Phase I study to evaluate safety, tolerability, pharmacokinetics and anti-tumor activity of WSD0922-FU

I期研究评估WSD0922-FU的安全性、耐受性、药代动力学和抗肿瘤活性

• 批准号: 10274704
• 负责人: Sani Haider Kizilbash
• 金额: $ 28.7万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10274704
• 关键词: Phase; study; evaluate; safety; tolerability

PROJECT SUMMARY/ABSTRACT: High-grade astrocytomas (HGA) are rare incurable cancers (combined USA prevalence < 30,000) with few treatment options. Mayo Clinic is collaborating with Wayshine Biopharma to develop WSD0922-FU (WSD) (IND 145566) – a novel oral, small molecule orphan drug which potently inhibits EGFR aberrations specific to high-grade astrocytoma (HGA) (EGFR amplification, EGFRvIII mutation). Our central hypothesis is that safe and tolerable doses of WSD achieve sufficient tumor concentrations in HGA to inhibit EGFR signaling and improve efficacy in patients with EGFR-amplified / EGFRvIII HGA. This is being examined in a first-in-human phase I basket trial which is the subject of this three-year R01 submission to the FDA (“Phase I Study to Evaluate Safety, Tolerability, Pharmacokinetics and Anti-Tumor Activity of WSD0922- FU”). The investigators have broad clinical trial experience in early drug development and neuro-oncology. Early input on trial design was obtained from patient advocates to ensure study feasibility and to reduce patient burden. We expect that study completion will advance available treatments for HGA with EGFR alterations by establishing the maximum tolerated dose (MTD) for WSD, while generating critical data on central nervous system (CNS) PK (pharmacokinetics), impact on tumor EGFR signaling, preliminary efficacy and relevant genetic biomarkers of response/resistance. These data will provide robust evidence to optimize phase II/III trial design, which may lead to a new indication for WSD in HGA. The central hypothesis is evaluated in three aims: Aim 1: Evaluate the safety, tolerability and systemic PK of WSD at MTD. Patients with EGFR-amplified / EGFRvIII HGA or non-small cell lung cancer with CNS metastases will be treated with WSD in a dose escalation cohort to define the MTD and evaluate the toxicity profile of WSD. Plasma PK will be quantified by LC-MS/MS to evaluate systemic exposure. A dose expansion cohort will also include a food-effect study prior to starting continuous dosing. Plasma PK will be quantified in both the fed (WSD dosed after a high fat meal) and fasted states (WSD dosed one hour before or two hours after eating) to evaluate the effect of food on systemic PK. Aim 2: Evaluate intratumoral PK of WSD and assess its pharmacodynamic (PD) impact on EGFR pathway signaling in HGA. Patients with EGFR-amplified / EGFRvIII HGA requiring a therapeutic surgical tumor resection as part of routine clinical care will preoperatively be dosed with WSD at MTD. During surgery, tumor tissue will be collected and flash frozen. Tumor PK will be quantified by LC-MS/MS and PD impact on EGFR pathway signaling will be evaluated by functional proteomics. Aim 3: Characterize the molecular biomarkers which influence efficacy of WSD in patients with EGFR aberrant HGA. Patients with EGFR- amplified / EGFRvIII HGA will be treated continuously with WSD at MTD and monitored for treatment efficacy. Plasma PK will be quantified by LC-MS/MS to confirm sufficient exposure. DNA/RNA sequencing will be performed on archived tissue to evaluate biomarkers of response and resistance (e.g. EGFRvIII, TP53, etc.).

项目总结/摘要：高级别星形细胞瘤（HGA）是罕见的不可治愈的癌症（结合 美国患病率<30，000），治疗选择很少。马约诊所与Wayshine Bioburma合作 开发WSD 0922-FU（WSD）（IND 145566）-一种新型口服小分子孤儿药， 抑制高级星形细胞瘤（HGA）特有的EGFR畸变（EGFR扩增、EGFRvIII突变）。 我们的中心假设是安全和耐受剂量的WSD在HGA中达到足够的肿瘤浓度 抑制EGFR信号传导并改善EGFR扩增/EGFRvIII HGA患者的疗效。这项工作正在 在首次人体I期篮式试验中进行了检查，该试验是提交给 FDA（"评价WSD 0922的安全性、耐受性、药代动力学和抗肿瘤活性的I期研究- FU "）。研究人员在早期药物开发和神经肿瘤学方面具有广泛的临床试验经验。 从患者倡导者处获得试验设计的早期输入，以确保研究可行性并减少患者 负担我们预计，研究的完成将推进EGFR改变的HGA的可用治疗， 确定WSD的最大耐受剂量（MTD），同时生成中枢神经系统的关键数据 系统（CNS）PK（药代动力学）、对肿瘤EGFR信号传导的影响、初步疗效和相关 反应/耐药性的遗传生物标志物。这些数据将为优化II/III期试验提供有力证据 设计，这可能会导致一个新的适应症，水务署在HGA。中心假设的评估有三个目标： 目的1：评价WSD在MTD时的安全性、耐受性和全身PK。EGFR扩增/ EGFRvIII HGA或伴有CNS转移的非小细胞肺癌将接受WSD治疗，剂量为 递增队列，以确定MTD并评估WSD的毒性特征。血浆PK将通过以下方法定量： LC-MS/MS评价全身暴露。剂量扩展队列还将包括食物效应研究， 开始连续给药将在进食（WSD在高脂肪餐后给药）后定量血浆PK 和禁食状态（WSD在进食前一小时或进食后两小时给药），以评估食物对 全身PK。目的2：评价WSD的瘤内PK并评估其对EGFR的药效学（PD）影响 HGA中的信号通路。需要治疗性外科手术的EGFR扩增/EGFRvIII HGA患者 作为常规临床护理的一部分的肿瘤切除术将在手术前以MTD给药WSD。在手术过程中， 收集肿瘤组织并快速冷冻。将通过LC-MS/MS定量肿瘤PK和PD对 EGFR通路信号传导将通过功能蛋白质组学进行评价。目的3：表征分子 影响EGFR异常HGA患者WSD疗效的生物标志物。EGFR患者- 扩增的/EGFRvIII HGA将以MTD用WSD连续治疗，并监测治疗功效。 将通过LC-MS/MS定量血浆PK，以确认充分暴露。DNA/RNA测序将是 在存档组织上进行，以评价应答和耐药性的生物标志物（例如EGFRvIII、TP 53等）。