Stevenson J P, DeMaria D, Sludden J, Kaye S B, Paz-Ares L, Grochow L B, McDonald A, Selinger K, Wissel P, O'Dwyer P J, Twelves C
University of Pennsylvania Cancer Center, Philadelphia, USA.
Ann Oncol. 1999 Mar;10(3):339-44. doi: 10.1023/a:1008313011289.
Preclinical results support a prolonged schedule of administration for topoisomerase I inhibitors, and we have previously demonstrated the safety and activity of the novel water-soluble topoisomerase I inhibitor GG211 when given as a 72-hour continuous infusion to cancer patients.
In a three-center international phase I trial, 38 patients received GG211 doses from 0.3 to 0.5 mg/m2/day by continuous intravenous infusions for seven, 14, and 21 days. Patients' median performance status was 1; nearly half had colorectal cancer, and 35 patients had prior chemotherapy.
The first patient cohort received 0.3 mg/m2/day for seven days with no significant toxicities. Subsequent cohorts received continuous infusions for 14 and 21 days at this dose level with only mild myelosuppression noted. Dose-escalation on the 21-day schedule was then performed. No dose-limiting toxicity occurred at the 0.4 mg/m2/day dose level. Thrombocytopenia was dose-limiting with 0.5 mg/m2/day dosing but was not cumulative. Other grade 3 4 toxicities included neutropenia, nausea, vomiting, diarrhea, and fatigue. Partial responses occurred with 21-day infusion in two patients with breast and ovarian cancer at the 0.3 and 0.4 mg/m2/day dose levels, respectively. Mean GG211 lactone Css ranged from 0.17 to 0.64 ng/ml.
The maximum tolerated dose of GG211 administered as a 21-day continuous infusion is 0.4 mg/m2/day with antitumor activity noted at tolerable doses.
临床前研究结果支持延长拓扑异构酶I抑制剂的给药方案，并且我们之前已经证明，新型水溶性拓扑异构酶I抑制剂GG211以72小时持续静脉输注方式给予癌症患者时具有安全性和活性。
在一项三中心国际I期试验中，38例患者接受GG211剂量为0.3至0.5mg/m²/天，通过持续静脉输注给药7天、14天和21天。患者的中位体能状态评分为1；近一半患者患有结直肠癌，35例患者曾接受过化疗。
第一组患者接受0.3mg/m²/天持续7天的治疗，未出现明显毒性。后续组在该剂量水平下接受14天和21天的持续输注，仅观察到轻度骨髓抑制。然后在21天给药方案上进行剂量递增。在0.4mg/m²/天剂量水平未发生剂量限制性毒性。血小板减少是0.5mg/m²/天剂量时的剂量限制性毒性，但不具有累积性。其他3/4级毒性包括中性粒细胞减少、恶心、呕吐、腹泻和疲劳。在0.3mg/m²/天和0.4mg/m²/天剂量水平下，分别有两名乳腺癌和卵巢癌患者在接受21天输注后出现部分缓解。GG211内酯的平均稳态血药浓度范围为0.17至0.64ng/ml。
以21天持续输注方式给药的GG211的最大耐受剂量为0.4mg/m²/天，在可耐受剂量下观察到抗肿瘤活性。
