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.

项目摘要 我们要求提供三年的支持，以进行开放标签，剂量提升的I期临床试验 具有复发性恶性神经胶质瘤（MG）的受试者确定建议的2阶段剂量（RP2D），安全性 和Δγ134.5单纯疱疹病毒（∆γ134.5 HSV）的新颖修饰的毒性和表达人类的毒性 白介素12（M032，NSC733972）。该溶瘤HSV是根据计划项目赠款开发的 （CA071933），并在包括非人类的两种动物物种中在体外和临床上进行了广泛的测试 灵长类动物。这些研究表明，M032与其他临床肿瘤Δγ134.5HSV一样安全（G207，1716） 在脑内使用，在免疫功能低下的小鼠或免疫能力中没有意外毒性 动物（小鼠，非人类素数），并且在各种临床前的复制比G207更好地复制10-1000倍 Mg的模型。我们已经在类似的患者人群中与G207进行了三项I期临床试验（其中17个 35个受试者具有客观回应），并将运用我们的独特知识和经验来评估这本小说 HSV。下一个程序在> 3 x 109 pfu/ml上生产CGMP临床级M032（NSC733972），生成 > 560个单剂量小瓶。 FDA已发布IND＃14,946，试验方案和知情同意书是IRB- 经过批准和第一个主题已在没有DLT的情况下进行治疗（NCT02062827）。在AIM 1中，第一个人类 第一阶段临床试验将使用经过修改的连续重新评估方法（CRM）来确定剂量修改 获得安全性和毒性数据以及二级生物学相关信息，对评估至关重要 该病毒在治疗恶性脑肿瘤方面的潜在应用。具有活检经过复发的受试者 将在增强的肿瘤质量中通过立体定向感染M032（400μl/hr x 6小时） 放置导管，将受到监测的不良反应和生存。随后的每个主题中的剂量升级 将在24天后发生，并由CRM定义。我们将确定RP2D，将确定任何 意外的毒性将确定无进展和整体生存。在AIM 2中，我们将 在指定的纵向时间表上，从每个受试者中获得了类似获取的生物标本， 处理这些以立即分析或以后进行冷冻保存和批处理分析。我们建议 TO：a）评估病毒培养和PCR的血液，唾液和结膜分泌的M032； b）文件 血清学（抗体滴度）和细胞免疫复杂（免疫的分析，增殖和功能 子集）至M032输注； c）定义从免疫抑制环境变为免疫抑制的变化 环境，包括循环细胞因子和外周血单核细胞的变化； d）建立 肿瘤基因型差异可能揭示了肿瘤敏感性或抗性的分子碱基。之前 将分析存档的肿瘤组织（如果有的话）和血液DNA，以提供深入的分子剖面 对于每个受试者的肿瘤。分析将集中于定义M032的RP2D，并将考虑所有临床变量 和相关参数，以更好地为未来的试验设计提供最佳结果。