Bombesin/gastrin-releasing peptides (BN/GRP) were shown to bind selectively to cell surface receptors, stimulating the growth of various types of malignancies in murine and human models. The novel BN/GRP synthetic receptor antagonist, RC-3095, was able to produce long-lasting tumor regressions in murine and human tumor models in vitro and in vivo. Animal toxicology studies showed no detectable organ toxicity apart from local irritation at the injection site. The purpose of this study was to determine the safety and feasibility of the administration of RC-3095 by daily subcutaneous injections in patients with advanced and refractory solid malignancies. Twenty-five patients received RC-3095 once or twice-daily at doses ranging from 8 to 96 ug/kg. Dose was escalated in groups of 3-5 patients per dose level. The only toxicity observed was local discomfort in the injection site at the highest doses. A single dose administration of RC-3095 at the highest dose level (96 ug/kg) was tested in a clearly hypergastrinemic individual with the Zollingen-Ellison syndrome and produced a decrease in plasma gastrin down to 50% of basal levels in 6 h. There was no objective tumor responses in patients included in the study. A short-lasting minor tumor response was observed in a patient with a GRP-expressing progressive medullary carcinoma of the thyroid. Due to problems with the analytical method, plasma pharmacokinetic data was obtained only from two patients included at the highest dose level. In these patients, RC-3095 reached plasma concentrations >100 ng/mL for about 8 h, which were within therapeutic levels on the basis of prior data obtained in mice and rats. The plasma elimination half-life was between 8.6-10.9 h. Due to the occurrence of local toxicity at the injection site, the dose escalation procedure could not be fully evaluated up to a maximum tolerated dose. Thus, a recommended dose of RC-3095 for Phase II trials could not be clearly established. Considering the novelty of its mechanism of action and impressive preclinical anti-tumor activity, further studies exploiting new formulations of RC-3095 for human use, such as slow-release preparations, and analogues with a more favorable pharmacokinetics are warranted.

中文翻译：

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胰岛素/胃泌素释放肽（BN / GRP）拮抗剂RC3095在晚期实体恶性肿瘤患者中进行的I期试验。

研究表明，Bombesin /胃泌素释放肽（BN / GRP）与细胞表面受体选择性结合，从而刺激鼠和人模型中各种类型的恶性肿瘤的生长。新型BN / GRP合成受体拮抗剂RC-3095能够在小鼠和人类肿瘤模型中在体内外产生长效的肿瘤消退。动物毒理学研究表明，除了注射部位的局部刺激外，没有可检测到的器官毒性。这项研究的目的是确定在患有晚期和难治性实体恶性肿瘤的患者中每天皮下注射RC-3095的安全性和可行性。25名患者每天一次或两次接受RC-3095，剂量范围为8至96 ug / kg。每剂量水平3-5名患者的剂量逐步增加。观察到的唯一毒性是在最高剂量下注射部位的局部不适。在患有Zollingen-Ellison综合征的明显高胃泌素的个体中测试了最高剂量水平（96 ug / kg）的单剂量RC-3095给药，并在6小时内使血浆胃泌素降低至基础水平的50％。研究中没有客观的肿瘤反应。在表达GRP的甲状腺进行性髓样癌患者中观察到短暂的轻微肿瘤反应。由于分析方法存在问题，仅从两名患者中获得了最高剂量水平的血浆药代动力学数据。在这些患者中，RC-3095在大约8小时内达到了> 100 ng / mL的血浆浓度，根据在小鼠和大鼠中获得的先前数据，这些均在治疗水平之内。血浆消除半衰期在8.6-10.9小时之间。由于在注射部位会发生局部毒性，因此不能完全评估剂量递增程序，直至达到最大耐受剂量。因此，目前尚不清楚II期临床试验的推荐剂量RC-3095。考虑到其作用机制的新颖性和令人印象深刻的临床前抗肿瘤活性，有必要进行进一步研究以开发供人类使用的RC-3095新制剂，例如缓释制剂以及具有更佳药代动力学的类似物。在最大耐受剂量之前无法完全评估剂量递增程序。因此，目前尚不清楚II期临床试验的推荐剂量RC-3095。考虑到其作用机制的新颖性和令人印象深刻的临床前抗肿瘤活性，有必要进行进一步研究以开发供人类使用的RC-3095新制剂，例如缓释制剂以及具有更佳药代动力学的类似物。在最大耐受剂量之前无法完全评估剂量递增程序。因此，目前尚不清楚II期临床试验的推荐剂量RC-3095。考虑到其作用机制的新颖性和令人印象深刻的临床前抗肿瘤活性，有必要进行进一步研究以开发供人类使用的RC-3095新制剂，例如缓释制剂以及具有更佳药代动力学的类似物。