Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol
Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol
复制标题
DOI：
10.1186/1471-2407-12-99
复制
发表时间：
2012-03-21
期刊：
影响因子：
3.8
通讯作者：
Hajda, Jacek
中科院分区：
文献类型：
--
作者：
Geletneky, Karsten;Huesing, Johannes;Hajda, Jacek
背景：恶性脑肿瘤患者的治疗仍然是一个主要的肿瘤学问题。恶性程度最高的多形性胶质母细胞瘤（GBM）患者的中位生存期在初次诊断后仅为15个月，在肿瘤复发后甚至更短。标准治疗的改进，包括手术和放射化学疗法，并没有导致重大改善。因此，正在研究替代疗法，如特异性靶向和破坏癌细胞的溶瘤病毒。溶瘤细小病毒H-1（H-1 PV）感染神经胶质瘤细胞的临床前数据显示出强烈的细胞毒性和肿瘤抑制作用，导致H-1 PV在复发性GBM患者中的I/IIa期试验（ParvOryx 01）。ParvOryx 01是德国第一项针对具有复制能力的溶瘤病毒的试验。方法：ParvOryx 01是一项开放、非对照、两组、组内剂量递增、单中心、I/IIa期试验。18例复发性GBM患者将分2组治疗，每组9例患者。治疗组1将首先通过瘤内注射接受H-1 PV，然后在肿瘤切除术期间向肿瘤腔壁给药。在治疗组2中，病毒最初将被静脉注射，然后与组1相同，在肿瘤切除期间注射到周围脑组织中。主要合格标准是：年龄18岁，单灶复发性GBM，适合完全或次全切除。剂量递增将基于持续再评估方法。试验的主要目的是局部和全身安全性和耐受性，并确定最大耐受剂量（MTD）。次要目标是概念验证（proof of concept，HSPs）和无进展生存期（Progression-free Survival，PFS）长达6 months.Discussion：这是第一次在复发性GBM患者中进行H-1 PV试验。参与者的风险似乎是可以预测和合理的。此外，ParvOryx 01将是溶瘤病毒联合瘤内和静脉内应用的首次评估。由于其研究设计，该试验不仅将生成关于H-1 PV局部效应的数据，而且还将研究全身给药后H-1 PV对肿瘤的渗透，并从全身给药中获得可能支持H-1 PV在其他非CNS恶性肿瘤中的临床试验的安全性数据。
Background: The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM), the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV) infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01). ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany.Methods: ParvOryx01 is an open, non-controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD). Secondary objectives are proof of concept (PoC) and Progression-free Survival (PFS) up to 6 months.Discussion: This is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment of combined intratumoral and intravenous application of an oncolytic virus. Due to its study design the trial will not only generate data on the local effect of H-1PV but it will also investigate the penetration of H-1PV into the tumor after systemic delivery and obtain safety data from systemic delivery possibly supporting clinical trials with H-1PV in other, non-CNS malignancies.