Abstract

Glioblastoma is a devastating disease with poor prognosis. Few effective chemotherapeutics are currently available, and much effort has been expended to identify new drugs capable of slowing tumor progression. The phase 0 trial design was developed to facilitate early identification of promising agents for cancer that should undergo accelerated approval. This design features an early in-human study that enrolls a small number of patients who receive subtherapeutic doses of medication with the goals of describing pharmacokinetics through drug blood level measurements and determining intratumoral concentrations of the investigational compound as well as pharmacodynamics by studying the biochemical and physiological effects of drugs. In neuro-oncology, however, the presence of the blood–brain barrier and difficulty in obtaining brain tumor tissue warrant a separate set of considerations. In this paper, we critically reviewed the protocols used in all brain tumor related in-human phase 0 and phase 0–like (“window of opportunity”) studies between 1993 and 2018, as well as ongoing clinical trials, and identified major challenges in trial design as applied to central nervous system tumors that include surgical specimen collection and storage, brain tumor drug level analysis, and confirmation of drug action. We therefore propose that phase 0 trials in neuro-oncology should include (i) only patients in whom a resection of the tumor is planned, (ii) use of clinical doses of an investigational agent, (iii) tissue sampling from enhancing and non-enhancing portions of the tumor, and (iv) assessment of drug-specific target effects. Standardization of clinical protocols for phase 0/window of opportunity studies can help accelerate the development of effective treatments for glioblastoma.

中文翻译：

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神经肿瘤学的第0阶段和机会临床试验设计窗口：RANO评论。

摘要

胶质母细胞瘤是一种破坏性疾病，预后较差。当前很少有有效的化学疗法，并且已经花费大量努力来鉴定能够减缓肿瘤进展的新药物。制定了0期试验设计，以促进早期识别有希望的癌症药物，这些药物应接受加速批准。该设计具有一项早期的人体研究，该研究招募了少数接受亚治疗剂量药物的患者，其目的是通过药物血药浓度测量来描述药代动力学，并通过研究生化和代谢动力学来确定研究化合物的瘤内浓度以及药效学。药物的生理作用。但是在神经肿瘤学中，血脑屏障的存在和获取脑肿瘤组织的困难需要单独考虑。在本文中，我们严格审查了1993年至2018年间所有与脑肿瘤相关的人类0期和0期样（“机会之窗”）研究以及正在进行的临床试验中使用的方案，并确定了主要挑战。用于中枢神经系统肿瘤的试验设计，包括手术标本的收集和存储，脑肿瘤药物水平分析以及药物作用的确认。因此，我们建议神经肿瘤的0期临床试验应包括（i）仅计划进行肿瘤切除的患者，（ii）使用临床剂量的研究药物，（iii）增强和非增强组织采样增强部分肿瘤，（iv）评估针对药物的靶标作用。0期/机会研究窗口的临床方案的标准化可以帮助加速胶质母细胞瘤有效治疗方法的开发。