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: 6486188
• 负责人: SIDNEY WALLACE
• 金额: $ 25.25万
• 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/6486188
• 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; nonhuman therapy evaluation; 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(R)相比，化疗提高了局部晚期非小细胞肺癌(NSCLC)患者的存活率。超过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药物和放射增敏剂。外周神经毒性和粒细胞减少限制了它的剂量；TXL输注的急性反应包括恶心、低血压和与克莫弗和乙醇有关的心律失常。将TXL与多聚L谷氨酸(PG-TXL/CT-2103)偶联，使其具有水溶性，允许两倍的游离TXL输注量和更高的肿瘤内药物浓度，这一点得到了临床前试验的证实。与其他紫杉烷或核苷类似物相比，PG-TXL与辐射的协同增强作用更强。CT-2103作为治疗晚期实体肿瘤患者的单一药物抢救疗法的I期临床试验表明，剂量高达266毫克当量紫杉醇/平方米是安全和耐受性的，没有明显的脱发。这项第二阶段的STTR建议进行一项CT-213的I/II期临床试验，与胸部放疗同时用于不能切除的III期或医学上无法手术的II期非小细胞肺癌患者。这项研究将确定MTD，DLT，药代动力学，评估毒性，并记录患者成本。我们希望这种RT和CT-2103的结合能提高患者的存活率和对治疗的反应。建议的商业应用：在M.D.安德森癌症中心，在放射治疗的同时给予紫杉醇和顺铂是肺癌患者的首选治疗方案。在动物实验中，CT-2103是水溶性的，无需预先给药，10分钟内静脉注射即可感染，比紫杉醇更有效(2-3倍)，毒性较小。CT-2103有可能取代紫杉醇。