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

摘要 2018年，全球新诊断癌症的发病率估计超过1800万例，癌症- 相关死亡人数估计超过960万。在这些病例中，绝大多数是实体瘤，占 超过1600万新病例和800万癌症死亡病例。这包括软组织肉瘤（STS）， 异质性侵袭性恶性肿瘤组，5年生存率仅为65%。在 美国，据估计，到2020年，将有13,000人被诊断患有STS，5,000多人将死于STS。 疾病对于诊断为STS的患者，治疗通常涉及使用细胞毒性剂进行化疗，例如 如多柔比星（Dox），一种蒽环类抗生素，已用于在多种肿瘤中诱导肿瘤消退， 条件还已知Dox诱导免疫原性细胞死亡并增强肿瘤对免疫应答的反应性。 检查点阻断疗法。不幸的是，由于严重的毒副作用， 最显著的是不可逆的心脏毒性和骨髓抑制，这可能危及生命。 因此，迫切需要新的方法来降低药物的全身毒性和脱靶效应。 Dox在保持其抗肿瘤功效的同时，Shasqi开发了SQ 3370，这是一种新型药物产品， 改善接受基于阿霉素（Dox）的注射性实体瘤患者的治疗 化疗迄今为止进行的临床前研究表明，SQ 3370可显著抑制 肿瘤生长（注射和非注射肿瘤），免疫激活，延长生存期，和 对肿瘤再激发的保护，同时与 传统的Dox。SQ 3370的广泛临床前数据已导致开放研究新药（IND） 向美国食品药品监督管理局（FDA）申请。一项I期、首次人体、剂量递增研究 目前正在招募，以评价SQ 3370在以下患者中的安全性/耐受性、PK和初步疗效： 局部晚期或转移性实体瘤。这个直接到第二阶段的应用程序有两个主要目标：1） 获得SQ 3370免疫激活的额外机制见解，以支持进一步的临床开发; 2） 通过生产工艺优化和稳定性支持临床和商业开发 研究，这在5个具体目标中进一步描述。这些目标将加速SQ 3370的开发， 这一疗法有望最终改善数百万患有实体瘤的患者的治疗和结局， 肿瘤的

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.