Development of Poly-L-Glutamic Acid Paclitaxel Conjugate

聚-L-谷氨酸紫杉醇缀合物的开发

• 批准号: 6943891
• 负责人: SIDNEY WALLACE
• 金额: $ 4.9万
• 依托单位: FEM CADET
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-15 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6943891
• 关键词: antineoplastics; chemical conjugate; clinical research; clinical trial phase I; combination cancer therapy; human subject; human therapy evaluation; lung neoplasms; neoplasm /cancer chemotherapy; neoplasm /cancer radiation therapy; paclitaxel; patient oriented research; pharmacokinetics; polyglutamates; positron emission tomography

Chemoradiation improves survival for patients with locally advanced non-small cell lung cancer (NSCLC) over radiotherapy (R) alone. Les than 20% of patients have complete pathologic response to combination therapy. Paclitaxel (TXL) is effective as an anti-tumor agent and a radiosensitizer. Peripheral neurotoxicity and granulocytopenia limit its dosage; acute effects from TXL's infusion include nausea, hypotension, and cardiac arrhythmias related to Cremophor and ethanol. Conjugating TXL with poly-L-glutamate (PG-TXL/CT-2103) makes it water-soluble, allowing infusion of twice the amount of free TXL and higher intratumoral drug concentrations, which was confirmed by preclinical testing. Combining PG-TXL with radiation demonstrated synergistic radiation enhancement higher than that seen with other taxane or nucleoside analog. A phase I clinical trial of CT-2103 as single agent salvage therapy for patients with advanced solid tumors demonstrated safety and tolerability in dose up to 266 mg equivalent paclitaxel/m2 without significant alopecia. This Phase II STTR proposes a Phase I/II clinical trial of CT-213 given concurrently with chest RT in patients with unresectable Stage III or medically inoperable Stage II NSCLC. This study will determine MTD, DLT, pharmacokinetics, assess toxicity, and document patient costs. We expect this combination RT and CT-2103 to improve patient survival and response to treatment. PROPOSED COMMERCIAL APPLICATIONS: At M.D. Anderson Cancer Center, the combination of Taxol and cisplatin given concurrently with radiation therapy is the treatment of choice for lung cancer patients. In animal studies, CT-2103 is water soluble, infectable intravenously in 10 minutes without pre-medication, more effective (2-3X) and less toxic than Taxol. CT-2103 could possibly replace Taxol.

与单纯放疗相比，放化疗可提高局部晚期非小细胞肺癌（NSCLC）患者的生存率。不到20%的患者对联合治疗有完全的病理反应。 紫杉醇（TXL）是一种有效的抗肿瘤剂和放射增敏剂。外周神经毒性和粒细胞减少症限制了其剂量; TXL输注的急性效应包括恶心、低血压和与Cremophor和乙醇相关的心律失常。将TXL与聚-L-谷氨酸（PG-TXL/CT-2103）结合使其可溶于水，允许输注两倍量的游离TXL和更高的肿瘤内药物浓度，这已通过临床前试验证实。 PG-TXL与放射联合使用显示出比其他紫杉烷或核苷类似物更高的协同放射增强作用。CT-2103作为晚期实体瘤患者单药挽救治疗的I期临床试验证明了剂量高达266 mg当量紫杉醇/m2的安全性和耐受性，无明显脱发。该II期STTR提出了一项在不可切除的III期或医学上不可手术的II期NSCLC患者中进行CT-213与胸部RT同时给药的I/II期临床试验。本研究将确定MTD、DLT、药代动力学、评估毒性并记录患者成本。我们期望RT和CT-2103的组合能够改善患者的生存率和对治疗的反应。拟定商业应用：在M.D.根据安德森癌症中心的研究，紫杉醇和顺铂的联合治疗与放射治疗同时给予是肺癌患者的治疗选择。在动物研究中，CT-2103是水溶性的，在10分钟内静脉注射即可感染，无需预先用药，比紫杉醇更有效（2- 3倍）且毒性更低。CT-2103可能取代紫杉醇。