Eisenberger M A, Sinibaldi V J, Reyno L M, Sridhara R, Jodrell D I, Zuhowski E G, Tkaczuk K H, Lowitt M H, Hemady R K, Jacobs S C
Division of Medical Oncology and Developmental Therapeutics, University of Maryland Cancer Center, Baltimore, USA.
J Clin Oncol. 1995 Sep;13(9):2174-86. doi: 10.1200/JCO.1995.13.9.2174.
This phase I study was designed with the following objectives: (1) to describe the overall and dose-limiting toxicity (DLT) of suramin administered by intermittent short intravenous infusions until DLT or disease progression; (2) to determine the ability of an adaptive control with feedback (ACF) dosing strategy to maintain suramin plasma concentrations within a preselected range; (3) to develop a population model of suramin pharmacokinetics; and (4) to identify preliminary evidence of antitumor activity.
Seventy-three patients with advanced, incurable, solid tumors (including 69 with hormone-refractory prostate cancer) received an initial 5- to 7-day daily loading treatment followed by intermittent infusions individually determined by ACF using a Bayesian algorithm and relying on population models of suramin pharmacokinetics. Treatment was given to three cohorts of patients based on target plasma suramin concentration ranges (peak, 30 minutes postsuramin, and trough on morning of the treatment day), as follows: cohort 1, 175 to 300 micrograms/mL (27 patients); cohort 2, 150 to 250 micrograms/mL (23 patients); and cohort 3, 100 to 200 micrograms/mL (23 patients). All patients were to receive suramin until DLT or disease progression.
The DLT was most commonly seen in cohort 1 and included a syndrome of malaise and fatigue, associated with weight loss, anorexia, and changes in taste. Other reversible toxicities were neurologic, renal, cutaneous, edema, lymphopenia and anemia, ophthalmologic, and alopecia. Forty of 67 assessable patients (60%) had a 50% reduction and 25 of 67 (37%) a 75% reduction in prostate-specific antigen (PSA) levels that lasted more than 4 weeks, seven of 18 (40%) had measurable responses, and 18 of 37 (49%) demonstrated major pain improvement. The overall times to disease progression and survival were 170 and 492 days, respectively.
We have characterized all toxicities with suramin in a pharmacologically guided phase I study designed to maintain plasma suramin concentrations of 100 to 300 micrograms/mL (cohorts 1 to 3). The incidence of grade 3 to 4 neurologic abnormalities was relatively low, particularly in cohorts 2 and 3 (100 to 250 micrograms/mL). Evidence of significant and durable antitumor activity was seen in all three cohorts.
本I期研究设计了以下目标：（1）描述通过间歇性短时间静脉输注给予苏拉明直至出现剂量限制性毒性（DLT）或疾病进展的总体毒性和DLT；（2）确定具有反馈的自适应控制（ACF）给药策略将苏拉明血浆浓度维持在预选范围内的能力；（3）建立苏拉明药代动力学的群体模型；（4）识别抗肿瘤活性的初步证据。
73例晚期、无法治愈的实体瘤患者（包括69例激素难治性前列腺癌患者）接受了为期5至7天的初始每日负荷治疗，随后通过ACF使用贝叶斯算法并依赖苏拉明药代动力学的群体模型进行个体确定的间歇性输注。根据目标血浆苏拉明浓度范围（峰值、苏拉明给药后30分钟以及治疗日早晨的谷值）将治疗给予三组患者，如下：第1组，175至300微克/毫升（27例患者）；第2组，150至250微克/毫升（23例患者）；第3组，100至200微克/毫升（23例患者）。所有患者均接受苏拉明治疗直至出现DLT或疾病进展。
DLT最常见于第1组，包括一种不适和疲劳综合征，伴有体重减轻、厌食和味觉改变。其他可逆毒性包括神经、肾脏、皮肤、水肿、淋巴细胞减少和贫血、眼科和脱发。67例可评估患者中有40例（60%）前列腺特异性抗原（PSA）水平降低50%，67例中有25例（37%）降低75%，持续超过4周，18例中有7例（40%）有可测量的反应，37例中有18例（49%）疼痛明显改善。疾病进展和生存的总体时间分别为170天和492天。
在一项旨在将血浆苏拉明浓度维持在100至300微克/毫升（第1至3组）的药理学指导的I期研究中，我们已对苏拉明的所有毒性进行了特征描述。3至4级神经异常的发生率相对较低，特别是在第2组和第3组（100至250微克/毫升）。在所有三组中均观察到显著且持久的抗肿瘤活性证据。
