In-Situ Autovaccination against Solid Cancers with Intratumoral Hiltonol (Poly-ICLC): A phase II Adaptive Multicenter Clinical Study

使用瘤内希尔顿醇（Poly-ICLC）针对实体癌进行原位自动疫苗接种：一项 II 期适应性多中心临床研究

• 批准号: 9336054
• 负责人: Andres Mario Salazar
• 金额: $ 73.22万
• 依托单位: ONCOVIR, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336054
• 关键词: Antigens; Antiviral Agents; Biopsy; Blood; Cancer Patient; Carboxymethylcellulose; Cessation of life; Clinical; Clinical Research; Data; Development; Disease; Disease Progression; Disease regression; Double-Stranded RNA; Elements; Evaluation; Head and Neck Cancer; Health; Histologic; Immune response; Immunologics; Immunomodulators; In Situ; Incidence; Industry; Inflammation; Injection of therapeutic agent; Intramuscular; Intramuscular Injections; Lead; Lesion; Maintenance; Malignant Neoplasms; Metastatic Squamous Cell Carcinoma; Natural Immunity; Neoplasm Metastasis; Patients; Phase; Phase II Clinical Trials; Poly I-C; Poly ICLC; Polylysine; Progression-Free Survivals; Research Design; Rest; Safety; Signal Transduction; Site; Skin; Small Business Innovation Research Grant; Solid; Solid Neoplasm; Staging; T-Lymphocyte; Therapeutic; Treatment Efficacy; Tumor Antigens; Unresectable; Viral; Weight; adaptive immunity; base; clinically significant; design; disorder control; follow-up; meetings; melanoma; response; sarcoma; skin squamous cell carcinoma; statistics; treatment effect; tumor; tumor progression; vaccination strategy; volunteer

DESCRIPTION (provided by applicant): Hiltonol (poly-ICLC) is a stabilized dsRNA therapeutic viral mimic or 'danger signal' that activates multiple elements of innate and adaptive immunity. It is a standalone immunomodulator, but when properly combined with antigen it generates a comprehensive Th-1 weighted immune response best suited for antiviral and antitumor action. This project will combine Hiltonol with cancer patients' own tumor antigens in-situ to generate a comprehensive systemic immune response against the tumor and its metastases. Objectives: 1) To determine the safety of intratumoral (IT) Poly-ICLC. 2) To explore efficacy as manifested by irRC defined disease control and progression-free survival at 26 weeks. Secondary objectives are overall survival and immunologic response in blood and tumor biopsy, including immunoscore. Indications/Tumor groups: 1) Unresectable stage 3b, 3c or IV, M1a or M1b melanomas that are accessible to IT injections 2) Unresectable head and neck cancers that are accessible to IT injections 3) Sarcomas that are accessible to IT injections 4) Squamous cell carcinoma of the skin accessible to IT injections Study Design: A two-stage adaptive design Phase II clinical study with a pilot segment and an extension segment for the single tumor type showing the best clinical responses in the pilot phase. Pilot (SBIR phase I segment): Ten volunteer patients will be treated per group, for a total of 40 patients in the initil pilot phase of the study. Treatment consists of two cycles of intratumoral (IT) Hiltonol priming plus intramuscular (IM) Hiltonol® maintenance. One accessible tumor site will be targeted for initial IT injections of poly-ICLC thrice weekly for 2 weeks, followed by IM maintenance twice weekly for six weeks in each cycle. A second cycle will be followed by a 6-week no-treatment rest period to allow for evaluation of tumor response at week 26 in the absence of inflammation. Extension (SBIR phase II segment): Based on the safety and clinical response for patients in each tumor group during the pilot phase of the study, one of the 4 groups showing IRRC-defined stabilization or regression of disease at 26 weeks in at least two of the initial ten patiets will be selected for further study under this proposal. Appropriate, indication-specific statistics will be applied and an estimated 60 additional patients will be accrued to that group, for an estimated total of 70 patients in that group. Accrual targets may be further modified depending on the extent of response, other data collected, and results of a planned industry meeting with FDA. Survival and PFS will be estimated using Kaplan-Meir curves.

描述（由申请人提供）：Hiltonol (poly-ICLC) 是一种稳定的 dsRNA 治疗病毒模拟物或“危险信号”，可激活先天性和适应性免疫的多个要素。它是一种独立的免疫调节剂，但当与抗原正确结合时，它会产生最适合抗病毒和抗肿瘤作用的全面 Th-1 加权免疫反应。该项目将希尔顿诺与癌症患者自身的肿瘤抗原原位结合，产生针对肿瘤及其转移的全面的全身免疫反应。目标：1) 确定瘤内 (IT) Poly-ICLC 的安全性。 2) 探讨 irRC 定义的疾病控制和 26 周无进展生存期所体现的疗效。次要目标是血液和肿瘤活检中的总体生存率和免疫反应，包括免疫评分。适应症/肿瘤组： 1) 可进行 IT 注射的不可切除的 3b、3c 或 IV 期、M1a 或 M1b 黑色素瘤 2) 可进行 IT 注射的不可切除的头颈癌 3) 可进行 IT 注射的肉瘤 4) 可进行 IT 注射的皮肤鳞状细胞癌 研究设计：两阶段适应性设计 II 期临床研究 单一肿瘤类型的片段和延伸片段在试验阶段显示出最佳的临床反应。 试点（SBIR 第一阶段部分）：每组将接受 10 名志愿者患者的治疗，在该研究的初始试点阶段总共有 40 名患者。治疗包括两个周期的瘤内 (IT) Hiltonol 预充加肌肉注射 (IM) Hiltonol® 维护。将针对一个可触及的肿瘤部位进行初始 IT 注射，每周三次，持续两周，然后在每个周期中每周两次进行肌内注射，持续六周。第二个周期之后是 6 周的无治疗休息期，以便在第 26 周在没有炎症的情况下评估肿瘤反应。 扩展（SBIR II 期部分）：根据每个肿瘤组患者在研究试验阶段的安全性和临床反应，将选择最初 10 名患者中的至少 2 名在 26 周时表现出 IRRC 定义的疾病稳定或消退的 4 组中的一组进行进一步研究。适当的、特定于适应症的统计数据 将应用该组，估计将有 60 名额外患者加入该组，该组中的患者总数估计为 70 名。应计目标可能会根据反应程度、收集的其他数据以及计划与 FDA 举行的行业会议的结果进一步修改。将使用 Kaplan-Meir 曲线估计生存率和 PFS。