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 Trethera是一家临床阶段生物制药公司，已开发出一种小分子药物TRE-515，以靶向 通过关键限制酶，脱氧胞苷激酶（DCK）的核苷拯救途径。我们已经显示了 DCK在多种实体瘤中以高水平表达，而TRE-515有选择地靶向癌细胞 基于它们对DCK的高表达和依赖性。值得注意的是，TRE-515是唯一的打捞途径 目前正在临床开发中的抑制剂，并且没有批准保证途径抑制剂作为癌症 疗法。目前，Trethera在1A期开放标签，剂量升级研究中评估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例患者中有3次TRE-515剂量（40mg，80mg，160mg）。初步药代动力学（PK）数据表明 可接受的半衰期，快速吸收和患者的变异性较低，早期和药效学（PD） 数据证明了有效的靶标抑制。值得注意的是，已经注意到抗肿瘤活性的早期迹象，其中50％ 最低剂量队列中的患者表现出稳定的疾病。我们的目标是执行1阶段剂量 扩展试验部署基于定量LC/MS的分析以确定血清 脱氧胞苷（DC）/ 脱氧尿苷 （DU）水平和一种新型的PET成像方法作为互补的生物标志物来监测药物活动并评估 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， 可以通过测量等离子体的变化来常规监测DCK活性的降低DCK活性。 DC/DU使用我们开发的LC-MS测定法。 [18F] CFA是一种宠物放射性示踪剂，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口服剂量施用320 mg TRE-515。 LC/MS 测量血清DC/DU水平的基于基于的测定将进一步开发并用作易于访问的方法 生物标志物评估患者对TRE-515的反应（AIM 1）。生物标志物研究使用最近发明的 公认的正电子发射断层扫描（PET）探针，[18F]克洛法拉滨（[18F] CFA）将用于体内 监测TRE-515对DCK活性的影响（AIM 2）。安全评估，生物标志物研究和 实体瘤的反应评估标准（RECIST）将用于评估患者的肿瘤反应。审判 里程碑包括i）> 1.5倍，在启动TRE-515治疗后血清 + DU的血清水平增加，反映药物 靶标的抑制作用和II）TRE-515治疗后[18F] CFA肿瘤摄取的降低33％。 拟议的试验中的成功将支持将来的第1和2阶段试验，以确定功效，安全性， TRE-515的组合，患者选择和最佳剂量方案。