Clinical study of AdV-tk radiogenetherapy for malignant*

描述（由申请人提供）：恶性胶质瘤预后非常差，中位生存期以月而非年计算。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）一直是研究最广泛和最有前途的方法之一。一些剂量递增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，其临床疗效尚未对任何肿瘤类型进行评估。因此，需要临床i期和i期研究来评估AdV-tk的真正潜力。一项已完成的AdV4k + prod药物基因治疗复发性恶性胶质瘤的I期研究表明，advk在脑肿瘤中的剂量范围是安全的，并取得了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联合使用时，疗效得到改善，而毒性没有增加。本研究旨在评估AdV-tk +前药基因治疗联合放射治疗恶性胶质瘤的疗效。由于这种放射-基因治疗组合以前没有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）。本提案中描述的研究的长期目标是开发一种产品，将增加诊断为恶性胶质瘤患者的生存时间或生活质量。

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.