Villalona-Calero M A, Petit T, Kuhn J, Cobb P, Kraynak M, Eckhardt S G, Drengler R, Simmons C, Santabarbara P, Von Hoff D D, Rowinsky E K
Institute for Drug Development, Cancer Therapy and Research Center, and The University of Texas Health Science Center at San Antonio, 78229, USA.
Clin Cancer Res. 1999 Nov;5(11):3369-78.
This Phase I and pharmacological study was performed to assess the feasibility of administering the polycyclic aromatic hydrocarbon crisnatol in increasingly prolonged continuous i.v. infusions to patients with advanced solid malignancies. The study also sought to characterize the-principal toxicities of crisnatol on this schedule, to recommend doses for subsequent disease-directed studies, and to characterize possible associations between pharmacological parameters and toxicity. Sixteen patients were treated with 40 courses of crisnatol administered as a continuous i.v. infusion. The initial dose-schedule was 750 mg/m2/day for 6 days, and the duration of the infusion was to be progressively increased by 3-day increments to 9, 12, 15, 18, and 21. Courses were to be repeated every 4 weeks. Moderate to severe central nervous system (CNS) toxicity precluded the administration of crisnatol 750 mg/m2/day for longer than 6 days, and, therefore, the dose of crisnatol was reduced to 600 mg/m2/day. At this dose, three of five patients receiving a 12-day infusion experienced dose-limiting toxicity, which consisted of pulmonary thromboembolism (two patients) and grade 4 thrombocytopenia (one patient). None of the six patients completing a 9-day infusion at 600 mg/m2/day developed dose-limiting toxicity during the first or second course of crisnatol. At this dose level, the plasma concentrations at steady state (Css) averaged 1607.8+/-261.1 ng/ml, which exceeds minimal inhibitory concentrations for most tumors in vitro (1000 ng/ml). In fact, the administration of crisnatol at a dose of 600 mg/m2/day for 9 days resulted in the longest duration that biologically relevant plasma crisnatol concentrations have been sustained. Plasma Css values were significantly higher in patients who experienced severe CNS toxicity compared with those who did not (2465.3+/-1213.5 versus 1342+/-447.3 ng/ml; P = 0.04). There were no relationships evident between the clearance of crisnatol and indices reflecting renal and hepatic functions. One patient with a glioblastoma multiforme experienced a partial response lasting 14 months. The relative lack of intolerable CNS toxicity at the recommended dose for Phase II studies of crisnatol, 600 mg/m2/day for 9 days, as well as the magnitude of the Css values achieved and the antitumor activity observed at this dose, are encouraging. However, the mechanisms for the apparently increased thrombogenicity observed in this trial are unclear and require further elucidation.
本I期药理研究旨在评估对晚期实体恶性肿瘤患者进行越来越长时间的持续静脉输注多环芳烃克立那托的可行性。该研究还试图确定在此给药方案下克立那托的主要毒性，推荐后续针对疾病研究的剂量，并确定药理参数与毒性之间可能的关联。16例患者接受了40个疗程的克立那托静脉持续输注治疗。初始剂量方案为750mg/m²/天，持续6天，输注时间以3天为增量逐步增加至9天、12天、15天、18天和21天。疗程每4周重复一次。中度至重度中枢神经系统（CNS）毒性使得无法给予750mg/m²/天的克立那托超过6天，因此，克立那托剂量降至600mg/m²/天。在此剂量下，5例接受12天输注的患者中有3例出现剂量限制性毒性，包括肺血栓栓塞（2例患者）和4级血小板减少症（1例患者）。6例以600mg/m²/天完成9天输注的患者在克立那托的第一个或第二个疗程中均未出现剂量限制性毒性。在此剂量水平下，稳态血浆浓度（Css）平均为1607.8±261.1ng/ml，超过了大多数肿瘤体外最小抑菌浓度（1000ng/ml）。事实上，以600mg/m²/天的剂量给予克立那托9天导致了生物学相关血浆克立那托浓度持续的最长时间。与未经历严重CNS毒性的患者相比，经历严重CNS毒性的患者血浆Css值显著更高（2465.3±1213.5对1342±447.3ng/ml；P = 0.04）。克立那托的清除率与反映肾和肝功能的指标之间没有明显关系。1例多形性胶质母细胞瘤患者出现了持续14个月的部分缓解。克立那托在II期研究中的推荐剂量为600mg/m²/天，持续9天，相对缺乏难以耐受的CNS毒性，以及在此剂量下达到的Css值大小和观察到的抗肿瘤活性，令人鼓舞。然而，该试验中观察到的明显增加的血栓形成倾向的机制尚不清楚，需要进一步阐明。
