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

• 批准号: 7497957
• 负责人: Estuardo Aguilar-Cordova
• 金额: $ 79.44万
• 依托单位: ADVANTAGENE, INC
• 依托单位国家: 美国
• 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/7497957
• 关键词: Adenovirus Vector; 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

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较差，中位生存期在几个月而不是几年中。 这是一种非常需要新型治疗方法的疾病。 在癌症基因治疗中，使用腺病毒载体提供HSV-TK（ADV-TK）是研究最广泛和有希望的方法之一。 一些剂量升级的I期研究表明了良好的安全性，并鼓励了轶事结果。 但是，尚未评估其临床功效的任何肿瘤类型。 因此，需要临床期IL和不良研究来评估ADV-TK的真正潜力。 对复发性神经胶质瘤中ADV4K + POD地毯基因治疗的完整I期研究表明，脑肿瘤中ADV-TK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基因疗法与放射治疗结合使用时，没有添加毒性的疗效提高。 本应用中提出的当前研究旨在评估Adv-TK +前药基因治疗与恶性神经胶质瘤的放射治疗的结合。 由于这种无线电疗法组合以前尚未在人脑肿瘤中进行研究，因此必须首先进行I期研究以评估组合的潜在毒性（本应用I期应用的主题）。 该提案中描述的研究的长期目标是开发一种产品，该产品将增加诊断为恶性神经胶质瘤的患者的生存时间或生活质量。 选择了无法切除的恶性神经胶质瘤的患者人群，因为这些患者在立体定位活检后接受放射治疗作为护理标准，以确认诊断。 此外，这些患者没有其他局部疗法。 这一阶段研究的主要目的是用固定剂量的口服前药，valaceclovir和标准放射疗法评估ADV-TK剂量不断升级的安全性。 三个剂量水平的ADV-TK范围从3x1010到3x1011矢量颗粒的一半差量增量，每剂量为3-6名患者。 这项研究将由Advantagene进行，该研究具有实验室研究为临床基因治疗研究有效翻译为临床基因治疗研究的记录，马萨诸塞州综合医院（MGH）的患者应计为脑肿瘤临床组。 II期部分将评估最大耐受剂量（MTD）的临床疗效或本研究I阶段研究中达到的最高剂量水平。