Third line treatment of drug resistant FLT3-positive acute myeloid leukemia with a novel FLT3 kinase inhibitor

使用新型 FLT3 激酶抑制剂治疗耐药 FLT3 阳性急性髓系白血病的三线治疗

基本信息

批准号：
9908776
负责人：
Frederick Wayne Holtsberg
金额：
$ 100万
依托单位：
KINARX, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908776
关键词：
Acute Myelocytic Leukemia Adult Aftercare Aggressive course Animal Cancer Model Animal Model Antineoplastic Agents Automobile Driving Baltimore Bioavailable Biological Assay Biotechnology Businesses Canis familiaris Cardiovascular system Cessation of life Chemistry Clinical Clinical Management Clinical Research Contracts Cyclic GMP Cytotoxic Chemotherapy Data Development Disease Disease remission Dose Drug resistance Enzymes FLT3 gene FLT3 inhibitor Generations Hematologic Neoplasms Hematology Hematopoietic Stem Cell Transplantation In Vitro International Lead Malignant Neoplasms Maryland Medical Methods Modeling Mutate Mutation Newly Diagnosed Oncology Oral Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacology Study Pharmacology and Toxicology Phase Phase I Clinical Trials Phosphotransferases Positioning Attribute Procedures Process Production Protein Tyrosine Kinase Protocols documentation Rattus Refractory Regulatory Affairs Relapse Reporting Research Contracts Research Personnel Resistance Resistance development Safety Seasons Series Small Business Innovation Research Grant Survival Rate Technology Transfer Therapeutic Time Toxic effect Toxicology Treatment Efficacy Tyrosine Kinase Domain Tyrosine Kinase Inhibitor Universities Up-Regulation Work Xenograft Model acute myeloid leukemia cell analytical method chemotherapy clinical candidate clinical development commercialization cytotoxic design drug development drug discovery efficacy study experience genotoxicity in vivo kinase inhibitor leukemia treatment manufacturing process meetings mid-career faculty mouse model mutant myeloblast novel older patient operation outcome forecast preclinical efficacy professor relapse patients respiratory safety study scale up

项目摘要

Project Summary Acute myeloid leukemia (AML) is one of the most challenging malignancies with the 5-year survival for younger and medically fit patients hovering around the 30% mark for over 3 decades. About 30% of AML patients harbor activating mutations in FLT3 kinase that are associated with very poor prognosis. The non-specific tyrosine kinase inhibitor (TKI) Midostaurin was approved in 2017 for combination treatment with standard chemotherapy. However, remission achieved with this treatment, if any, is short-lived. FLT3-AML patients that relapse or are refractory to this treatment are treated with newly developed, more specific, FLT3 inhibitors Quizartinib and Crenolanib that are in clinical development or Gilteritinib that was recently approved. However, this treatment also eventually fails due to emergence of secondary FLT3 mutations within the tyrosine kinase domain and/or upregulation of compensatory resistance pathways. For these patients the time to death is around 3 months with no 3rd line treatment option available. KinaRx has developed a novel class of orally bioavailable 5-substituted aminonapthyridine TKIs that are active against secondary mutated FLT3 resistant to the 1st and 2nd generation FLT3 inhibitors. Extensive in vitro and in vivo data, including protection in orthotopic mouse models of drug resistant FLT3-AML presented in this proposal, establish our lead compound KRX-101 as the best-in-class FLT3 inhibitor and a strong candidate as 3rd line treatment option for FLT3 mutated relapsed or refractory patients that do not respond to gilteritinib, crenolanib or quizartinib. In this multiple PI, Direct to Phase II SBIR, we propose to advance KRX-101 through completion of IND-enabling studies. In Aim 1 we will technology transfer the synthesis procedure and analytical methods to CMO for process scale up, analytical development, and production of a 100 g demonstration lot. In Aim 2, we will complete efficacy data package including activity toward primary AML cells and efficacy in patient-derived xenograft models and conduct preliminary safety studies. Aim 3 will focus on developing a regulatory strategy and holding a Pre-IND meeting with FDA. A GLP toxicology lot (5 kg) will be produced in Aim 4 and used to conduct a full battery of IND-enabling GLP safety-pharmacology studies in Aim 5. The project brings together a strong team of investigators with decades of experience in drug discovery and development: Dr. Holtsberg, VP of Operations at KinaRx with 25 years of experience in pharma and biotech, Dr. Sintim, Professor of Chemistry at Purdue University an expert in anti-cancer drug discovery and the inventor of KRX compound series, Dr. Emadi, Professor of Hematology and Oncology at University of Maryland (UMB), a highly experienced clinician, former regulatory officer at FDA, and a recognized expert in hematological malignancies with a focus on clinical research and management of AML, Dr. Lapidus, Associate Professor at UMB, an expert in animal models of hematological malignancies, seasoned ex-FDA and ex-Pharma subject matter experts in development of oncology drugs from RRD International, and two of the most experienced contract manufacturing (CMO) and contract research (CRO) organizations Olon-Ricerca and Frontage.

项目概要急性髓系白血病 (AML) 是最具挑战性的恶性肿瘤之一，年轻人的 5 年生存率较低健康状况良好的患者在过去 30 多年里一直徘徊在 30% 左右。大约 30% 的 AML 患者患有激活与极差预后相关的 FLT3 激酶突变。非特异性酪氨酸激酶抑制剂 (TKI) Midostaurin 于 2017 年被批准用于与标准化疗联合治疗。然而，通过这种治疗实现的缓解（如果有的话）也是短暂的。复发或正在治疗的 FLT3-AML 患者对这种治疗无效的患者可使用新开发的、更具特异性的 FLT3 抑制剂 Quizartinib 和正在进行临床开发的 Crenolanib 或最近批准的 Gilteritinib。然而，这种治疗由于酪氨酸激酶结构域内出现继发性 FLT3 突变和/或，最终也会失败代偿性抵抗途径的上调。对于这些患者来说，死亡时间约为 3 个月没有可用的第三线治疗选择。 KinaRx 开发了一种新型口服生物可利用的 5-取代对第一代和第二代耐药的二次突变 FLT3 具有活性的氨基萘啶 TKI FLT3抑制剂。广泛的体外和体内数据，包括药物对原位小鼠模型的保护作用本提案中提出的耐药 FLT3-AML，使我们的先导化合物 KRX-101 成为同类最佳的 FLT3 抑制剂，是 FLT3 突变复发或难治性患者第三线治疗选择的有力候选者对gilteritinib、crenolanib 或quizartinib 没有反应。在这个直接进入第二阶段 SBIR 的多项 PI 中，我们建议通过完成 IND 支持研究来推进 KRX-101。在目标 1 中，我们将技术转让合成 CMO 的程序和分析方法，用于工艺放大、分析开发和生产 100 g 示范地段。在目标 2 中，我们将完成功效数据包，包括对原代 AML 细胞的活性和患者来源的异种移植模型的疗效，并进行初步的安全性研究。目标3将重点关注制定监管策略并与 FDA 召开 IND 前会议。 GLP 毒理学批次（5 公斤）将在 Aim 4 中生产并用于在 Aim 中进行全套支持 IND 的 GLP 安全药理学研究 5. 该项目汇集了一支强大的研究人员团队，他们在药物发现和研究方面拥有数十年的经验。开发：Holtsberg 博士，KinaRx 运营副总裁，在制药和生物技术领域拥有 25 年经验。 Sintim，普渡大学化学教授，抗癌药物发现专家和发明人 KRX 复合系列，Emadi 博士，马里兰大学 (UMB) 血液学和肿瘤学教授，经验丰富的临床医生、FDA 前监管官员以及公认的血液学专家 Lapidus 博士，副教授，专注于 AML 的临床研究和管理。 UMB，血液系统恶性肿瘤动物模型专家，经验丰富的前 FDA 和前制药主题 RRD International 的肿瘤药物开发专家，以及两位最有经验的专家合同制造 (CMO) 和合同研究 (CRO) 组织 Olon-Ricerca 和 Frontage。