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

开发用于创新肉瘤治疗的新型小分子 MDM2 抑制剂

基本信息

批准号：
10699023
负责人：
Gabi Hanna
金额：
$ 130.41万
依托单位：
LAMASSU BIO INC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-07 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10699023
关键词：
Abdomen Adjuvant Therapy Advanced Development Apoptosis Area Under Curve Biological Availability Cell Death Chemotherapy and/or radiation Clinic Clinical Clinical Trials Collaborations Data Defense Mechanisms Desmoplastic Small Round Cell Tumor Development Dose Drug Kinetics Foundations Funding Future Goals Growth Half-Life High Prevalence Human Light MDM2 gene Malignant Neoplasms Modeling Molecular Monkeys Mutate Newly Diagnosed Normal tissue morphology Operative Surgical Procedures Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Positioning Attribute Pre-Clinical Model Primary Neoplasm Proteins Rattus Recommendation Recurrence Refractory Safety Small Business Innovation Research Grant Soft tissue sarcoma Solid Neoplasm TP53 gene Testing Therapeutic Thrombocytopenia Toxic effect Toxicology Treatment Protocols Tumor Suppressor Proteins United States Work arm burden of illness cancer therapy cancer type cell growth clinical development cohort drug metabolism early phase trial efficacy study experience first-in-human in vivo inhibitor innovation liposarcoma manufacture morphogens neoplastic cell novel novel therapeutics phase I trial prevent programs rare cancer sarcoma screening small molecule therapy resistant tumor tumor growth tumor initiation

项目摘要

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.

项目概要/摘要该提案推动了 p53 野生型肉瘤新型疗法的开发。我们的团队有鉴定出一种新型 MDM2 抑制剂 SA53，该抑制剂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，适合支持 IND 提交，并确定人体起始剂量。 SA53 有潜力促进 p53 野生型癌症的细胞凋亡并保护正常组织。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) 建立药代动力学概况和适当的安全终点，3) 在扩展队列中，建立可行性和早期迹象治疗p53野生型软组织肉瘤的功效。我们的首要目标是快速有效地推进 SA53通过临床试验对p53野生型软组织实施新颖的创新疗法肉瘤。我们的方法是首先在 p53 野生型试验中确定推荐的 2 期剂量难治性实体瘤，然后将这种新疗法应用于针对手术前窗口的扩展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：完成药品的GMP生产和适合完成临床制剂的临床产品一期临床试验。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的可行性和有效性的指示。完成该提案后，我们将完成第一阶段试验，以确定安全性和初步疗效，这将作为注册定向研究的基础。鉴于我们的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。