Clinical study of AdV-tk radiogene therapy for malignant glioma

AdV-tk放射基因治疗恶性胶质瘤的临床研究

基本信息

批准号：
7445382
负责人：
Estuardo Aguilar-Cordova
金额：
$ 78.82万
依托单位：
ADVANTAGENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-07 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7445382
关键词：
Appendix Applications Grants Biopsy Brain Neoplasms Caring Clinical Clinical Research Common Terminology Criteria for Adverse Events Diagnosis Disease Dose General Hospitals Goals Grant HSV-Tk Gene Human Injection of therapeutic agent Laboratory Study Local Therapy Malignant Glioma Massachusetts Maximum Tolerated Dose Measurable Measures Oncogenes Oral Patients Phase Phase I Clinical Trials Phase II Clinical Trials Population Process Prodrugs Protocols documentation Quality of life Radiation Radiation Therapy Oncology Group Radiation therapy Radio Range Recurrence Research Safety Standards of Weights and Measures Testing Time Toxic effect Translations Unresectable Writing base clinical efficacy combination gene therapy gene therapy gene therapy clinical study improved novel therapeutics outcome forecast particle preclinical study tumor valacyclovir vector

项目摘要

DESCRIPTION (provided by applicant): Malignant gliomas have a very poor prognosis with median survival measured in months rather than years. It is a disease with great need of novel therapeutic approaches. Within cancer gene therapy the use of adenoviral vectors to deliver HSV-tk (AdV-tk) has been one of the most widely studied and promising approaches. A few dose escalation Phase I studies have shown good safety profiles with encouraging anecdotal results. However, its clinical efficacy has not yet been assessed for any tumor type. Thus, clinical Phase Il and Ill studies are needed to evaluate the true potential of AdV-tk. A completed phase I study of AdV4k + prod rug gene therapy in recurrent malignant gliomas demonstrated a safe dose range for AdV-tk in brain tumors and some encouraging results. Preclinical studies demonstrate improved efficacy without added toxicity when AdV-tk gene therapy is combined with radiation therapy. The current study proposed in this application seeks to evaluate the combination of AdV-tk + prodrug gene therapy in combination with radiation therapy for malignant gliomas. Since this radio-gene therapy combination has not previously been studied in human brain tumors, a Phase I study must first be performed to assess potential toxicity of the combination (the subject of this Phase I application). The long-term goal of the research described in this proposal is to develop a product that will increase survival time or quality of life for patients diagnosed with malignant gliomas. The patient population with unresectable malignant gliomas was chosen since these patients receive radiation therapy as standard of care following stereotactic biopsy for confirmation of diagnosis. In addition, no other local therapies are available for these patients. The primary objective for this Phase I study is to evaluate the safety of escalating doses of AdV-tk with a fixed dose of the oral prodrug, valacyclovir, and standard radiation therapy. Three dose levels of AdV-tk, ranging from 3x1010 to 3x1011 vector particles in half log increments, will be evaluated with 3-6 patients per dose. The study will be conducted by Advantagene, which has a track record of efficient translation of laboratory studies into clinical gene therapy studies, with patient accrual at the Massachusetts General Hospital (MGH), which has an active brain tumor clinical group. The Phase II portion will assess clinical efficacy at the maximum tolerated dose (MTD) or the highest dose level reached in this Phase I study.

描述（由申请人提供）：恶性神经胶质瘤的预后非常差，中位生存期以月而不是年为单位。这是一种非常需要新的治疗方法的疾病。在癌症基因治疗中，使用腺病毒载体传递 HSV-tk (AdV-tk) 一直是研究最广泛、最有前景的方法之一。一些剂量递增的 I 期研究显示出良好的安全性和令人鼓舞的轶事结果。然而，其临床疗效尚未针对任何肿瘤类型进行评估。因此，需要临床II期和III期研究来评估AdV-tk的真正潜力。一项已完成的 AdV4k + 前药基因治疗复发性恶性神经胶质瘤的 I 期研究证明了 AdV-tk 在脑肿瘤中的安全剂量范围和一些令人鼓舞的结果。临床前研究表明，当 AdV-tk 基因治疗与放射治疗相结合时，可提高疗效，且不会增加毒性。本申请中提出的当前研究旨在评估 AdV-tk + 前药基因疗法与放射疗法联合治疗恶性神经胶质瘤的效果。由于这种放射基因疗法组合之前尚未在人类脑肿瘤中进行过研究，因此必须首先进行 I 期研究以评估该组合的潜在毒性（本 I 期申请的主题）。该提案中描述的研究的长期目标是开发一种产品，可以延长诊断为恶性神经胶质瘤的患者的生存时间或生活质量。选择患有不可切除的恶性神经胶质瘤的患者群体是因为这些患者在立体定向活检确认诊断后接受放射治疗作为标准护理。此外，这些患者没有其他局部疗法可用。这项 I 期研究的主要目的是评估递增剂量的 AdV-tk 与固定剂量的口服前药伐昔洛韦和标准放射治疗的安全性。 AdV-tk 的三个剂量水平（范围从 3x1010 到 3x1011 个载体颗粒，以半对数增量）将针对每剂 3-6 名患者进行评估。该研究将由 Advantagene 进行，该公司在将实验室研究有效转化为临床基因治疗研究方面拥有良好的记录，并在马萨诸塞州总医院 (MGH) 招募患者，该医院拥有活跃的脑肿瘤临床小组。 II 期部分将评估最大耐受剂量 (MTD) 或本 I 期研究达到的最高剂量水平的临床疗效。