Patel S R, Burgess M A, Papadopolous N E, Sidhu G, Gray R, Plager C, Jenkins J, Benjamin R S
Department of Melanoma/Sarcoma Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston 77030, USA.
Invest New Drugs. 1998;16(1):87-92. doi: 10.1023/a:1006078930550.
Doxorubicin and ifosfamide are the two most active agents in the treatment of soft-tissue sarcomas. Patients whose tumors have failed these two drugs have very limited systemic therapy options. It is, therefore, important to identify newer drugs with activity against this disease. CI-980 is a synthetic mitotic inhibitor that binds to tubulin at the colchicine binding site and inhibits the polymerization of tubulin and blocks cell cycle progression in mitosis. Given its broad spectrum activity against several solid tumor models in vivo, we decided to perform a phase 2 study of this drug in previously treated soft-tissue sarcomas. A total of 18 eligible and evaluable patients were entered in the first stage of the trial. The median age was 53 yrs (range, 17-72). No objective responses have been noted. Six patients had stable disease after a median of 3.5 cycles of chemotherapy while 12 others had progressive disease. A total of 48 cycles were administered, 42 of which were administered at dose level 0 (4.5 mg/m2/d x 3). The median AGC nadir was 1.2/microl(0.1 -4.7) on day 10 and the median platelet nadir was 150,000/microl (31,000-338,000). Twenty cycles were complicated with grade 3-4 neutropenia and two cycles were complicated with FUO. There were no CNS toxicities. One patient had a grade 1 thrombophlebitis in 2 cycles and one other patient had a grade 4 thrombophlebitis in one cycle. In conclusion, CI-980 was well tolerated at this dose and schedule but inactive in soft-tissue sarcomas.
多柔比星和异环磷酰胺是治疗软组织肉瘤最有效的两种药物。肿瘤对这两种药物治疗无效的患者，其全身治疗选择非常有限。因此，识别对该疾病有效的新药很重要。CI-980是一种合成的有丝分裂抑制剂，它在秋水仙碱结合位点与微管蛋白结合，抑制微管蛋白的聚合，并阻断有丝分裂中的细胞周期进程。鉴于其在体内对多种实体瘤模型具有广谱活性，我们决定对该药物在先前接受过治疗的软组织肉瘤中进行2期研究。共有18名符合条件且可评估的患者进入试验的第一阶段。中位年龄为53岁（范围17 - 72岁）。未观察到客观缓解。6名患者在接受中位3.5个周期化疗后病情稳定，而其他12名患者病情进展。总共给予了48个周期的化疗，其中42个周期是在剂量水平0（4.5mg/m²/天×3）下进行的。第10天时，平均绝对粒细胞计数最低点为1.2/μl（0.1 - 4.7），平均血小板最低点为150,000/μl（31,000 - 338,000）。20个周期出现3 - 4级中性粒细胞减少，2个周期出现不明原因发热。无中枢神经系统毒性。1名患者在2个周期中出现1级血栓性静脉炎，另1名患者在1个周期中出现4级血栓性静脉炎。总之，CI-980在该剂量和给药方案下耐受性良好，但对软组织肉瘤无效。
