http://repub.eur.nl/res/aut/46892/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/31168/ 2011-04-01T00:00:00Z Background: Because chemotherapy for metastatic breast cancer (MBC) is associated with relevant toxicity, sequential monotherapy trastuzumab followed by cytotoxic therapy at disease progression might be an attractive approach. Methods: In a multicenter phase II trial, 101 patients with overexpression of human epidermal growth factor receptor 2 (HER2+) MBC were randomized between combination-therapy trastuzumab (Herceptin) plus docetaxel (H + D) and sequential therapy of single-agent trastuzumab followed at disease progression by docetaxel alone (H→D) as first-line chemotherapy for metastatic disease. The primary endpoint was progression-free survival (PFS) after completed sequential or combination therapy. Results: For the H + D group the median PFS was 9.4 vs. 9.9 months for the H→D group and 1-year PFS rates were 44% vs. 35%, respectively. However the overall response rates (ORRs) were 79% vs. 53%, respectively (P =.016), and overall survival was 30.5 vs. 19.7 months, respectively (P =.11). In the H→D group, response rates to monotherapy trastuzumab and subsequent docetaxel were 34% and 39%, respectively, with a median PFS during single-agent trastuzumab of 3.9 months. The incidence and severity of neuropathy were significantly higher in the H + D group. Retrospective analysis of trastuzumab treatment beyond progression (applied in 46% of patients in the H + D group and 37% in the H→D group) showed a correlation with longer overall survival in both treatment arms (36.0 vs. 18.0 months and 30.3 vs. 18.6 months, respectively). Conclusion: First-line treatment in patients with MBC with H→D resulted in a similar PFS compared with H + D, but the response rate was lower and the overall survival nonsignificantly shorter. http://repub.eur.nl/res/pub/32025/ 2002-11-06T00:00:00Z Il-12 has a number of immunoregulatory properties indicating its therapeutic potential against cancer. The encouraging anti-tumor effects, observed in a variety of animal tumor models, have stimulated the development of Il-12 as a single agent for systemic cytokine therapy of cancer in humans. Metastatic renal cell cancer is one of the few human cancers that are more responsive to immunotherapy than to conventional cytotoxic therapies. Therefore, a phase I study of Il-12 was performed in patients with advanced renal cell cancer. The choice of schedule and route of administration were based on experiments in cynomolgus monkeys. Il-12 in s.c. doses of 0.1 to 1.0 Jlg /kg /day, three times a week, was shown to modulate immune activity without provoking substantial toxicity in these animals. The objective of the study described in chapter 2 was to evaluate the safety and tolerability of subcutaneous IL-12 in humans and establish the pharmacokinetic profile. The observation of a non-linear relationship between dose and drug exposure in animal models formed the rationale to study the effects of a single and multiple doses of Il-12. In chapter 3 the immunomodulatory activities of IL-12 in humans are described in detail, with emphasis on the induction of secondary cytokines and the effects on circulating leucocyte subset counts. Based on the observation that side effects decreased upon repeated injections of IL-12, we specifically studied whether or not immunomodulatory effects were downregulated in the course of multiple IL-12 injections with special attention for the role of the immunosuppressive cytokine IL-10. Chapter 4 describes a study of the effect of IL-12 on fibrinolysis and coagulation in humans. This study was performed because several bleeding episodes were reported in simultaneously performed clinical studies, whereas studies in mice and non-human primates had shown that IL-12 induced activation of coagulation and fibrinolysis. Il-12 is a strong pro-inflammatory cytokine. Studies in patients and experimental animals have demonstrated that endogenously produced IL-12 plays an important role in the toxic sequel of sepsis and endotoxemia. In these situations, excessive activation of various components of the inflammatory cascade contributes to the development of tissue injury and mortality. In chapter 5 we describe the in-vivo effects of different doses of subcutaneous Il-12 on components of the inflammatory cascade. We specifically addressed the degranulation of neutrophils and the formation of secretory phospholipase Az, a regulatory enzyme in the formation of eicosanoids. The study described in chapter 2 was one of four phase I studies, that were simultaneously performed in Europe and the US. Subsequent phase II studies in patients with advanced renal cell cancer and ovarian cancer demonstrated disappointing anti-tumor effects. The results described in chapter 3, together with other pharmacodynamic studies, indicate that the lack of efficacy was accompanied by, and probably related to, declining biological effects of IL-12 in the course of repeated administrations at doses approaching the maximum tolerated dose (MTD). Nevertheless, IL-12 remains a promising immunotherapeutic agent because recent cancer vaccination studies in animal models and humans have demonstrated its powerful adjuvant properties. Chapter 6 reviews the adjuvant properties of IL-12 and delineates how the immuneregulatory properties of IL-12 described in the previous chapters may contribute to the adjuvant effects. In addition, it is discussed how the studies presented in this paper, together with other clinical studies of systemic IL-12, indicate that IL- 12 may exert optimal adjuvant effects only at low dose levels. Finally, the future perspectives of IL-12 in the treatment of cancer are addressed.