A Phase 1 Study of M032, a Genetically Engineered HSV-1 Expressing IL-12, in Patients with Recurrent/Progressive Glioblastoma Multiforme, Anaplastic Astrocytoma, or Gliosarcoma.

M032（一种表达 IL-12 的基因工程 HSV-1）在复发/进行性多形性胶质母细胞瘤、间变性星形细胞瘤或胶质肉瘤患者中的 1 期研究。

• 批准号: 9455636
• 负责人: G. YANCEY GILLESPIE
• 金额: $ 55.93万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9455636
• 关键词: Adult; Adverse effects; Anaplastic astrocytoma; Animals; Antibody titer measurement; Antitumor Response; Archives; Biological; Biological Markers; Biopsy; Blood; Catheters; Cells; Clinical; Clinical Research; Clinical Trials; Cryopreservation; Cyclic GMP; Cytolysis; DNA; Data; Dose; Engineering; Enrollment; Environment; Future; G207; Gene Transduction Agent; Generations; Genetic Engineering; Genotype; Glioblastoma; Glioma; Grant; Herpesvirus 1; Human; Immune; Immune response; Immunocompetent; Immunocompromised Host; Immunotherapeutic agent; Informed Consent; Infusion procedures; Injections; Institutional Review Boards; Interferons; Interleukin-12; Investigational Drugs; Knowledge; Lymphocyte; Lytic; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Methods; Modeling; Modification; Molecular; Molecular Profiling; Monitor; Mus; National Cancer Institute; New Drug Approvals; Oncolytic; Oncolytic viruses; Outcome; Patients; Peripheral Blood Mononuclear Cell; Phase; Phase I Clinical Trials; Physiological; Pre-Clinical Model; Predisposition; Primary Brain Neoplasms; Process; Program Research Project Grants; Property; Protocols documentation; Publishing; Recurrence; Resistance; Safety; Saliva; Serological; Serum; Simplexvirus; Site; Specimen; Testing; Time; TimeLine; Toxic effect; Tumor Antigens; Tumor Tissue; United States Food and Drug Administration; Vial device; Virus; Virus Replication; anti-tumor immune response; base; cytokine; effective therapy; experience; first-in-human; glioma cell line; gliosarcoma; human study; immune function; improved; improved outcome; in vitro testing; melanoma; neoplastic cell; nonhuman primate; novel; oncolytic herpes simplex virus; oncolytic virotherapy; open label; outcome forecast; patient population; phase 1 study; phase I trial; pre-clinical; preclinical study; predicting response; programs; response; trial design; tumor; virus culture

PROJECT SUMMARY We are requesting three years of support to conduct an open-label, dose-escalating, Phase I clinical trial in subjects with recurrent malignant glioma (MG) to determine the Recommended Phase 2 Dose (RP2D), safety and toxicities of a novel modification of a ∆γ134.5 Herpes Simplex Virus (∆γ134.5 HSV) that expresses human interleukin-12 (M032, NSC733972). This oncolytic HSV was developed under a Program Project Grant (CA071933) and has been extensively tested in vitro and preclinically in two animal species, including nonhuman primates. These studies have shown M032 to be as safe as other clinical oncolytic ∆γ134.5 HSV (G207, 1716) used intracerebrally, to have no unexpected toxicities in immunocompromised mice or immunocompetent animals (mice, non-human primates), and to replicate 10-1000 fold better than G207 in a variety of preclinical models of MG. We have conducted three Phase I clinical trials with G207 in a similar patient population (17 of 35 subjects had objective responses) and will apply our unique knowledge and experience to evaluate this novel HSV. The NExT program produced cGMP clinical grade M032 (NSC733972) at >3 x 109 PFU/ml, generating >560 single-dose vials. The FDA has issued IND #14,946, a trial protocol and informed consent were IRB- approved and the first subject has been treated without DLTs (NCT02062827). In Aim 1, this first-in-human Phase I clinical trial will use a modified Continual Reassessment Method (CRM) to determine dose modifications to obtain both safety and toxicity data as well as secondary biologic correlative information critical to assessing the potential application of this virus to treat malignant brain tumors. Subjects with biopsy-proven recurrent MG will have M032 infused (400μl/hr x 6 hrs) in up to four sites in the enhancing tumor mass via stereotactically placed catheters and will be monitored adverse effects and survival. Dose escalation in each subsequent subject will occur after a 24 day interval and will be defined by the CRM. We will determine the RP2D, will identify any unanticipated toxicities and will determine, secondarily, progression-free and overall survivals. In Aim 2, we will simultaneously acquire biological specimens from each subject on a designated longitudinal timeline and process these for immediate analyses or for cryopreservation and batch analyses at a later time. We propose to: a) assess M032 shedding in blood, saliva, and conjunctival secretions by virus culture and PCR; b) document serological (antibody titers) and cellular immune responses (profiling, proliferation and function of immune subsets) to M032 infusion; c) define changes from an immune suppressing environment to an immune enhancing environment, including changes in circulating cytokines and peripheral blood mononuclear cells; and d) establish tumor genotype differences that might reveal molecular bases for tumor susceptibility or resistance. Previously archived tumor tissues (when available) and blood DNA will be analyzed to provide an in-depth molecular profile for each subject's tumor. Analyses will be focused to define a RP2D of M032 and will consider all clinical variables and correlative parameters to better inform future trial designs for the best outcomes.

项目概要 我们请求三年的支持来开展一项开放标签、剂量递增的 I 期临床试验 复发性恶性神经胶质瘤 (MG) 受试者确定推荐的 2 期剂量 (RP2D)、安全性 表达人类的 Δγ134.5 单纯疱疹病毒 (Δγ134.5 HSV) 的新变异体的毒性和毒性 interleukin-12（M032，NSC733972）这种溶瘤 HSV 是根据计划项目拨款开发的。 (CA071933)，并已在两种动物物种（包括非人类）中进行了广泛的体外和临床前测试 这些研究表明 M032 与其他临床溶瘤 Δγ134.5 HSV 一样安全（G207，1716） 用于脑内，对免疫功能低下的小鼠或免疫功能正常的小鼠没有意外的毒性 动物（小鼠、非人灵长类动物），在各种临床前试验中复制效果比 G207 好 10-1000 倍 我们已经在类似的患者群体中使用 G207 进行了三项 I 期临床试验（其中 17 例）。 35名受试者做出了客观反应）并将运用我们独特的知识和经验来评价这部小说 HSV。 NExT 计划生产了 >3 x 109 PFU/ml 的 cGMP 临床级 M032 (NSC733972)，产生 > 560 瓶单剂量小瓶 FDA 已发布 IND #14,946、一项试验方案和知情同意书。 在目标 1 中，第一个受试者已在没有 DLT 的情况下接受治疗（NCT02062827），这是首次在人类中进行的治疗。 I 期临床试验将使用改良的持续重新评估方法 (CRM) 来确定剂量调整 获得安全性和毒性数据以及对评估至关重要的二级生物相关信息 该病毒有望用于治疗经活检证实复发性 MG 的恶性脑肿瘤。 将通过立体定向将 M032 输注（400μl/小时 x 6 小时）至增强肿瘤块的最多四个位点 导管，并将监测每个后续受试者的剂量递增情况。 将在 24 天间隔后发生，并将由 CRM 定义。我们将确定 RP2D，识别任何情况。 其次，在目标 2 中，我们将决定无进展生存期和总生存期。 在指定的纵向时间线上同时采集每个受试者的生物样本，并且 我们建议对这些进行处理以进行立即分析或稍后进行冷冻保存和批量分析。 a) 通过病毒培养和 PCR 评估血液、唾液和结膜分泌物中 M032 的脱落情况 b) 记录； 血清学（抗体滴度）和细胞免疫反应（免疫分析、增殖和功能） 子集）到 M032 输注；c）定义从免疫抑制环境到免疫增强环境的变化 环境，包括循环细胞因子和外周血单核细胞的变化；以及 d) 建立 肿瘤基因型差异可能揭示肿瘤易感性或耐药性的分子基础。 将分析存档的肿瘤组织（如果有）和血液 DNA，以提供深入的分子谱 对于每个受试者的肿瘤，分析将集中于定义 M032 的 RP2D 并考虑所有临床变量。 和相关参数，以便更好地为未来的试验设计提供最佳结果。