Clinical study of AdV-tk radiogenetherapy for malignant*

描述（由申请人提供）：恶性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，使用腺病毒载体递送HSV-tk（AdV-tk）已成为最广泛研究和最有前途的方法之一。 一些剂量递增I期研究显示了良好的安全性特征，并有令人鼓舞的轶事结果。 然而，尚未评估其对任何肿瘤类型的临床疗效。 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AdV 4k + prod rug基因治疗复发性恶性胶质瘤的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，疗效提高而不增加毒性。 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组合用于恶性胶质瘤的组合。 由于这种放射性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，该产品将增加诊断为恶性胶质瘤的患者的生存时间或生活质量。 选择不可切除的恶性胶质瘤患者人群，因为这些患者在立体定向活检确诊后接受放射治疗作为标准治疗。 此外，没有其他局部治疗可用于这些患者。 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。 将评价三种剂量水平的AdV-tk，范围为3 × 1010 - 3 × 1011载体颗粒，以半对数增量，每剂3-6例患者。 本研究将由Cumberene进行，该公司有将实验室研究有效转化为临床基因治疗研究的记录，患者在马萨诸塞州总医院（MGH）招募，该医院有一个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。

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.