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An intrapleural administration of zoledronic acid for inoperable malignant mesothelioma patients: a phase I clinical study protocol

机译:不可应用的恶性间皮瘤患者胸膜内注射唑来膦酸:I期临床研究方案

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摘要

BackgroundThe third generation of bisphosphonates is clinically in use for patients of osteoporosis or malignancy-linked hypercalcemia. The agents can also produce anti-tumor effects on bone metastasis of several types of tumors. We recently found that one of the agents achieved cytotoxicity to mesothelioma in vitro and in an orthotopic animal model. Mesothelioma is resistant to a number of chemotherapeutic agents, and suppression of local tumor growth is beneficial to the patients since metastasis to extra-thoracic organs is relatively infrequent until a late stage.Methods/designWe demonstrated in an orthotopic mouse model that an intrapleural but not intravenous injection of zoledronic acid, one of the third generation bisphosphonates, at a clinically equivalent dose suppressed the tumor growth. Nevertheless, a high concentration of zoledronic acid administrated in the pleural cavity produced pleural adhesion. We also showed that zoledronic acid produced synergistic cytotoxic effects with cisplatin, the first-line chemotherapeutic agent for mesothelioma. We then planned to conduct a phase I clinical study to investigate any adverse effects and a possible clinical benefits produced by an intrapleural administration of zoledronic acid to mesothelioma patients who became resistant to the first-line chemotherapeutic agents. The clinical trial is a dose escalation study starting with 0.4, 1, 4, 8 and 16 mg per person since safety of administration of zoledronic acid into the pleural cavity remains unknown. Each dose group consists of three persons and the protocol allows to repeat administration of the same dose into the pleural cavity at a 4-weeks interval.DiscussionWe will conduct a possible combinatory study of intrapleural administration of zoledronic acid and systemic administration of the first-line agent to a chemotherapy-naïve patient based on the maximum tolerance dose of zoledronic acid determined by the present clinical trial. We propose that administration of bisphosphonates in a closed cavity is a treatment strategy for tumors developed in the cavity probably through the direct cytotoxic activity.
机译:背景技术第三代双膦酸盐临床上用于骨质疏松症或恶性肿瘤相关的高钙血症患者。该药物还可以对几种类型的肿瘤的骨转移产生抗肿瘤作用。我们最近发现一种药物在体外和原位动物模型中获得了对间皮瘤的细胞毒性。间皮瘤对多种化学治疗药物具有抗性,并且抑制局部肿瘤生长对患者有益,因为直到晚期,转移到胸外器官的频率相对较低。以临床等效剂量静脉注射唑来膦酸(第三代双膦酸盐之一)可抑制肿瘤的生长。然而,在胸膜腔内施用高浓度的唑来膦酸会产生胸膜粘连。我们还显示了唑来膦酸与间皮瘤的一线化疗药物顺铂产生协同的细胞毒性作用。然后,我们计划进行I期临床研究,以调查对一线化疗药物耐药的间皮瘤患者通过胸腔内注射唑来膦酸产生的任何不良反应和可能的临床益处。该临床试验是一项剂量递增研究,起始剂量为每人0.4、1、4、8和16 mg,因为尚不清楚唑来膦酸进入胸膜腔的安全性。每个剂量组由三人组成,并且该方案允许每隔4周重复向胸膜腔内重复给药相同剂量。讨论我们将进行唑来膦酸胸膜内给药和一线全身给药的可能组合研究根据目前的临床试验确定的唑来膦酸的最大耐受剂量,对未接受过化疗的患者使用这种药物。我们建议在封闭的腔中使用双膦酸盐是可能通过直接的细胞毒活性而在腔中发展的肿瘤的治疗策略。

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