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

描述(由申请人提供)： PTC299是一种新型的口服生物利用型小分子药物，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)的蛋白表达来控制肿瘤生长。在体外培养的肿瘤细胞中的研究表明，PTC299在多种肿瘤类型中损害了血管内皮生长因子的产生。临床前动物模型的体内研究表明，PTC299可降低肿瘤和血浆中血管内皮生长因子的浓度，减少肿瘤微血管密度，实质上阻止肿瘤的进展，并延长荷有颅内人多形性胶质母细胞瘤(GBM)的小鼠的生存时间。药物处置评估表明，PTC299可以穿透血脑屏障。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第一阶段研究表明，在下面概述的拟议研究中使用的剂量水平下，PTC299通常具有良好的耐受性。 这项赠款申请描述了一项第二阶段的开放标签、有效性、安全性和药效学研究。复发的成年GBM患者将接受PTC299治疗，周期为4周，包括每天口服PTC299 100毫克/剂，每天2次。治疗将一直进行到肿瘤进展。主要目标将是评估接受PTC299治疗的患者的6个月无进展生存(PFS-6)。招生将分一个阶段进行，将招收30个科目。这项研究将检验PFS-6比率为10%的零假设，而替代方案是&gt；35%，显著性水平为0.05，幂为0.90。如果7名受试者达到PFS-6，零假设将被拒绝。次要目标将包括确定客观应答率、无进展生存；评估肿瘤血流；测量循环血管生成因子浓度；测量胶质瘤来源的循环外切体中血管生成标志物的变化；以及与健康相关的生活质量的表征。还将评估PTC299的安全性、药代动力学和依从性。 GBM是一种高度促血管生成和致命性的恶性肿瘤，依赖于血管内皮生长因子的过度表达来维持肿瘤的生长。抗血管内皮生长因子治疗有望改善这种疾病的临床表现。PTC299的S研发代表了一种独特的转化式研究方法，将在两个领域-肿瘤血管生成和转录后控制-的十年研究转变为旨在控制肿瘤生长的靶向、实用、口服治疗，同时为患者提供安全性、给药灵活性和便利性。PTC299在GBM和其他肿瘤类型中的开发代表了第一次努力验证通过口服生物可用小分子作为治疗人类疾病的手段来调节转录后控制机制的概念。研究目标的成功实现将支持注册导向的开发计划，该计划可能导致监管部门批准PTC299用于复发的GBM患者。

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.