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

项目概要/摘要 这一建议推进了p53野生型肉瘤的新治疗方法的开发。我们的团队已被 确定了一种新的MDM 2抑制剂，SA 53，具有同类最佳的效力，生物利用度和体内功效， 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， 用于支持IND提交，并确定人体起始剂量。SA 53有潜力 促进p53野生型癌症中的细胞凋亡并使正常组织免于损伤。为了推动概念验证，我们将 进行首次人体试验，以1）确定未来临床试验的安全剂量，2）确定药代动力学 特征和适当的安全性终点，3）在扩展队列中，确定 治疗p53野生型软组织肉瘤的疗效。我们的首要目标是快速有效地推进 SA 53通过临床试验对p53野生型软组织实施新颖和创新的治疗 肉瘤。我们的方法是首先在p53野生型试验中建立推荐的2期剂量 难治性实体瘤，然后在针对术前窗口期的扩展队列中应用这种新疗法 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：我们将完成药品的GMP生产，并制定适合于完成一个 1期临床试验。 目标2：我们将进行1期临床试验，以确定2期和早期的推荐剂量。 软组织肉瘤患者中可行性和有效性指示。 在完成本提案时，我们将完成第1阶段试验，以确定安全性， 初步疗效，这将作为注册指导研究的基础。根据我们 由于具有出色的体内疗效数据，我们进一步相信这可能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.