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.

项目摘要 我们正在申请三年的支持，以进行一项开放标签，剂量递增，I期临床试验， 复发性恶性胶质瘤（MG）受试者，以确定推荐的II期剂量（RP 2D）、安全性 一种新的修饰的γ134.5单纯疱疹病毒（γ134.5 HSV），表达人 白细胞介素-12（M032，NSC 733972）。这种溶瘤HSV是在一项计划项目资助下开发的 （CA 071933），并已在两种动物种属（包括非人）中进行了广泛的体外和临床前试验 灵长类动物这些研究表明，M032与其他临床溶瘤性β γ134.5 HSV（G207，1716）一样安全。 脑内使用，在免疫功能低下小鼠或免疫功能正常的小鼠中无意外毒性 动物（小鼠，非人灵长类动物），并复制10-1000倍优于G207在各种临床前 MG车型我们已经在类似的患者人群中进行了三次G207的I期临床试验（17例）。 35名受试者有客观的反应），并将运用我们独特的知识和经验来评估这部小说 HSV。NExT程序产生了> 3x 109 PFU/ml的cGMP临床级M032（NSC 733972），产生了 >560个单剂量小瓶。FDA已发布IND #14，946，试验方案和知情同意书由IRB- 已获得批准，且首例受试者已接受治疗，未发生DLT（NCT 02062827）。在目标1中， I期临床试验将使用改良的持续再评估方法（CRM）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次要生物学相关信息 这种病毒治疗恶性脑肿瘤的潜在应用。活检证实复发性MG的受试者 将通过立体定向在增强肿瘤块的最多4个部位输注M032（400μl/hr x 6小时） 放置导管，并将监测不良反应和生存率。随后每例受试者的剂量递增 将在24天间隔后发生，并由CRM定义。我们将确定RP 2D，将识别任何 非预期毒性，并将决定，其次，无进展和总生存期。在目标2中，我们 在指定纵向时间轴上同时从每个受检者获取生物样本， 处理这些样品用于立即分析或用于低温保存和稍后的批量分析。我们提出 目的：a）通过病毒培养和PCR评估血液、唾液和结膜分泌物中的M032散毒; B）记录 血清学（抗体滴度）和细胞免疫应答（免疫细胞的分布、增殖和功能） 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;和 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。先前 将分析存档的肿瘤组织（如可用）和血液DNA，以提供深入的分子特征 每个受试者的肿瘤。分析将重点确定M032的RP 2D，并将考虑所有临床变量 以及相关参数，以更好地为未来的试验设计提供信息，从而获得最佳结果。

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.