Discovering novel therapies for glioma patients

发现神经胶质瘤患者的新疗法

• 批准号: 10702707
• 负责人: Jing Wu
• 金额: $ 58.06万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702707
• 关键词: Apoptosis; Apoptotic; Biological; Biopsy; Brain Neoplasms; CDK9 Protein Kinase; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Databases; Disease Resistance; Doctor of Medicine; Dose; Drug Exposure; Equipment and supply inventories; Excision; Genetic Transcription; Glioma; Grant; Hour; In Vitro; Isocitrate Dehydrogenase; Malignant Glioma; Malignant neoplasm of brain; Modeling; Molecular; Mus; Mutation; Operative Surgical Procedures; Orphan Drugs; Outcome; Outcome Measure; Participant; Pathway interactions; Patient Outcomes Assessments; Patient Self-Report; Patients; Pharmaceutical Preparations; Pharmacogenetics; Phase; Phase I/II Clinical Trial; Prognostic Factor; Progression-Free Survivals; Proteins; Publishing; Quality of life; Recurrence; Reporting; Safety; Sampling; Severities; Survival Rate; Symptoms; Testing; Therapeutic Effect; Toxic effect; Transcription Process; Treatment-related toxicity; Tumor Biology; Vertebral column; Work; World Health Organization; antitumor effect; base; cell type; clinical prognostic; clinical trial analysis; cohort; design; disease heterogeneity; improved; in vivo Model; inhibitor; instrument; mitochondrial dysfunction; mouse model; mutant; novel therapeutics; phase 1 study; phase I trial; phase II trial; pre-clinical; preclinical study; preservation; primary endpoint; resistance mechanism; response; systemic toxicity; targeted treatment; therapy development; therapy resistant; treatment response; tumor

Based on our previous preclinical and clinical works in high-grade malignant gliomas, FDA granted the orphan drug designation for ZOT in malignant gliomas treatment. Based on the observations from the previous clinical study, we continued to investigate the selective effect of ZOT in a subset of gliomas. This ongoing project includes both preclinical and clinical studies of ZOT in IDH-mutant gliomas. In the preclinical studies, we tested the responses to ZOT in both IDH mutant and wildtype glioma models. We demonstrated the increased sensitivity to ZOT in IDH-mutant gliomas compared to the IDH-wildtype tumor. A lower IC50 in IDH-mutant cells compared to the IDH-wildtype glioma cells was demonstrated in patient-derived GSC lines and isogenic mouse cells with and without IDH mutation. A lower dose of ZOT was able to suppress transcription through inhibition of cyclin-dependent kinase 9 (CDK9) and RNAPOL II in mutant cells but not in wild-type cells. Apoptosis, mitochondrial dysfunction and ATP reduction are also seen in low dose ZOT-treated IDH-mutant gliomas but not in IDH wildtype tumors. A significant survival benefit of single-agent ZOT is observed in mouse model of IDH-mutant but not wild-type gliomas. Based on the preclinical findings, we hypothesized that IDH-mutant glioma has increased sensitivity to ZOT due to its unique tumor biology. Single-agent ZOT in patients with IDH-mutant gliomas will improve clinical outcomes, including survival benefits and less of toxicities. To test the hypothesis in the clinical trial setting, I have designed a clinical trial in IDH-mutant glioma patients. Entitled "A Phase I/II Study of Zotiraciclib for Recurrent High-Grade Gliomas with Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations". In Phase I part, the primary objective is to estimate recommended phase II dose (RP2D) of ZOT. In Phase II, the primary objective is to determine 12-month progression-free survival (PFS) in participants with recurrent glioma, IDH1/2-mutant, World Health Organization (WHO) grade 3 treated with ZOT in comparison with the established brain tumor database matched for tumor molecular characteristics and clinical prognostic factors. In the phase II part, we built a surgical cohort. Participants in the surgical cohort will get an additional single pre-treatment with one dose of the study drug at the RP2D on Day 1 of Cycle 0, followed by brain tumor biopsy or surgical resection within 24 hours. The surgical sample will be used for PK and PD analysis to determine the drug exposure and biological effect of the study drug in the tumor. More importantly, we plan to longitudinally evaluate Participant Reported Outcomes (PRO)s measures using self-reported symptom severity and interference with daily activities using the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) or the M.D. Anderson Symptom Inventory-Spine Module (MDASI-SP) instrument. This will evaluate the symptom burdens and quality of life while patients receiving the treatment for tumor control. Lastly, the pharmacogenetic (PG) features of participants receiving ZOT will be determined and correlate with treatment response and toxicities. The results of this Phase 1 study have been completed and published.

基于我们之前在高级别恶性胶质瘤中的临床前和临床工作， FDA授予ZOT治疗恶性胶质瘤的孤儿药资格。基于 从以前的临床研究观察，我们继续研究选择性 ZOT在神经胶质瘤亚群中作用。这个正在进行的项目包括临床前和 ZOT在IDH突变型胶质瘤中的临床研究。在临床前研究中，我们测试了 在IDH突变体和野生型胶质瘤模型中对ZOT的反应。我们证明了 与IDH野生型肿瘤相比，IDH突变型胶质瘤对ZOT的敏感性。较低的IC 50 与IDH野生型胶质瘤细胞相比，IDH突变型细胞在患者源性胶质瘤细胞中被证明。 具有和不具有IDH突变的GSC系和同基因小鼠细胞。较低剂量的ZOT 通过抑制细胞周期蛋白依赖性激酶9（CDK 9）和RNAPOL II来抑制转录 在突变型细胞中，而不是在野生型细胞中。细胞凋亡、线粒体功能障碍和ATP 在低剂量ZOT治疗的IDH突变型胶质瘤中也观察到减少，但在IDH野生型中没有 肿瘤的在小鼠模型中观察到单药ZOT的显著存活益处。 IDH突变型而非野生型胶质瘤。基于临床前研究结果，我们假设， IDH突变型胶质瘤由于其独特的肿瘤生物学特性而对ZOT的敏感性增加。 单药ZOT治疗IDH突变型胶质瘤患者将改善临床结局，包括 生存益处和较少的毒性。为了在临床试验中验证假设 在这种背景下，我设计了一项IDH突变型胶质瘤患者的临床试验。被称为“A阶段 Zotiraciclib治疗复发性高级别胶质瘤伴异柠檬酸脱氢酶1或 2（IDH 1或IDH 2）突变”。在第一阶段，主要目标是估计建议的 II期剂量（RP 2D）的ZOT。在第二阶段，主要目标是确定12个月 复发性胶质瘤受试者的无进展生存期（PFS），IDH 1/2突变，世界 与已建立的脑相比，使用ZOT治疗的WHO 3级 肿瘤数据库匹配肿瘤分子特征和临床预后因素。在 在第二阶段，我们建立了一个外科队列。手术队列的参与者将获得 在周期第1天以RP 2D接受一剂研究药物的额外单次预治疗 0，随后在24小时内进行脑肿瘤活检或手术切除。手术样本 将用于PK和PD分析，以确定药物暴露和生物学效应 肿瘤中的研究药物。更重要的是，我们计划纵向评估参与者 使用自我报告的症状严重程度和干扰的报告结局（PRO）指标 日常活动使用的MD。安德森症状量表-脑肿瘤（MDASI-BT）或医学博士 安德森症状量表-脊柱模块（MDASI-SP）仪器。这将评估症状 患者在接受肿瘤控制治疗时的负担和生活质量。最后， 将确定接受ZOT的受试者的药物遗传学（PG）特征， 与治疗反应和毒性相关。这项1期研究的结果已经 完成并出版。