Clinical efficacy of the antitumor agent ONC201 in GBM

 说明(申请人提供)：ONC201是一种临床阶段一流的小分子药物，在体外、体外和体内均显示出对侵袭性难治性/复发性多形性胶质母细胞瘤(GBM)肿瘤的抗癌活性。这种新型化合物通过一种独特的作用机制发挥其抗肿瘤作用，该机制涉及肿瘤细胞中Akt和ERK的间接双重失活，而不是正常细胞。顶尖机构的几位学术研究人员已经在多种模型中展示了ONC201的最佳临床前配置。这些发现促使肿瘤学公司迅速将该产品转化为临床，用于治疗晚期癌症患者。第一人试验是一项I/II期研究，将包括GBM患者，计划于2014年初在MGH开始，并已由FDA作为接受的IND的一部分进行审查。在Ondiceutics支持的试验的剂量递增第一阶段完成后，第二阶段试验可以开始评估ONC201在晚期GBM患者中的单剂疗效。在这一快速通道应用中，我们建议开发一种自动化生产流程来提供临床供应的药物产品，然后评估所产生的产品在GBM患者中的临床疗效。阶段/目标1：优化ONC201配方并为GBM试验生产GMP产品；阶段/目标2：评估口服ONC201治疗GBM的临床疗效。这些研究将为ONC201治疗GBM开辟一条发展道路，否则根据投资者的反馈，这是无法实现的，因为投资者的反馈表明，显然需要试点临床数据来实现私人支持。这项提案旨在为迫切需要治疗选择的患者提供一种新的抗癌药物，将推动该产品走向商业化，充分降低私人投资以实现后续开发，并将通过允许对新的治疗机制进行临床评估来推动该领域的发展。

 DESCRIPTION (provided by applicant): ONC201 is a clinical-stage first-in-class small molecule with demonstrated anticancer activity against aggressive refractory/recurrent glioblastoma multiforme (GBM) tumors in vitro, ex vivo, and in vivo. This novel compound imparts its antitumor effects through a unique mechanism of action that involves indirect dual inactivation of Akt and ERK in tumor but not normal cells. Several academic investigators at premier institutions have demonstrated the optimal preclinical profile of ONC201 in a multitude of models. These findings have prompted Oncoceutics to rapidly translate this product into the clinic to treat advanced cancer patients. The first-in-man trial is a phase I/II study that will include patients with GBM is scheduled to begin in early 2014 at MGH and has been reviewed by the FDA as part of the accepted IND. Following completion of the dose-escalation phase I portion of the trial supported by Oncoceutics, the phase II trial can begin to evaluate the monoagent efficacy of ONC201 in patients with advanced GBM. In this fast-track application, we propose to develop an automated manufacturing process to provide the clinical supply of drug product followed by evaluation of the clinical efficacy of the resulting product in patients with GBM. Phase/Aim #1: Optimize ONC201 formulation and produce GMP product for GBM trial; Phase/Aim #2: Evaluate clinical efficacy of oral ONC201 in GBM. These studies will enable a development path for ONC201 to treat GBM, which is otherwise unattainable based on investor feedback that indicates a clear need for pilot clinical data in the indication to enable private support. This proposal seeks to make a novel anticancer agent available to patients in dire need of treatment options, will push the product toward commercialization, sufficiently derisk private investments to enable subsequent development, and will advance the field forward by enabling clinical evaluation of a novel therapeutic mechanism.