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Patricia Vrignaud,1 Dorothée Semiond,2 Veronique Benning,2 Eric Beys,2 Hervé Bouchard,3 Sunil Gupta4 1Sanofi Oncology, Vitry-sur-Seine, France; 2Sanofi DSAR, Alfortville, France; 3Sanofi LGCR, Vitry-sur-Seine, France; 4Sanofi Oncology, Cambridge, MA, USA Abstract: First-generation taxanes have changed the treatment paradigm for a wide variety of cancers, but innate or acquired resistance frequently limits their use. Cabazitaxel is a novel second-generation taxane developed to overcome such resistance. In vitro, cabazitaxel showed similar antiproliferative activity to docetaxel in taxane-sensitive cell lines and markedly greater activity in cell lines resistant to taxanes. In vivo, cabazitaxel demonstrated excellent antitumor activity in a broad spectrum of docetaxel-sensitive tumor xenografts, including a castration-resistant prostate tumor xenograft, HID28, where cabazitaxel exhibited greater efficacy than docetaxel. Importantly, cabazitaxel was also active against tumors with innate or acquired resistance to docetaxel, suggesting therapeutic potential for patients progressing following taxane treatment and those with docetaxel-refractory tumors. In patients with tumors of the central nervous system (CNS), and in patients with pediatric tumors, therapeutic success with first-generation taxanes has been limited. Cabazitaxel demonstrated greater antitumor activity than docetaxel in xenograft models of CNS disease and pediatric tumors, suggesting potential clinical utility in these special patient populations. Based on therapeutic synergism observed in an in vivo tumor model, cabazitaxel is also being investigated clinically in combination with cisplatin. Nonclinical evaluation of the safety of cabazitaxel in a range of animal species showed largely reversible changes in the bone marrow, lymphoid system, gastrointestinal tract, and male reproductive system. Preclinical safety signals of cabazitaxel were consistent with the previously reported safety profiles of paclitaxel and docetaxel. Clinical observations with cabazitaxel were consistent with preclinical results, and cabazitaxel is indicated, in combination with prednisone, for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with docetaxel. In conclusion, the demonstrated activity of cabazitaxel in tumors with innate or acquired resistance to docetaxel, CNS tumors, and pediatric tumors made this agent a candidate for further clinical evaluation in a broader range of patient populations compared with first-generation taxanes. Keywords: XRP6258, CNS tumors, mCRPC, pediatric tumor, taxane resistance, xenograft

Background & Aims: The association between pancreatic intraductal papillary mucinous neoplasms (IPMNs) and extrapancreatic neoplasms (EPNs) is controversial. We performed a multicenter observational study to assess the incidence of EPNs after an IPMN diagnosis., Methods: 1340 patients with IPMNs were evaluated from 2000 through 2013 at 4 academic institutions in Europe for development of EPN. To estimate the actual incidence of EPN, we excluded patients with an EPN previous or synchronous to the IPMN, and patients who had been followed for less than 12 months, resulting in a study population of 816 patients. The incidence of EPN was compared with sex-specific, age-adjusted European cancer statistics; the standardized incidence ratio (SIR), and the 5- and 10-year cumulative incidence rates were calculated., Results: A total of 290/1340 patients had a history of EPN (prevalence of 21.6%). In this subgroup of patients, the IPMN was discovered incidentally in 241. Among the 816 patients included in the incidence analysis, 50 developed an EPN after a median time of 46 months from study enrollment. The incidence of any EPN was not greater in patients with than without IPMN with a SIR of 1.48 (95% confidence interval, 0.94-2.22) in males and of 1.39 (95% CI 0.90-2.05) in females. The 5- and 10-year cumulative incidence rates for development of EPN in patients with IPMN were 7.9% and 16.6% in men, and 3.4% and 23.1% in women., Conclusions: Patients with IPMN do not have a significantly higher incidence of EPNs than the general European population. It might not be necessary to screen patients with IPMN for EPN., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Minimizing the number of animals in regulatory toxicity studies while achieving study objectives to support the development of future medicines contributes to good scientific and ethical practices. Recent advances in technology have enabled the development of miniaturized blood sampling methods (including microsampling and dried blood spots) applicable to toxicokinetic determinations of small-molecule drugs. Implementation of miniaturized blood sampling methods in the context of biotherapeutic drugs is desirable because a limitation to this type of medicine remains the total blood volume needed from a single animal to support toxicokinetic determinations of several analytes (parent drug, metabolites[s], antidrug antibodies, and so forth). We describe here the technical details, applicability, and relevance of new miniaturized blood sampling procedures in mice and nonhuman primates in the context of the toxicologic evaluation of biotherapeutic drugs consisting of antibody-drug conjugates developed for oncology indications. These examples illustrate how these techniques can benefit the reduction of animal usage in mouse toxicity studies by decreasing the number of animals dedicated to toxicokinetic determinations and the refinement of practices in nonhuman primate toxicity studies by decreasing the blood volume repeatedly drawn for toxicokinetic determinations.