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 （poly-ICLC）是一种稳定的dsRNA治疗性病毒模拟物或“危险信号”，可激活先天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，它会产生全面的Th-1加权免疫反应，最适合抗病毒和抗肿瘤作用。该项目将Hiltonol与癌症患者自身的原位肿瘤抗原结合，产生针对肿瘤及其转移的全面全身免疫反应。目的：1)确定肿瘤内（IT） Poly-ICLC的安全性。2)通过irc定义的疾病控制和26周无进展生存期来探讨疗效。次要目标是总体生存和血液和肿瘤活检的免疫反应，包括免疫评分。适应症/肿瘤组：1)IT注射可切除的3b、3c或IV期、M1a或M1b期黑色素瘤2)IT注射可切除的头颈癌3)IT注射可切除的肉瘤4)IT注射可切除的皮肤鳞状细胞癌一项两阶段适应性设计II期临床研究，针对单一肿瘤类型进行试点和扩展，在试点阶段显示最佳临床反应。试点（SBIR I期）：每组10名志愿者患者将接受治疗，在研究的初始试点阶段共有40名患者。治疗包括肿瘤内（IT） Hiltonol注入和肌肉注射两个周期

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.