Phase I clinical and pharmacokinetic study of BBR 3576, a novel aza-anthrapyrazole, administered i.v. every 4 weeks in patients with advanced solid tumors: a phase I study group trial of the Central European Society of Anticancer-Drug Research (CESAR).
ABSTRACT BBR 3576 is a novel aza-anthrapyrazole with limited potential for cardiotoxicity in preclinical models. This phase I clinical and pharmacokinetic study was performed to determine the maximum tolerated dose, the dose-limiting toxicity (DLT) and the pharmacokinetic profile of BBR 3576 administered i.v. as a 1-h infusion repeated every 4 weeks. In total, 27 patients were treated at doses starting from 1 to 150 mg/m2. The dose levels 1, 2, 4, 8, 16, 32, 64, 90, 125 and 150 mg/m2 were investigated in one, three, one, three, two, one, three, four, three and six patients, respectively. The DLT was a grade 3 stomatitis at 150 mg/m2. At this dose level as well as at 125 mg/m2, neutropenia grade 3 and 4 were frequently seen, but not reaching the criteria for DLT. Time to neutrophil nadir was about 2 weeks and recovery took place within 1 week. Other bone marrow toxicities were mild; lymphopenia was also observed. No significant drug-induced cardiotoxicity was observed. The plasma concentration versus time curves of BBR 3576 showed a biexponential profile with a linear kinetic behavior. A very large volume of distribution, a high plasma clearance and long elimination half-lives were calculated. Renal unchanged drug excretion was less than 10% and therefore a minor excretion route. No objective antitumor responses were found. On the basis of this study, the recommended dose for phase II studies is 150 mg/m2, although the maximum tolerated dose as per protocol definition was not reached. This trial showed that BBR 3576 has a manageable toxicity profile on a 4-week schedule. Phase II studies have started in patients with solid tumors, as suggested by preclinical data in different in vivo model systems.
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ABSTRACT: Heterojunction bipolar transistors (HBTs) are attracting interest around the world, finding use in power amplifiers and low phase noise oscillators. There is little information, however, on the performance of HBT devices as mixers, specifically as upconverters in the transmitter path. Using a proprietary HBT model implemented on Libra<sup>TM</sup> by the Communications Research Centre, the HBT is investigated for its suitability as a mixer. A single-ended microwave monolithic integrated circuit (MMIC) upconverter is designed with the IF and LO fed through the base and emitter, respectively, thereby eliminating the need for a diplexer. The simulated upconverter (IF=3.6 GHz and RF=30.1 GHz) yields a conversion gain greater than 2 dB over a bandwidth of 300 MHz. At the RF port, the IF, LO and image frequency isolations are 19 dB, 18 dB and 13 dB respectively, while at the IF port, the RF, LO and image frequency isolations are all greater than 40 dBElectrical and Computer Engineering, 1996. Canadian Conference on; 06/1996
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ABSTRACT: The goal of treatment for patients with advanced cancer is to prolong survival, control symptoms, and reduce disease-related complications. Despite the introduction of many cytotoxic agents during the past decade, only modest improvement in survival has been achieved. In order to urgently improve these situations, new cytotoxic agents as well as molecular-targeted agents are now under investigation. In this article, we reviewed the latest information regarding antitumor activity, toxicity, pharmacokinetics, and clinical application of the new cytotoxic agents.Critical Reviews in Oncology/Hematology 08/2005; 55(1):45-65. DOI:10.1016/j.critrevonc.2005.01.006 · 4.03 Impact Factor
Chapter: Accelerated Titration DesignsStatistical Methods for Dose-Finding Experiments, 06/2006: pages 91 - 113; , ISBN: 9780470861257