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

项目总结 临床阶段生物制药公司Trethera已经开发出一种小分子药物tre-515，用于靶向 核苷挽救途径通过一个关键的限速酶，脱氧胞苷酶(DCK)。我们已经展示了 DCK在多种实体瘤中高水平表达，而tre-515选择性地靶向癌细胞。 基于他们对DCK的高度表达和依赖。值得注意的是，tre-515是唯一的打捞途径。 目前正在临床开发的抑制剂，没有挽救途径的抑制剂被批准为癌症 治疗学。目前，Trethera正在对tre-515进行1a期开放标签剂量递增研究 实体瘤患者(IND#131939)。可接受的安全性和耐受性已在以下方面得到证明 10例患者共3次TRE-515剂量(40 mg、80 mg、160 mg)。初步药代动力学(PK)数据表明 患者可接受的半衰期、快速吸收和低变异性，以及早期和药效学(PD) 数据证明了有效的靶向抑制。值得注意的是，已经注意到了抗肿瘤活性的早期迹象，50% 在显示病情稳定的最低剂量队列中的患者中。我们在这里的目标是进行第一阶段的剂量 一种基于LC/MS定量检测血清的扩展试验 脱氧胞苷(DC)/ 脱氧尿苷 (Du)水平和一种新的PET成像方法作为监测药物活性和评估药物活性的补充生物标志物 初步的抗肿瘤活性。全身DCK活性调节血清DC及其代谢物Du的水平， 而通过抑制tre-515而降低DCK活性可以通过测量血浆中的变化来常规监测。 Dc/Du使用我们建立的LC-MS分析方法。[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)。FDA接受的男性和女性患者(N=12) 晚期难治性实体肿瘤每天口服一次320毫克TRE-515。LC/MS 基于检测血清DC/Du水平的方法将进一步发展并作为一种简便的方法使用 评估患者对TRE-515反应的生物标记物(目标1)。使用最近发明的生物标志物研究，IND- 被接受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、生物标记物研究和 实体肿瘤的反应评估标准(RECIST)将用于评估患者的肿瘤反应。审判 里程碑包括i)&gt；在开始tre-515治疗后，血清DC+Du水平增加1.5倍，反映药物 靶向抑制和ii)在TRE-515治疗后[18F]CFA肿瘤摄取减少33%以上。 拟议试验的成功将支持未来的第一阶段和第二阶段临床试验，以确定有效性、安全性、 Tre-515的组合、患者选择和最佳剂量方案。

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.