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

描述(申请人提供)：希尔托诺(PolyICLC)是一种稳定的dsRNA治疗性病毒模拟物或“危险信号”，可激活多种天然和获得性免疫元件。它是一种独立的免疫调节剂，但当与抗原适当结合时，它会产生一种全面的Th-1加权免疫反应，最适合于抗病毒和抗肿瘤行动。该项目将希尔托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系统免疫反应。目的：1)确定肿瘤内(IT)Poly-ICLC的安全性。2)探讨IRRC定义的疾病控制率和26周无进展生存期的疗效。次要目标是血液和肿瘤活检中的总体存活率和免疫反应，包括免疫评分。适应症/肿瘤分组：1)IT注射可触及的3b、3c或IV期、M1A或M1B期黑色素瘤2)IT注射可触及的无法切除的头颈癌3)IT注射可触及的皮肤鳞状细胞癌4)IT注射可触及的皮肤鳞状细胞癌研究设计：一项针对单一肿瘤类型的两阶段适应性设计II期临床研究，其中试点部分和延伸部分在试点阶段显示出最佳的临床疗效。Pilot(SBIR第一阶段)：每组将治疗10名志愿者患者，在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)希尔托诺注射和肌肉(IM)希尔托诺(R)维持。一个可接近的肿瘤部位将作为初始IT注射的目标，每周三次，持续2周，然后每周维持两次IM，每个周期持续6周。第二个周期之后是6周的非治疗休息期，以便在第26周时在没有炎症的情况下评估肿瘤的反应。扩展(SBIR第二阶段)：根据每个肿瘤组患者在试验阶段的安全性和临床反应，在最初的10个患者中，至少有两个患者在26周内表现出IRRC定义的疾病稳定或消退的4个组中的一个将被选择用于根据这项建议进行进一步研究。适当的、特定于适应症的统计数据 将适用，估计将为该群体增加60名患者，估计该群体中的患者总数为70人。应计目标可能会根据反应的程度、收集的其他数据以及计划与FDA举行的行业会议的结果而进一步修改。生存率和PFS将使用Kaplan-Meir曲线进行估计。

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.