Phase I study of the Hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors.
Phase I study of the Hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors.
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DOI：
10.1158/1078-0432.ccr-12-3654
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发表时间：
2013-05-15
期刊：
影响因子：
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通讯作者：
Rudin CM
中科院分区：
文献类型：
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作者：
Jimeno A;Weiss GJ;Miller WH Jr;Gettinger S;Eigl BJ;Chang AL;Dunbar J;Devens S;Faia K;Skliris G;Kutok J;Lewis KD;Tibes R;Sharfman WH;Ross RW;Rudin CM
进行首次人体I期研究，以确定剂量限制性毒性（DLT），表征药代动力学特征，并记录IPI-926（一种抑制Hedgehog通路（HhP）的新化学实体）的抗肿瘤活性。标准治疗难治性实体瘤患者口服IPI-926，每日一次（QD），28天为一个周期。起始剂量为20 mg，使用加速滴定方案，直至实施标准3 + 3剂量递增队列。在第1周期第-7天和第22天评价药代动力学。94例患者（32例女性，62例男性;年龄：39-87岁）接受的剂量范围为20 - 210 mg QD。剂量水平高达160 mg（包括160 mg）QD给药耐受性良好。毒性包括天冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）和胆红素可逆性升高、疲乏、恶心、脱发和肌肉痉挛。IPI-926与血液学毒性无关。IPI-926的药代动力学特征为吸收缓慢（Tmax = 2-8小时），终末半衰期（t1/2）为20 - 40小时，支持QD给药。在接受过一次以上IPI-926剂量并进行了随访临床或实体瘤疗效评价标准（RECIST）评估的HhP初治基底细胞癌（BCC）患者中，近三分之一（28例患者中的8例）在剂量≥130 mg时显示出对IPI-926的反应。IPI-926在28天周期内高达160 mg QD耐受性良好，这被确定为该药物的推荐II期剂量和时间表。IPI-926的单药活性在HhP初治BCC患者中观察到。
To conduct a first-in-human phase I study to determine the dose-limiting toxicities (DLT), characterize the pharmacokinetic profile, and document the antitumor activity of IPI-926, a new chemical entity that inhibits the Hedgehog pathway (HhP). Patients with solid tumors refractory to standard therapy were given IPI-926 once daily (QD) by mouth in 28-day cycles. The starting dose was 20 mg, and an accelerated titration schedule was used until standard 3 + 3 dose-escalation cohorts were implemented. Pharmacokinetics were evaluated on day −7 and day 22 of cycle 1. Ninety-four patients (32F, 62M; ages, 39–87) received doses ranging from 20 to 210 mg QD. Dose levels up to and including 160 mg administered QD were well tolerated. Toxicities consisted of reversible elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin, fatigue, nausea, alopecia, and muscle spasms. IPI-926 was not associated with hematologic toxicity. IPI-926 pharmacokinetics were characterized by a slow absorption (Tmax = 2–8 hours) and a terminal half-life (t1/2) between 20 and 40 hours, supporting QD dosing. Of those HhP inhibitor-naïve patients with basal cell carcinoma (BCC) who received more than one dose of IPI-926 and had a follow-up clinical or Response Evaluation Criteria in Solid Tumors (RECIST) assessment, nearly a third (8 of 28 patients) showed a response to IPI-926 at doses ≥130 mg. IPI-926 was well tolerated up to 160 mg QD within 28-day cycles, which was established as the recommended phase II dose and schedule for this agent. Single-agent activity of IPI-926 was observed in HhP inhibitor–naïve patients with BCC.