LoRusso P, Foster B J, Poplin E, McCormick J, Kraut M, Flaherty L, Heilbrun L K, Valdivieso M, Baker L
Department of Internal Medicine, Division of Hematology/Oncology, Wayne State University, Harper Hospital, Detroit, Michigan 48201, USA.
Clin Cancer Res. 1995 Dec;1(12):1487-93.
The pyrazoloacridine (PZA) analogue NSC366140 (PD115934) entered clinical trial based on unique preclinical characteristics including solid tumor selectivity in vitro, marked antitumor activity in vivo against murine solid tumors, selectivity against noncycling cells, and activity against multidrug-resistant tumor cells. After identification of the pre-clinical efficacy and an acceptable toxicity profile, a Phase I study of PZA was carried out. A total of 28 patients was entered and received a total of 67 treatment courses. The drug was administered via a 1-h infusion every 21 days. The starting dose was 30 mg/m2 with 2-fold dose escalations through 480 mg/m2. The next dose escalation was 50%, to 720 mg/m2. Grade I through grade IV toxicities were observed. Since no dose-limiting toxicities were observed at 480 mg/m2, and up to grade IV toxicities were observed at 720 mg/m2, an intermediate dose, 600 mg/m2, was evaluated. Dose-limiting toxicities at 720 mg/m2 were hematological (grade III and IV neutropenia) in four of six patients and neurological (up to grade III cerebral toxicities, including restlessness, dizziness, agitation/anxiety, personality changes, and nightmares, as well as myoclonus) in three of six patients treated. The pharmacokinetic parameters which helped predict these toxicities included area under the curve and peak plasma level. Pharmacokinetic studies showed interpatient variations in all parameters studied. The mean area under the curve levels of PZA at the highest two dose levels in patients were near the level detected in mice at their maximum tolerated total dose. The recommended starting dose for Phase II trials using this schedule is 600 mg/m2.
吡唑并吖啶（PZA）类似物NSC366140（PD115934）基于其独特的临床前特征进入临床试验，这些特征包括体外对实体瘤的选择性、体内对小鼠实体瘤的显著抗肿瘤活性、对非循环细胞的选择性以及对多药耐药肿瘤细胞的活性。在确定临床前疗效和可接受的毒性特征后，开展了PZA的I期研究。共有28例患者入组并接受了总共67个疗程的治疗。药物通过每21天1小时静脉输注给药。起始剂量为30mg/m²，以2倍剂量递增至480mg/m²。下一次剂量递增为50%，至720mg/m²。观察到了I级至IV级毒性。由于在480mg/m²未观察到剂量限制性毒性，而在720mg/m²观察到了高达IV级的毒性，因此对中间剂量600mg/m²进行了评估。在接受治疗的6例患者中，有4例在720mg/m²时出现血液学剂量限制性毒性（III级和IV级中性粒细胞减少），6例患者中有3例出现神经学毒性（高达III级脑毒性，包括烦躁、头晕、激动/焦虑、人格改变和噩梦，以及肌阵挛）。有助于预测这些毒性的药代动力学参数包括曲线下面积和血浆峰浓度。药代动力学研究表明，所研究的所有参数在患者之间存在差异。患者中最高两个剂量水平下PZA的平均曲线下面积水平接近小鼠在其最大耐受总剂量时检测到的水平。使用该方案进行II期试验的推荐起始剂量为600mg/m²。
