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

评估 SQ3370 在 1b 期剂量扩展队列中以推荐的 2 期剂量治疗晚期肉瘤患者的安全性和有效性

• 批准号: 10489789
• 负责人: Jose M Mejia Oneto
• 金额: $ 29.88万
• 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: 2021-09-16 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10489789
• 关键词: Acceleration; Accounting; Animals; Anthracycline; Attenuated; Biological; Biological Factors; Biological Markers; Biopolymers; Bone Marrow Suppression; Cancerous; Cardiotoxicity; Cessation of life; Characteristics; Chemistry; Clinical Trials; Cyclooctenes; Cytotoxic agent; Data; Development; Diagnosis; Disease; Dose; Doxorubicin; Drug Kinetics; Enrollment; Evaluation; Exhibits; Future; In Situ; Incidence; Injectable; Injections; Investigational New Drug Application; Knowledge; Life; Malignant Neoplasms; Methods; Oxygen; Patients; Persons; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Poisoning; Reaction; Recommendation; Refractory; Relapse; Safety; Site; Sodium Hyaluronate; Soft tissue sarcoma; Solid Neoplasm; Survival Rate; Tissues; Toxicity Attenuation; Tumor Promotion; United States Food and Drug Administration; cancer diagnosis; cancer type; chemotherapy; cohort; cytotoxic; design; first-in-human; immune activation; immune checkpoint blockade; immunogenic cell death; improved; lead candidate; mortality; neoplastic; novel therapeutics; objective response rate; phase I trial; phase II trial; pre-clinical; preclinical study; protein expression; safety assessment; sarcoma; side effect; systemic toxicity; treatment and outcome; 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, 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.

抽象的 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 万人。这些病例中，绝大多数是实体瘤， 新增病例超过 1600 万，癌症死亡人数超过 800 万。这包括软组织肉瘤 (STS)，一组异质性侵袭性恶性肿瘤，其 5 年生存率仅为 65%。在美国，预计 2020 年将有 13,000 人被诊断出患有 STS，超过 5,000 人将死亡 的疾病。对于诊断为 STS 的患者，治疗通常包括使用细胞毒剂进行化疗 例如多柔比星 (Dox)，一种蒽环类药物，已用于诱导多种肿瘤消退 肿瘤状况。 Dox 还可以诱导免疫原性细胞死亡并增强肿瘤 对免疫检查点阻断疗法的反应。不幸的是，Dox 在患者中的长期使用 受到严重毒副作用的限制——最显着的是不可逆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 的毒性和脱靶效应，同时保持其抗肿瘤功效 Shasqi 开发了 SQ3370，这是一种 新型药物产品将改善注射实体瘤患者的治疗 基于阿霉素（Dox）的化疗。迄今为止完成的临床前研究表明，SQ3370 结果 显着抑制肿瘤生长（注射和非注射肿瘤）、免疫激活、 延长生存期并防止肿瘤再攻击，同时减少全身副作用 与传统 Dox 相比的效果。 SQ3370 的广泛临床前数据已导致开放 向美国食品和药物管理局 (FDA) 提交研究性新药 (IND) 申请。第一阶段，首先- 目前正在招募人体剂量递增研究，以评估安全性/耐受性、药代动力学和 SQ3370对局部晚期或转移性实体瘤患者的初步疗效。这直接到 II 期申请寻求在达到推荐的 2 期剂量 (RP2D) 后扩大该试验 通过使用西蒙两阶段设计添加由 30 名软组织肉瘤患者组成的剂量扩展队列。 该项目的目的是评估 SQ3370 在该队列中的 1) 安全性/耐受性和 2) 功效，以确定 研究是否应进入二期临床试验。这些目标将加速 SQ3370 的开发， 新疗法有望最终改善数百万患者的治疗和结果 患有实体瘤。