Diab S G, Baker S D, Joshi A, Burris H A, Cobb P W, Villalona-Calero M A, Eckhardt S G, Weiss G R, Rodriguez G I, Drengler R, Kraynak M, Hammond L, Finizio M, Von Hoff D D, Rowinsky E K
The University of Texas Health Science Center at San Antonio, Division of Medical Oncology, 78234, USA.
Clin Cancer Res. 1999 Feb;5(2):299-308.
A Phase I and pharmacological study was performed to evaluate the feasibility, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics of the anthrapyrazole losoxantrone in combination with paclitaxel in adult patients with advanced solid malignancies. Losoxantrone was administered as a 10-min infusion in combination with paclitaxel on either a 24- or 3-h schedule. The starting dose level was 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel (as a 24- or 3-h i.v. infusion) without granulocyte colony-stimulating factor (G-CSF). Administration of these agents at the starting dose level and dose escalation was feasible only with G-CSF support. The following dose levels (losoxantrone/paclitaxel, in mg/m2) of losoxantrone and paclitaxel as a 3-h infusion were also evaluated: 50/135, 50/175, 50/200, 50/225, and 60/225. The sequence-dependent toxicological and pharmacological effects of losoxantrone and paclitaxel on the 24- and 3-h schedules of paclitaxel were also assessed. The MTD was defined as the dose at which >50% of the patients experienced DLT during the first two courses of therapy. DLTs, mainly myelosuppression, occurring during the first course of therapy were noted in four of six and five of eight patients treated with 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel over 24 and 3 h, respectively, without G-CSF. DLTs during the first two courses of therapy were observed in one of six patients at the 50/175 (losoxantrone/paclitaxel) mg/m2 dose level, two of four patients at the 50/200 mg/m2 dose level, one of four patients at the 50/225 mg/m2 dose level, and two of five patients at the 60/225 mg/m2 dose level. The degree of thrombocytopenia was worse, albeit not statistically significant, when 24-h paclitaxel preceded losoxantrone, with a mean percentage decrement in platelet count during course 1 of 80.7%, compared to 43.8% with the reverse sequence (P = 0.19). Losoxantrone clearance was not significantly altered by the sequence or schedule of paclitaxel. Cardiac toxicity was observed; however, it was not related to total cumulative dose of losoxantrone. An unacceptably high rate of DLTs at the first dose level of 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel administered as either a 24- or 3-h i.v. infusion precluded dose escalation without G-CSF support. The addition of G-CSF to the regimen permitted further dose escalation without reaching the MTD. Losoxantrone at 50 mg/m2 followed by paclitaxel (3-h i.v. infusion) at 175 mg/m2 with G-CSF support is recommended for further clinical trials.
进行了一项I期和药理学研究，以评估蒽吡唑洛索蒽醌与紫杉醇联合应用于晚期实体恶性肿瘤成年患者的可行性、最大耐受剂量（MTD）、剂量限制毒性（DLT）和药代动力学。洛索蒽醌与紫杉醇联合应用时，以10分钟输注的方式给药，给药方案为24小时或3小时。起始剂量水平为洛索蒽醌40mg/m²和紫杉醇135mg/m²（作为24小时或3小时静脉输注），不使用粒细胞集落刺激因子（G-CSF）。仅在G-CSF支持下，以起始剂量水平给药及剂量递增才可行。还评估了洛索蒽醌和紫杉醇作为3小时输注的以下剂量水平（洛索蒽醌/紫杉醇，mg/m²）：50/135、50/175、50/200、50/225和60/225。还评估了洛索蒽醌和紫杉醇在紫杉醇24小时和3小时给药方案中的顺序依赖性毒理学和药理学效应。MTD定义为在前两个疗程中>50%的患者出现DLT的剂量。在未使用G-CSF的情况下，分别接受24小时和3小时40mg/m²洛索蒽醌和135mg/m²紫杉醇治疗的6例患者中有4例、8例患者中有5例在第一个疗程中出现DLT，主要为骨髓抑制。在前两个疗程中，在50/175（洛索蒽醌/紫杉醇）mg/m²剂量水平的6例患者中有1例、50/200mg/m²剂量水平的4例患者中有2例、50/225mg/m²剂量水平的4例患者中有1例以及60/225mg/m²剂量水平的5例患者中有2例观察到DLT。当紫杉醇24小时给药先于洛索蒽醌时，血小板减少程度更严重，尽管无统计学意义，第1疗程血小板计数平均下降百分比为80.7%，而顺序相反时为43.8%（P = 0.19）。紫杉醇的给药顺序或方案未显著改变洛索蒽醌的清除率。观察到心脏毒性；然而，这与洛索蒽醌的总累积剂量无关。在40mg/m²洛索蒽醌和135mg/m²紫杉醇作为24小时或3小时静脉输注的第一个剂量水平时，DLT发生率高得不可接受，若无G-CSF支持则无法进行剂量递增。在方案中添加G-CSF可允许进一步剂量递增而未达到MTD。推荐在G-CSF支持下，洛索蒽醌50mg/m²随后紫杉醇（3小时静脉输注）175mg/m²用于进一步的临床试验。
