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

描述（由申请人提供）：Hiltonol（聚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种元素。它是一种独立的免疫调节剂，但当与抗原适当结合时，它会产生最适合抗病毒和抗肿瘤作用的全面Th-1加权免疫应答。该项目将联合收割机Hiltonol与癌症患者自身的肿瘤抗原原位结合，以产生针对肿瘤及其转移的全面系统免疫应答。目的：1）确定瘤内（IT）聚ICLC的安全性。2)通过irRC定义的疾病控制和26周时的无进展生存期来探索疗效。次要目标是血液和肿瘤活检中的总生存率和免疫学应答，包括免疫评分。适应症/肿瘤组：1）IT注射可触及的不可切除的3b、3c或IV期、M1a或M1 b黑色素瘤2）IT注射可触及的不可切除的头颈癌3）IT注射可触及的肉瘤4）IT注射可触及的皮肤鳞状细胞癌一项两阶段自适应设计II期临床研究，针对单一肿瘤类型，包括一个先导阶段和一个扩展阶段，在先导阶段显示出最佳临床缓解。 初探性（SBIR I期部分）：每组将治疗10例志愿者患者，研究的初始初探性阶段共40例患者。治疗包括两个周期的肿瘤内（IT）Hiltonol预充加肌内（IM）Hiltonol（R）维持。在每个周期中，将靶向一个可触及的肿瘤部位，每周三次进行聚ICLC的初始IT注射，持续2周，然后每周两次进行IM维持，持续6周。第二个周期之后将是6周的无治疗休息期，以便在没有炎症的情况下评估第26周的肿瘤反应。 扩展（SBIR II期部分）：根据研究初步阶段每个肿瘤组患者的安全性和临床应答，将选择4个组中的1个组在26周时在最初10例患者中至少2例患者中显示IRRC定义的疾病稳定或消退，用于本提案下的进一步研究。适当的适应症特定统计数据 将被应用，估计将有60名额外的患者加入该组，该组估计共有70名患者。应计目标可能会根据响应程度、收集的其他数据以及计划与FDA举行的行业会议的结果进行进一步修改。将使用Kaplan-Meir曲线估计生存期和PFS。

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(R) 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.