Phase 2 Study of PTC299 in Glioblastoma Multiforme (IND 71,033)

描述（由申请人提供）： PTC 299是一种新型的口服生物可利用的小分子药物，旨在通过在转录后水平选择性抑制肿瘤血管内皮生长因子（VEGF）蛋白表达来控制肿瘤生长。 在培养的肿瘤细胞中的体外研究表明，PTC 299在多种肿瘤类型中损害VEGF的产生。 在人类肿瘤临床前动物模型中的体内研究表明，PTC 299降低了肿瘤和血浆VEGF浓度，降低了肿瘤微血管密度，基本上阻止了肿瘤进展，并延长了患有颅内人类多形性胶质母细胞瘤（GBM）的小鼠的生存期。 药物处置的评价表明，PTC 299穿透血脑屏障。 在健康志愿者和癌症患者中进行的安全性药理学和毒理学研究以及I期研究表明，在下文概述的拟定研究中使用的剂量水平下，PTC 299通常耐受良好。 该资助申请描述了一项2期、开放标签、疗效、安全性和药效学研究。 患有复发性GBM的成人患者将在重复的4周周期中接受PTC 299，包括每天口服100 mg/剂量的PTC 299，每天2次。 治疗将持续至肿瘤进展。 主要目的是评估接受PTC 299治疗的患者的6个月无进展生存期（PFS-6）。 入组将在单个阶段进行，其中将招募30例受试者。 本研究将检验零假设，即PFS-6率为35%，显著性水平为0.90。< 10% against the alternative that it is ><0.05 and power of > 如果&gt; 7名受试者达到PFS-6，则拒绝零假设。 次要目的将包括确定客观缓解率、无进展生存期;评价肿瘤血流;测量循环血管生成因子的浓度;测量胶质瘤源性循环外来体中存在的血管生成标志物的变化;以及表征健康相关的生活质量。 还将评估PTC 299的安全性、药代动力学和依从性特征。 GBM是一种高度血管生成的致命恶性肿瘤，依赖于VEGF过表达来维持肿瘤生长。 抗VEGF治疗提供了改善这种疾病的临床表现的希望。 PTC 299的开发代表了一种独特的转化研究方法，将两个领域（肿瘤血管生成和转录后控制）的十年研究转化为一种靶向的、实用的口服治疗，旨在控制肿瘤生长，同时为患者提供安全性、给药灵活性和便利性。 在GBM和其他肿瘤类型中开发PTC 299代表了首次尝试验证用口服生物可利用的小分子调节转录后控制机制作为治疗人类疾病的手段的概念。 研究目标的成功实现将支持注册导向的开发计划，该计划可能导致PTC 299在复发性GBM患者中的监管批准。

DESCRIPTION (provided by applicant): PTC299 is a novel, orally bioavailable, small-molecule drug designed to control tumor growth by selectively inhibiting tumor vascular endothelial growth factor (VEGF) protein expression at the post-transcriptional level. In vitro studies in cultured tumor cells demonstrate that PTC299 impairs VEGF production in multiple tumor types. In vivo studies in preclinical animal models of human tumor show that PTC299 reduces tumor and plasma VEGF concentrations, decreases tumor microvessel density, substantially impedes tumor progression, and prolongs survival in mice bearing intracranial human glioblastoma multiforme (GBM). Evaluation of drug disposition has indicated that PTC299 penetrates the blood-brain barrier. Safety pharmacology and toxicology studies and Phase 1 studies in healthy volunteers and patients with cancer have indicated that PTC299 is generally well tolerated at the dose levels to be used in the proposed study outlined below. This grant application describes a Phase 2, open-label, efficacy, safety and pharmacodynamic study. Adult patients with recurrent GBM will receive PTC299 in repeated 4-week cycles comprising daily oral PTC299 administration of 100mg/dose on a 2 times per day schedule. Treatment will be administered until tumor progression. The primary objective will be to assess 6-month progression-free-survival (PFS-6) in patients receiving PTC299 therapy. Enrollment will occur in a single stage in which 30 subjects will be recruited. The study will test the null hypothesis that the PFS-6 rate is < 10% against the alternative that it is >35% at a significance level of <0.05 and power of >0.90. If >7 subjects achieve a PFS-6, the null hypothesis will be rejected. Secondary objectives will include determination of objective response rates, progression-free-survival; evaluation of tumor blood flow; measurement of concentrations of circulating angiogenic factors; measurement of changes in angiogenic markers present in glioma-derived circulating exosomes; and characterization of health-related quality-of-life. The safety, pharmacokinetic, and compliance profile of PTC299 will also be assessed. GBM is a highly angiogenic and fatal malignancy that relies upon VEGF overexpression to maintain tumor growth. Anti-VEGF therapy offers promise in ameliorating the clinical manifestations of this disease. PTC299's development represents a unique translational research approach, transforming a decade of research in 2 areas - tumor angiogenesis and post-transcriptional control - into a targeted, practical-to-deliver, oral therapy intended to control tumor growth while offering safety, dosing flexibility, and convenience for patients. Development of PTC299 in GBM and other tumor types represents the first effort to validate the concept of modulating post-transcriptional control mechanisms with an orally bioavailable small molecule as a means to treat human disease. Successful achievement of study goals would support a registration-directed development program that could lead to regulatory approval of PTC299 in patients with recurrent GBM.