Development of a Novel, Targeted Small Molecule Inhibitor of the Nucleotide Salvage Pathway to Treat Underserved Tumor Types

开发一种新型的、靶向核苷酸挽救途径的小分子抑制剂来治疗治疗不足的肿瘤类型

• 批准号: 10697180
• 负责人: Kenneth Schultz
• 金额: $ 134.98万
• 依托单位: TRETHERA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697180
• 关键词: Aftercare; Area; Biological Assay; Biological Markers; Cancer Patient; Cause of Death; Cell division; Clinical; Clinical Protocols; Clinical Trials; Clofarabine; Companions; DNA biosynthesis; Data; Deoxycytidine; Deoxycytidine Kinase; Deoxyribonucleosides; Deoxyuridine; Dependence; Development; Dose; Drug Kinetics; Drug Monitoring; Drug Targeting; Ensure; Enzymes; Evaluation; FDA approved; Female; Future; Goals; Half-Life; Hour; Malignant Neoplasms; Measurement; Measures; Mediating; Methods; Monitor; Nucleosides; Nucleotide Biosynthesis; Nucleotides; Oral; Outcome; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Plasma; Positron-Emission Tomography; Proliferating; Qualifying; Refractory; Regimen; Resources; Safety; Sampling; Serum; Solid Neoplasm; Stable Disease; Therapeutic; Time; Validation; Work; absorption; biopharmaceutical industry; cancer cell; clinical development; clinical practice; cohort; companion diagnostics; deoxyribonucleoside triphosphate; efficacy evaluation; imaging approach; improved; in vivo monitoring; inhibitor; invention; liquid chromatography mass spectrometry; male; novel; novel marker; open label; patient response; patient stratification; phase I trial; radiotracer; response; response biomarker; safety assessment; side effect; small molecule; small molecule inhibitor; success; treatment response; trial design; tumor; tumor growth; uptake

PROJECT SUMMARY Trethera, a clinical stage biopharmaceutical company, has developed a small molecule drug, TRE-515, to target the nucleoside salvage pathway via a key rate-limiting enzyme, deoxycytidine kinase (dCK). We have shown that dCK is expressed at high levels in a variety of solid tumors, and TRE-515 selectively targets cancer cells based on their high expression of, and dependence on, dCK. Notably, TRE-515 is the only salvage pathway inhibitor currently in clinical development, and no salvage pathway inhibitors are approved as cancer therapeutics. Currently, Trethera is evaluating TRE-515 in a phase 1a open-label, dose escalation study in patients with solid tumors (IND #131939). Acceptable safety and tolerability have been demonstrated across three TRE-515 doses (40mg, 80mg, 160mg) in 10 patients. Preliminary pharmacokinetic (PK) data indicate an acceptable half-life, rapid absorption, and low variability among patients, and early and pharmacodynamic (PD) data demonstrate effective target inhibition. Notably, early signs of anti-tumor activity have been noted, with 50% of patients in the lowest dose cohorts showing stable disease. Our goal here is to perform a Phase 1 dose expansion trial deploying a quantitative LC/MS based assay to determine serum deoxycytidine (dC)/ deoxyuridine (dU) levels and a novel PET imaging approach as complementary biomarkers to monitor drug activity and assess preliminary antitumor activity. Whole-body dCK activity regulates the levels of serum dC and its metabolite dU, and reductions in dCK activity via TRE-515 inhibition can be routinely monitored by measuring changes in plasma dC/dU using an LC-MS assay we developed. [18F]CFA is a PET radiotracer that can be used to non-invasively measure dCK activity in tumors (IND #133911). As accepted by the FDA, male and female patients (N=12) with advanced refractory solid tumors will be administered 320 mg TRE-515 as a once daily oral dose. The LC/MS based assay to measure serum dC/dU levels will be further developed and used as an easily accessible biomarker to assess patient response to TRE-515 (Aim 1). Biomarker studies using the recently invented, IND- accepted positron emission tomography (PET) probe, [18F]Clofarabine ([18F]CFA), will be used for in vivo monitoring of the effects of TRE-515 on dCK activity (Aim 2). Safety assessments, biomarker studies, and Response Evaluation Criteria in Solid Tumors (RECIST) will be used to assess tumor responses in patients. Trial milestones include i) >1.5X increases in serum levels of dC + dU after initiating TRE-515 therapy, reflecting drug target inhibition and ii) greater than 33% reduction in [18F]CFA tumor uptake following TRE-515 treatment. Success in the proposed trial will support future Phase 1 and 2 clinical trials to determine efficacy, safety, combinations, patient selection, and optimal dose regimen of TRE-515.

项目摘要 临床阶段生物制药公司Trethera开发了一种小分子药物TRE-515， 通过关键限速酶脱氧胞苷激酶（dCK）的核苷补救途径。我们已经表明 dCK在多种实体瘤中以高水平表达，TRE-515选择性靶向癌细胞 基于它们对dCK的高表达和依赖性。值得注意的是，TRE-515是唯一的补救途径 抑制剂目前在临床开发中，并且没有补救途径抑制剂被批准用于癌症 治疗学目前，Trethera正在一项1a期开放标签、剂量递增研究中评估TRE-515， 实体瘤患者（IND #131939）。已在以下研究中证明了可接受的安全性和耐受性： 在10名患者中给予三种TRE-515剂量（40 mg、80 mg、160 mg）。初步药代动力学（PK）数据表明， 可接受的半衰期，快速吸收，患者间变异性低，早期和药效学（PD） 数据表明有效的靶抑制。值得注意的是，已经注意到抗肿瘤活性的早期迹象，其中50% 最低剂量队列中显示疾病稳定的患者。我们的目标是进行1期剂量 采用基于定量LC/MS的测定法测定血清 脱氧胞苷（dC）/ deoxyuridine (dU)水平和一种新的PET成像方法作为补充生物标志物，以监测药物活性和评估 初步的抗肿瘤活性。全身dCK活性调节血清dC及其代谢产物dU的水平， 并且通过TRE-515抑制而引起的dCK活性的降低可以通过测量血浆中 dC/dU使用我们开发的LC-MS测定。[18F]CFA是一种PET放射性示踪剂，可用于非侵入性 测量肿瘤中的dCK活性（IND #133911）。如FDA所接受的，男性和女性患者（N=12） 晚期难治性实体瘤将以每日一次口服剂量给予320 mgTRE-515。的LC/MS 将进一步开发用于测量血清dC/dU水平的基于检测的方法，并将其用作易于获得的 使用生物标志物来评估患者对TRE-515的反应（目的1）。生物标志物研究使用最近发明的IND- 接受的正电子发射断层扫描（PET）探针，[18 F]氯法拉滨（[18 F]CFA），将用于体内 监测TRE-515对dCK活性的影响（目的2）。安全性评估、生物标志物研究和 实体瘤疗效评价标准（RECIST）将用于评估患者的肿瘤缓解。审判 里程碑包括i）在开始TRE-515治疗后，dC + dU的血清水平增加> 1.5倍，反映了药物治疗的效果。 靶向抑制和ii）TRE-515处理后[18F]CFA肿瘤摄取减少大于33%。 拟议试验的成功将支持未来的1期和2期临床试验，以确定疗效，安全性， TRE-515的组合、患者选择和最佳剂量方案。