; GlaxoSmithKline B.V., Zeist; Janssen-Cilag B.V., Tilburg; J.E. Jurriaanse Stichting, Rotterdam; Merck Sharp & Dohme B.V., Haarlem; Pfizer B.V., Capelle aan den IJssel; Roche Nederland BV, Woerden; Sanofi The Netherlands B.V., Gouda; all in the Netherlands; Eisai Ltd, Hatfield, United Kingdom “If the history of medicine is told through stories of doctors, it is because their contributions stand in place of the more substantive heroism of their patients” by Siddhartha Mukherjee in “The emperor of all maladies: a biography of cancer” COnTEnTs Chapter 1 General introduction 11 Chapter 2 Pharmacokinetics of pazopanib and topotecan 15 2.1 Phase I study of safety, tolerability and pharmacokinetics of 17 pazopanib in combination with oral topotecan in patients with advanced solid tumors 2.2 Phase I study of oral topotecan in patients with cancer and 43 impaired renal function Chapter 3 Pharmacokinetics of eribulin mesylate 69 3.1 Eribulin mesylate pharmacokinetics in patients with solid tumors 61 and hepatic impairment 3.2 Eribulin mesylate pharmacokinetics in patients with solid tumors 89 receiving repeated oral ketoconazole 3.3 Eribulin mesylate pharmacokinetics in patients with solid tumors 107 receiving repeated oral rifampicin Chapter 4 Pharmacokinetics of lapatinib 125 4.1 Effects of low-fat and high-fat meals on steady-state 127 pharmacokinetics of lapatinib in patients with advanced solid tumors Chapter 5 Circulating tumor cells 147 5.1 Circulating tumor cells as pharmacodynamic biomarker in early 149 clinical oncological trials 5.2 A multi-marker QPCR-based platform for the detection of 179 circulating tumour cells in patients with early-stage breast cancer 5.3 Circulating tumor cell detection in advanced non-small cell 199 lung cancer patients by multi-marker QPCR analysis 5.4 Validation of a multi-parameter flow cytometry method for the 217 determination of DNA and phosphorylated extracellular-signal- regulated kinase in circulating tumor cells Chapter 6 Conclusions and perspectives 237 Appendix Chemical structures of anti-cancer drugs investigated in this thesis 245 Summary 249 Samenvatting 255 Dankwoord 261 Publications 267 Curriculum Vitae 269 Chapter 1 General Introduction General Introduction GEnERal inTROdUcTiOn Nearly 12.7 million persons per year are confronted worldwide with the diagnosis of cancer. The impact cancer has on the lives of cancer patients and on society is enormous. Within the European Union, 2.4 million inhabitants per year are diagnosed with cancer and 1.2 million people die as a result of cancer every year. It has been estimated that, currently, the risk of getting cancer before the age of 75 years is 18.7% 1. These numbers illustrate the imperative to improve therapies for the treatment of cancer. Anti-cancer treatment is based on combinations of surgery, radiotherapy and drug therapy. Previously, systemic oncolytic therapy used to consist only of chemotherapy with cytotoxic drugs and/or hormonal treatment. In the past decades, the insight in the pathobiology of cancer initiation and its progression has increased largely. Such has resulted in the identification of several proteins and intracellular signal transduction pathways that have been shown to be essential for cancer cell survival. These molecules have therefore become exposed as a specific target for anti-cancer therapy 2. Nowadays, many new drugs are being developed as “targeted” therapy and these drugs are currently being used in the clinic next to conventional chemotherapy. This thesis is focused on early clinical studies in the development anti-cancer drugs and reports on two aspects of drug development. The first part of the thesis encompasses phase I pharmacokinetic trials of novel anti-cancer drugs (chapters 2-5). Clinically relevant questions were studied and recommended doses of specific anti-cancer drugs for patients with renal- (chapter 2.2) and hepatic impairment (chapter 3.1) were established. Also, potential drug-drug interactions in oral (chapter 2.1) and intravenous anti-cancer drugs (chapters 3.2 and 3.3) were examined. Next to this, relevance of a food-drug interaction with another oral anti-cancer drug was investigated (chapter 4.1). The recommendations that resulted from these studies can be applied directly into the clinic. The second part of the thesis reports on dynamics of circulating tumor cells in the peripheral blood of cancer patients (CTCs; chapter 5). Techniques for the detection of CTCs in breast- (chapter 5.2) and non-small cell lung cancer (chapter 5.3) were optimized and applied in exploratory clinical studies. Next to this, the utility of these CTCs to be used as pharmacodynamic biomarkers in the development of anti-cancer drugs was reviewed (chapter 5.1). Finally, an assay was developed and subsequently validated that demonstrated actual intracellular pharmacodynamic changes in activation of specific proteins in CTCs (chapter 5.4). This “proof-of-principle” study 13 Chapter 1 showed that CTCs are amenable for pharmacodynamic measurements of drugs that target a specific signaling cascade or protein within CTCs. Further research should be pursued in order to fully exploit the potential of CTCs in this context. In summary, this thesis describes both pharmacokinetic trials and exploratory studies with CTCs as pharmacodynamic biomarkers. Some results are available directly for application in the clinic and other results will need to be further investigated before applying them in drug development of new drugs. Both contribute to further development of current and future pharmacologically based anti-cancer treatments, which will hopefully result in an improved outcome for cancer patients. REFERENCES 1. GLOBOCAN 2008 database International Agency for Research on Cancer-World Health Organization http:, globocan.iarc.fr/factsheets/cancers/all.asp Last update on 26 Jul; 2011, 2. Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 144:646-674, 2011 14 Chapter 2 Pharmacokinetics of pazopanib and topotecan Chapter 2.1 Phase I study of safety, tolerability and pharmacokinetics of pazopanib in combination with oral topotecan in patients with advanced solid tumors L.A. Devriese1,2, M.P.J. Lolkema3, P.O. Witteveen3, A. Nol2, J. Stoebenau4, P. Legenne4, D.A. Smith4, B.J. Giantonio5, J.H.M. Schellens1,2,6 and E.E. Voest 3 1. Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands 2. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands 3. Department of Medical Oncology, University Medical Center Utrecht, The Netherlands 4. GlaxoSmithKline, Research Triangle Park, North Carolina, U.S.A. 5. Abramson Cancer Center, University of Pennsylvania, Philadelphia, U.S.A. 6. Science Faculty, Department of Pharmaceutical Sciences, Utrecht University, The Netherlands Interim analysis Phase I study of pazopanib and oral topotecan ABSTRACT Purpose To determine the maximum-tolerated dose (MTD), safety, tolerability and pharmacokinetics of pazopanib in combination with oral topotecan. Experimental design Two-stage, two-arm, dose escalation and pharmacokinetic phase I study of pazopanib and oral topotecan in patients with advanced solid tumors. This interim report describes the results of the bioavailability part (1) and the dose escalation part (2A) of continuous pazopanib therapy combined with weekly topotecan in a 28-day cycle. Results At time of interim analysis, 32 patients were included of which 28 were evaluable. Three dose-limiting toxicities (DLTs) occurred that included grade 3 hand-foot-syndrome, diarrhea and neutropenia. The highest dose in dose-escalation (continuous pazopanib 800 mg in combination with topotecan 10 mg on day 1, 8, 15 in a 28-cycle), was found to exceed the MTD because two DLTs occurred in six patients. Therefore, the MTD is expected to be at the next-lower dose level (pazopanib 800 mg with topotecan 8 mg) and this dose level is currently being explored in an expansion cohort. The most frequently reported treatment-related toxicities were grade 3 anemia (3/28, 11%), leukocytopenia, neutropenia and fatigue (all 2/28, 7.1%). Pharmacokinetic analysis of the bioavailability part (n=7) showed an increase in topotecan exposure when co- administered with pazopanib compared to single administration. Topotecan AUC0-∞ was increased 1.58-fold (90%CI: 1.09–1.29) and Cmax 1.78-fold (90%CI: 1.08-2.92) when co-administered with pazopanib. Pazopanib AUC0-24 and Cmax ratios were not increased when co-administered with topotecan and were 0.98 (90%CI: 0.95-1.02) and 0.96 (90%CI: 0.92-1.01), respectively.
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