Assessing the safety and efficacy of SQ3370 in a phase 1b dose-expansion cohort at the recommended Phase 2 dose in patients with advanced sarcoma

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， 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)，一组异质性侵袭性恶性肿瘤，5年生存率仅为 百分之六十五在美国，据估计，到2020年，将有13,000人被诊断患有STS，5,000多人将死亡 疾病。对于诊断为STS的患者，治疗通常涉及使用细胞毒性剂的化疗 如阿霉素（Dox），一种蒽环类抗生素，已用于诱导多种肿瘤消退， 肿瘤条件。还已知Dox诱导免疫原性细胞死亡并增强肿瘤细胞的增殖。 对免疫检查点阻断疗法的反应性。不幸的是，在病人中广泛使用Dox 受到严重毒副作用的限制，最明显的是不可逆的心脏毒性和骨髓抑制， 这会危及生命因此，迫切需要新的方法来减少系统性的 毒性和脱靶效应，同时保持其抗肿瘤疗效Shasqi开发了SQ 3370， 一种新的药物产品，将改善接受注射的实体瘤患者的治疗， 阿霉素（Dox）为基础的化疗。迄今为止进行的临床前研究表明，SQ 3370的结果 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，并防止肿瘤再激发，同时表现出降低的全身性副作用 与传统的Dox相比。SQ 3370的广泛临床前数据导致了一个开放的 向美国食品药品监督管理局（FDA）提交研究性新药（IND）申请。A第一阶段，首先- 目前正在招募一项人体剂量递增研究，以评价安全性/耐受性、药代动力学和 SQ 3370在局部晚期或转移性实体瘤患者中的初步疗效。这直接到 一旦达到推荐的II期剂量（RP 2D），II期申请寻求扩大本试验 通过使用Simon两阶段设计增加30例软组织肉瘤患者的剂量扩展队列。 本项目的目的是评估SQ 3370在该队列中的1）安全性/耐受性和2）疗效，以确定 研究是否应进入II期临床试验。这些目标将加速SQ 3370的开发， 有望最终改善数百万患者的治疗和结局的新疗法 有实体瘤

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, pharmacokinetics, and preliminary efficacy of SQ3370 in patients with locally advanced or metastatic solid tumors. This Direct to Phase II application seeks to expand this trial once the recommended Phase 2 dose (RP2D) has been reached by adding a dose expansion cohort of 30 patients with soft-tissue sarcoma using a Simon two-stage design. The aims of this project are to assess 1) safety/tolerability and 2) efficacy of SQ3370 in this cohort to determine if the study should proceed to a Phase 2 clinical trial. 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.