Immune Biomarker Assessment and Manufacturing Development for SQ3370-001, a first-in-human phase I dose-escalation clinical trial to test a novel treatment against advanced solid tumors

SQ3370-001 的免疫生物标志物评估和制造开发，这是一项首次人体 I 期剂量递增临床试验，旨在测试针对晚期实体瘤的新型治疗方法

• 批准号: 10381692
• 负责人: Jose M Mejia Oneto
• 金额: $ 80.11万
• 依托单位: SHASQI, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381692
• 关键词: Accounting; Animals; Anthracycline; Attenuated; Biocompatible Materials; Biological; Bone Marrow Suppression; Cancerous; Cardiotoxicity; Cessation of life; Clinical; Clinical Trials; Cyclooctenes; Cytometry; Cytotoxic T-Lymphocytes; Cytotoxic agent; Data; Development; Diagnosis; Disease; Dose; Doxorubicin; Enrollment; Evaluation; Exhibits; Funding; Goals; Guidelines; Helper-Inducer T-Lymphocyte; Human; Immune system; Immunohistochemistry; Immunologic Markers; In Situ; Incidence; Injectable; Injections; International; Investigational New Drug Application; Life; Location; Malignant Neoplasms; Methods; Oxygen; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Pharmacologic Substance; Phase; Phase II Clinical Trials; Population; Process; Prodrugs; Production; Regulatory T-Lymphocyte; Safety; Sampling; Site; Sodium Hyaluronate; Soft tissue sarcoma; Solid Neoplasm; Survival Rate; Testing; Tissues; Toxic effect; Treatment outcome; Tumor-infiltrating immune cells; United States Food and Drug Administration; anti-tumor immune response; base; cancer diagnosis; cancer type; chemotherapy; clinical development; cytotoxic; data submission; first-in-human; immune activation; immune checkpoint blockade; immunogenic cell death; improved; insight; manufacturing process; mortality; neoplastic; novel; novel therapeutics; pre-clinical; preclinical study; process optimization; protein expression; side effect; stability testing; systemic toxicity; tumor; tumor growth

Abstract In 2018, the global incidence of new cancer diagnoses was estimated at over 18 million cases, and cancer- related deaths were estimated at over 9.6 million. Of these cases, the vast majority were solid tumors, accounting for more than 16 million new cases and 8 million cancer deaths. This includes soft tissue sarcoma (STS), a heterogeneous group of aggressive malignant tumors that have a poor 5-year survival rate of only 65%. In the U.S., an estimated 13,000 people will be diagnosed with STS in 2020, and more than 5,000 will die of the disease. For patients diagnosed with STS, treatment often involves chemotherapy with a cytotoxic agent such as doxorubicin (Dox), an anthracycline that has been used to induce tumor regression in a variety of neoplastic conditions. Dox is also known to induce immunogenic cell death and enhance tumor responsiveness to immune checkpoint blockade therapies. Unfortunately, the extended use of Dox in patients is limited by severe toxic side effects—most notably irreversible cardiotoxicity and bone marrow suppression—which can be life threatening. Therefore, there is an immediate need for new methods to reduce the systemic toxicity and off-target effects of Dox while maintaining its antitumor efficacy Shasqi has developed SQ3370, a novel drug product that will improve the treatment of patients with injectable solid tumors undergoing doxorubicin (Dox)-based chemotherapy. Preclinical studies done to-date have shown that SQ3370 results in significant inhibition of tumor growth (both injected and non-injected tumors), immune activation, prolonged survival, and protection against tumor rechallenge, while exhibiting reduced systemic side effects compared to conventional Dox. Extensive preclinical data with SQ3370 has led to an open investigational new drug (IND) application with the U.S. Food and Drug Administration (FDA). A Phase 1, first-in-human, dose-escalation study is currently enrolling, to evaluate the safety/tolerability, PK, and preliminary efficacy of SQ3370 in patients with locally advanced or metastatic solid tumors. This Direct-to-Phase-2 application has two main objectives: 1) To gain additional mechanistic insight of SQ3370 immune activation to support further clinical development; 2) To support both clinical and commercial development through manufacturing process optimization and stability studies, that is further described in 5 Specific Aims. These aims will accelerate development of SQ3370, a novel therapy that promises to ultimately result in improved treatment and outcomes for millions of patients with solid tumors.

摘要 2018年，全球癌症新诊断发病率估计超过1800万例，而癌症- 据估计，相关死亡人数超过960万人。在这些病例中，绝大多数是实体瘤，占 1600多万新病例和800多万癌症死亡。包括软组织肉瘤(STS)、 异质性侵袭性恶性肿瘤的5年生存率较差，仅为65%。在 在美国，预计2020年将有13,000人被诊断为性传播疾病，超过5,000人将死于 疾病。对于被诊断为STS的患者，治疗通常包括使用细胞毒剂进行化疗，如 如阿霉素(Dox)，一种已被用于诱导多种肿瘤患者肿瘤消退的蒽环类药物 条件。DOX还可以诱导免疫原性细胞死亡，增强肿瘤对免疫的反应性 检查站封锁疗法。不幸的是，Dox在患者中的推广使用受到严重毒副作用的限制 影响--最明显的是不可逆转的心脏毒性和骨髓抑制--可能危及生命。 因此，迫切需要新的方法来减少全身性毒性和脱靶效应。 DOX在保持其抗肿瘤功效的同时，开发了SQ3370，这是一种新的药物产品，将 改善以阿霉素为基础的可注射实体瘤患者的治疗 化疗。到目前为止所做的临床前研究表明，SQ3370导致显著抑制 肿瘤生长(包括注射和非注射肿瘤)、免疫激活、延长生存期和 对肿瘤再挑战的保护，同时显示出与 传统的Dox。SQ3370的大量临床前数据导致了一种开放的研究新药(IND) 向美国食品和药物管理局(FDA)提出申请。一项第一阶段的人类首例剂量递增研究 目前正在招募，以评估SQ3370在慢性阻塞性肺疾病患者中的安全性/耐受性、PK和初步疗效 局部进展期或转移性实体瘤。这一直接到第二阶段的应用有两个主要目标：1) 获得对SQ3370免疫激活的更多机制洞察，以支持进一步的临床开发；2) 通过制造流程优化和稳定性支持临床和商业开发 研究，这将在5个具体目标中进一步描述。这些目标将加速SQ3370这一小说的发展 有望最终改善数百万实体瘤患者的治疗和结果的治疗 肿瘤。