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800万癌症死亡。这包括软组织肉瘤。 (STS)，一组不同种类的侵袭性恶性肿瘤，其5年生存率仅为 65%。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人将死亡 这种疾病的危害。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 例如阿霉素(Dox)，这是一种已被用来诱导多种肿瘤消退的蒽环类药物 肿瘤的情况。DOX还可以诱导免疫原性细胞死亡和增强肿瘤 对免疫检查点阻断疗法的反应性。不幸的是，Dox在患者中的广泛使用 受到严重毒副作用的限制-最明显的是不可逆转的心脏毒性和骨髓抑制- 这可能会危及生命。因此，迫切需要新的方法来减少系统性的 Dox的毒性和靶外效应在保持其抗肿瘤效果的同时，沙旗开发出了SQ3370，一种 将改善可注射实体肿瘤患者治疗的新药物产品 以阿霉素(Dox)为基础的化疗。到目前为止所做的临床前研究表明，SQ3370结果 在显著抑制肿瘤生长(注射和非注射肿瘤)、免疫激活、 延长生存时间，保护肿瘤免受再挑战，同时全身副作用减少 与传统Dox相比，效果更佳。SQ3370的大量临床前数据导致了一个开放的 美国食品和药物管理局(FDA)的研究性新药(IND)申请。A阶段1，首先- 在人体内，剂量递增研究目前正在登记，以评估安全性/耐受性、药代动力学和 SQ3370治疗局部晚期或转移性实体瘤的初步疗效此直接发送至 一旦达到推荐的第二阶段剂量(RP2D)，第二阶段应用程序寻求扩大该试验 通过使用Simon两阶段设计增加30名软组织肉瘤患者的剂量扩展队列。 该项目的目的是评估1)安全性/耐受性和2)SQ3370在该队列中的有效性，以确定 这项研究是否应该进行二期临床试验。这些目标将加快SQ3370的发展， 有望最终改善数百万患者的治疗和结果的新疗法 患有实体瘤。

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.