Development of a novel small molecule MDM2 inhibitor for innovative sarcoma treatment

项目摘要/摘要 这一建议促进了P53野生型肉瘤的新治疗方法的开发。我们队有 发现了一种新的MDM2抑制剂SA53，具有同类中最好的效力、生物利用度和体内疗效 广泛的临床前模型。它还经过了广泛的安全性和药代动力学测试，适合 以支持IND提交，并确定人类的起始剂量。SA53有可能 促进p53野生型癌症的细胞凋亡，并节省正常组织。为了推动概念验证，我们将 进行第一次人体试验：1)确定用于未来临床试验的安全剂量；2)建立药物动力学 概况和适当的安全终端，3)在扩展队列中，确定可行性和早期迹象 P53野生型软组织肉瘤的治疗效果。我们的首要目标是快速有效地推进 SA53通过临床试验实施新颖创新的P53野生型软组织治疗 肉瘤。我们的方法是首先在P53野生型试验中确定推荐的第二阶段剂量 难治性实体瘤，然后将这一新疗法应用于以手术前窗口为靶点的扩大队列 在软组织肉瘤患者中。为实现这些目标，我们将完成以下具体目标： 目标1：完成药品和临床制剂的GMP生产，完成 1期临床试验。 目的2：我们将进行一期临床试验，以确定第二期及早期的推荐剂量。 软组织肉瘤患者的可行性和有效性的适应证。 在这项提议完成后，我们将完成第一阶段试验，以确定安全和 初步疗效，这将作为注册指导研究的基础。鉴于我们的 异常的体内疗效数据，我们进一步相信这可以是一种突破性的改变范式的疗法 用于癌症治疗。

Project summary/abstract This proposal advances the development of a novel therapeutic for p53 wild type sarcomas. Our team has identified a novel MDM2 inhibitor, SA53, with best-in-class potency, bioavailability and in vivo efficacy across a broad range of preclinical models. It has also undergone extensive safety and pharmacokinetic testing, suitable for support of an IND submission, with an identified starting dose in humans. SA53 has the potential to facilitate apoptosis in p53 wild-type cancers and to spare normal tissue. To drive proof of concept, we will conduct a first in human trial to 1) identify a safe dose for future clinical trials, 2) establish the pharmacokinetic profile and appropriate safety endpoints, 3) in an expansion cohort, establish feasibility and early indication of efficacy in treating p53 wild type soft tissue sarcoma. Our primary objective is to rapidly and efficiently advance SA53 through clinical trials to implement a novel and innovative treatment for p53 wild type soft tissue sarcoma. Our approach is first establishing the recommended phase 2 dose in a trial for p53 wild type refractory solid tumors, then to apply this novel therapy in an expansion cohort targeting a pre-surgical window in soft tissue sarcoma patients. To achieve these goals, we will complete the following specific aims: Aim 1: We will complete GMP manufacturing of the drug and formulated clinical product suitable to complete a phase 1 clinical trial. Aim 2: We will conduct a phase 1 clinical trial to establish the recommended dose for phase 2 and early indication of feasibility and efficacy in soft tissue sarcoma patients. At the completion of this proposal, we will have completed a phase 1 trial to have established safety and preliminary efficacy, which will serve as the foundation for registration directed studies. In light of our exceptional in vivo efficacy data, we further believe that this can be a breakthrough paradigm-changing therapy for cancer treatment.