Clinical study of AdV-tk radiogenetherapy for malignant*

AdV-tk 放射基因治疗恶性肿瘤的临床研究*

• 批准号: 6900996
• 负责人: Estuardo Aguilar-Cordova
• 金额: $ 40.2万
• 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 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6900996
• 关键词: Adenoviridae; biopsy; biotechnology; clinical research; clinical trial phase I; clinical trial phase II; combination cancer therapy; combination chemotherapy; drug administration rate /duration; drug adverse effect; drug screening /evaluation; gene therapy; glioma; human therapy evaluation; neoplasm /cancer radiation therapy; patient oriented research; radiation therapy dosage; stereotaxic techniques; therapy adverse effect; transfection /expression vector; valacyclovir

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(申请人提供)：恶性胶质瘤预后非常差，中位生存期以月为单位，而不是以年为单位。这是一种非常需要新的治疗方法的疾病。在肿瘤基因治疗中，使用腺病毒载体携带HSV-tk(AdV-tk)已成为研究最广泛、前景最好的方法之一。一些剂量递增的第一阶段研究已经显示出良好的安全性，并有令人鼓舞的轶事结果。然而，它的临床疗效尚未对任何肿瘤类型进行评估。因此，需要进行临床Il期和Ill期研究来评估Adv-tk的真正潜力。一项已完成的AdV4k+prod rug基因治疗复发性恶性胶质瘤的I期研究显示，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，可以改善疗效，而不会增加毒性。本申请中提出的这项研究旨在评估AdV-tk+前药基因治疗与放射治疗联合治疗恶性胶质瘤的效果。由于这种放射-基因治疗组合以前还没有在人脑肿瘤中进行研究，所以必须首先进行I期研究，以评估该组合的潜在毒性(此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，该产品将延长被诊断为恶性胶质瘤的患者的生存时间或生活质量。 选择不能切除的恶性胶质瘤患者，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，这些患者没有其他当地治疗方法可用。这项第一阶段研究的主要目标是评估在固定剂量的口服前药万乃洛韦和标准放射治疗的情况下递增剂量的ADV-tk的安全性。ADV-tk的三个剂量水平，从3x1010到3x1011个半对数增量的载体颗粒，将在每剂3-6名患者的情况下进行评估。这项研究将由Advantagene进行，该公司在有效地将实验室研究转化为临床基因治疗研究方面有着良好的记录，患者应计入马萨诸塞州综合医院(MGH)，该医院拥有一个活跃的脑瘤临床小组。第二阶段部分将评估在最大耐受剂量(MTD)或第一阶段研究中达到的最高剂量水平下的临床疗效。