Evaluate the clinical use of bevacizumab, both for cancer and for non-oncologic diseases, and discuss approved and investigational combination chemotherapies that include bevacizumab. Describe the pharmacology of bevacizumab and its mechanism of action in order to predict degrees of patient response. Phase I studies with anticancer drugs are used to evaluate safety and tolerability and to choose a recommended phase II dose (RP2D). Traditionally, phase I trial designs are rule-based, but for several years there is a trend towards model-based designs. Simulations have shown that model-based designs perform better, faster and are safer to establish the RP2D than rule-based designs. However Jan H.M. Schellens. Division of Experimental Therapy and. Department of Clinical Pharmacology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; Faculty of Science, Department of Pharmaceutical Sciences, Section of Biomedical Analysis, Division of Drug Toxicology, Utrecht University, Utrecht, The Clinical proteomics in breast cancer 15 IntroductionIntroduction Breast cancer imposes a significant healthcare burden to women worldwide. For example, in the USA, breast cancer is estimated to be the most commonly diagnosed neoplasm in women in 2008, as it will account for 26% of all new female cancer cases (1). Camptothecins (CPTs) are a unique class of chemotherapeutic agent which inhibit DNA synthesis by inhibiting topoisomerase I activity. Structure-activity studies on the original CPT alkaloid led to the development of the new analogues irinotecan (CPT-11), topotecan, and 9-aminocamptothecin, which have improved water solubility and lower toxicity. CPT analogues exhibit interesting Learning Objectives. After completing this course, the reader will be able to: Identify the main toxicity profile associated with capecitabine therapy.Identify AZD1775 (formerly MK-1775), a pyrazol-pyrimidine derivate, is a potent and ATP-competitive specific small-molecule inhibitor of the Wee1 kinase.An IC 50 of 5.2 nmol/L has been reported (). In vivo, AZD1775 has a relatively short terminal half-life (t 1/2), ranging from 9 to 12 hours.Results of a study by Cuneo and colleagues demonstrated that sensitization to radiation by Wee1 inhibition Detailed guidelines for the use of fluoropyrimidines, their clinical pharmacology as well as analyses of cost-effectiveness are beyond the scope of this document. The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines consider the situation of patients for which genotype data are already available ( 2 ) (updates available at This paper describes the application of the current insights in the use of PK-PD modeling to the design of clinical trials in oncology. The application of PK-PD modeling in each separate stage of (pre)clinical drug development of anticancer agents is discussed. 10 Beijnen JH, Rosing H. Bioanalytical methods for anti-cancer drugs. In: Cancer Clinical Pharmacology. Schellens JHM, McLeod HL, Newell DR (Eds). Oxford University Press (Oxford, UK), 1-17 (2005). Google Scholar; 11 Pucci V, Di Palma S, Alfieri A, Bonelli F, Monteagudo E. A novel strategy for reducing phospholipids-based matrix effect in LC Cancer Clinical Trials Optimization and Pharmacogenomics I. C. Baianu tested [23], and the development of a few new anti-cancer drugs which involved rational pharmacology [