Clinical efficacy of the antitumor agent ONC201 in GBM

抗肿瘤药物ONC201治疗GBM的临床疗效

• 批准号: 9132193
• 负责人: Wolfgang Oster
• 金额: $ 55.25万
• 依托单位: ONCOCEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132193
• 关键词: Advanced Malignant Neoplasm; Adverse effects; Animal Model; Animals; Apoptosis; Biological Markers; Blood - brain barrier anatomy; Brain Neoplasms; Cancer Patient; Canis familiaris; Capital; Cell Line; Cell model; Cells; Chemicals; Clinic; Clinical; Clinical Data; Clinical Protocols; Clinical Trials; Data; Development; Dose; Drug Targeting; Drug usage; Enrollment; Ensure; Evaluation; Excipients; Feedback; Formulation; Funding; Future; Genes; Glioblastoma; Health; Human; Image; In Vitro; Institution; Investments; Laboratories; Libraries; Ligands; Malignant Neoplasms; Medical; Methods; Modeling; Mutate; New Agents; Newly Diagnosed; Normal Cell; Oral; Patient Selection; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phosphotransferases; Probability; Process; Property; Radio; Rattus; Recurrence; Refractory; Reproducibility; Research Personnel; Resistance; Safety; Sampling; Schedule; Secure; Serum Markers; Staging; Statistical Data Interpretation; TNFRSF10B gene; TNFSF10 gene; Testing; Therapeutic; Time; Toxicology; Translating; Work; anticancer activity; antitumor agent; antitumor effect; arm; base; cancer cell; capsule; clinical efficacy; commercialization; improved; in vivo; killings; man; manufacturing process; nanomolar; neoplastic cell; novel; novel anticancer drug; novel therapeutics; phase 1 study; phase II trial; pre-clinical; predictive marker; receptor; research clinical testing; response; screening; small molecule; standard of care; success; targeted treatment; therapy resistant; transcription factor; tumor; unnecessary treatment

 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.

 描述（由申请人提供）：ONC 201是一种临床阶段的同类首个小分子，在体外、离体和体内对侵袭性难治性/复发性多形性胶质母细胞瘤（GBM）肿瘤具有抗癌活性。这种新型化合物通过一种独特的作用机制赋予其抗肿瘤作用，该机制涉及在肿瘤细胞而不是正常细胞中间接双重失活Akt和ERK。顶级机构的几位学术研究人员已经在多种模型中证明了ONC 201的最佳临床前特征。这些发现促使Oncoceutics迅速将该产品转化为临床治疗晚期癌症患者。首次人体试验是一项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作为公认IND的一部分进行审查。在完成由Oncoceutics支持的剂量递增I期试验部分后，II期试验可以开始，以评估ONC 201在晚期GBM患者中的单药疗效。在该快速通道申请中，我们建议开发一种自动化生产工艺，以提供药物产品的临床供应，然后评价所得产品在GBM患者中的临床疗效。阶段/目标#1：优化ONC 201制剂并生产用于GBM试验的GMP产品;阶段/目标#2：评价口服ONC 201在GBM中的临床疗效。这些研究将为ONC 201治疗GBM开辟一条发展道路，根据投资者的反馈，这是无法实现的，投资者的反馈表明，明确需要在适应症中获得试点临床数据，以获得私人支持。该提案旨在为迫切需要治疗选择的患者提供一种新型抗癌药物，将推动产品走向商业化，充分降低私人投资的风险，以实现后续开发，并将通过对新型治疗机制进行临床评价来推动该领域的发展。