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.

项目概要 Trethera是一家临床阶段的生物制药公司，开发了一种小分子药物TRE-515，以靶向 通过关键限速酶脱氧胞苷激酶（dCK）的核苷补救途径。我们已经展示了 dCK 在多种实体瘤中高水平表达，TRE-515 选择性靶向癌细胞 基于它们对 dCK 的高表达和依赖。值得注意的是，TRE-515是唯一的挽救途径 目前正在临床开发中，尚无补救途径抑制剂被批准用于癌症 疗法。目前，Trethera 正在 1a 期开放标签剂量递增研究中评估 TRE-515 实体瘤患者（IND #131939）。可接受的安全性和耐受性已被证明 10 名患者接受 3 剂 TRE-515（40mg、80mg、160mg）。初步药代动力学 (PK) 数据表明 可接受的半衰期、快速吸收和患者之间的低变异性以及早期和药效学 (PD) 数据表明有效的目标抑制。值得注意的是，抗肿瘤活性的早期迹象已被注意到，50% 最低剂量组中的患者表现出疾病稳定。我们的目标是进行第一阶段剂量 扩展试验采用基于 LC/MS 的定量测定来测定血清 脱氧胞苷（dC）/ 脱氧尿苷 (dU) 水平和新型 PET 成像方法作为补充生物标志物来监测药物活性和评估 初步抗肿瘤活性。全身 dCK 活性调节血清 dC 及其代谢物 dU 的水平， 可以通过测量血浆的变化来常规监测 TRE-515 抑制导致的 dCK 活性降低 使用我们开发的 LC-MS 测定法进行 dC/dU。 [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）。根据 FDA 的认可，男性和女性患者 (N=12) 晚期难治性实体瘤将每日口服一次 320 mg TRE-515。液质联用仪 将进一步开发测量血清 dC/dU 水平的测定法，并将其用作易于获取的方法 评估患者对 TRE-515 反应的生物标志物（目标 1）。使用最近发明的 IND- 进行生物标志物研究 公认的正电子发射断层扫描 (PET) 探针 [18F]氯法拉滨 ([18F]CFA) 将用于体内 监测 TRE-515 对 dCK 活性的影响（目标 2）。安全评估、生物标志物研究和 实体瘤疗效评估标准 (RECIST) 将用于评估患者的肿瘤反应。审判 里程碑包括 i) 开始 TRE-515 治疗后 dC + dU 血清水平增加 >1.5 倍，反映药物 目标抑制和 ii) TRE-515 治疗后 [18F]CFA 肿瘤摄取减少超过 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。