Tolcher A W, Eckhardt S G, Kuhn J, Hammond L, Weiss G, Rizzo J, Aylesworth C, Hidalgo M, Patnaik A, Schwartz G, Felton S, Campbell E, Rowinsky E K
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78229, USA.
J Clin Oncol. 2001 Jun 1;19(11):2937-47. doi: 10.1200/JCO.2001.19.11.2937.
To assess the feasibility of administering NSC 655649, a water-soluble, rebeccamycin analog with topoisomerase inhibitory properties, as a brief intravenous (IV) infusion once every 3 weeks and to determine the maximum-tolerated dose (MTD) of NSC 655649, characterize its pharmacokinetic behavior, and seek preliminary evidence of antitumor activity.
Patients with advanced solid malignancies were treated with escalating doses of NSC 655649 administered over 30 to 60 minutes IV once every 3 weeks. An accelerated dose-escalation method was used to guide dose escalation. After three patients were treated at the first dose level, doses were escalated in increments that ranged up to 150% using single patient cohorts until moderate toxicity was observed, when a more conservative dose-escalation scheme was invoked. MTD was defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%. MTD was determined for both minimally pretreated (MP) and heavily pretreated (HP) patients. Plasma and urine were sampled to characterize the pharmacokinetic and excretory behavior of NSC 655649.
Forty-five patients were treated with 130 courses of NSC 655649 at doses ranging from 20 mg/m(2) to 744 mg/m(2). Myelosuppression was the principal toxicity. Severe neutropenia, which was often associated with thrombocytopenia, was unacceptably high in HP and MP patients treated at 572 mg/m(2) and 744 mg/m(2), respectively. Nausea, vomiting, and diarrhea were common but rarely severe. The pharmacokinetics of NSC 655649 were dose dependent and fit a three-compartment model. The clearance and terminal elimination half-lives for NSC 655649 averaged 7.57 (SD = 4.2) L/h/m(2) and 48.85 (SD = 23.65) hours, respectively. Despite a heterogeneous population of MP and HP patients, the magnitude of drug exposure correlated well with the severity of myelosuppression. Antitumor activity was observed in two HP ovarian cancer patients and one patient with a soft tissue sarcoma refractory to etoposide and doxorubicin.
Recommended phase II doses are 500 mg/m(2) and 572 mg/m(2) IV once every 3 weeks for HP and MP patients, respectively. The absence of severe nonhematologic toxicities, the encouraging antitumor activity in HP patients, and the unique mechanism of antineoplastic activity of NSC 655649 warrant further clinical development.
评估每3周静脉快速输注一次水溶性、具有拓扑异构酶抑制特性的瑞贝卡霉素类似物NSC 655649的可行性，确定NSC 655649的最大耐受剂量（MTD），描述其药代动力学行为，并寻找抗肿瘤活性的初步证据。
晚期实体恶性肿瘤患者接受NSC 655649剂量递增治疗，每3周静脉输注一次，输注时间为30至60分钟。采用加速剂量递增法指导剂量递增。在第一个剂量水平治疗3例患者后，使用单例患者队列将剂量递增幅度提高至150%，直至观察到中度毒性，此时采用更保守的剂量递增方案。MTD定义为剂量限制性毒性发生率不超过20%的最高剂量水平。分别确定了轻度预处理（MP）和重度预处理（HP）患者的MTD。采集血浆和尿液样本以描述NSC 655649的药代动力学和排泄行为。
45例患者接受了130个疗程的NSC 655649治疗，剂量范围为20mg/m²至744mg/m²。骨髓抑制是主要毒性。在分别接受572mg/m²和744mg/m²治疗的HP和MP患者中，严重中性粒细胞减少症（常伴有血小板减少症）的发生率高得令人无法接受。恶心、呕吐和腹泻很常见，但很少严重。NSC 655649的药代动力学呈剂量依赖性，符合三室模型。NSC 655649的清除率和终末消除半衰期平均分别为7.57（标准差 = 4.2）L/h/m²和48.85（标准差 = 23.65）小时。尽管MP和HP患者群体存在异质性，但药物暴露程度与骨髓抑制的严重程度密切相关。在2例HP卵巢癌患者和1例对依托泊苷和阿霉素耐药的软组织肉瘤患者中观察到了抗肿瘤活性。
对于HP和MP患者，推荐的II期剂量分别为每3周静脉输注一次500mg/m²和572mg/m²。NSC 655649不存在严重的非血液学毒性、HP患者中令人鼓舞的抗肿瘤活性以及独特的抗肿瘤活性机制，因此有必要进一步开展临床研究。
