Purpose: While cytotoxic chemotherapy is standard first-line treatment for patients with metastatic soft tissue sarcoma (STS), clinical outcomes remain suboptimal. Our prior study showed lurbinectedin plus doxorubicin is well-tolerated with promising clinical activity in STS. We designed this phase 1b trial to optimize dosing as the basis for a randomized trial in leiomyosarcoma (LMS) and to further explore the safety profile and efficacy signal. Patients and Methods: Patients had advanced/metastatic STS and no prior anthracycline/lurbinectedin/trabectedin. Escalation followed a 3+3 design with 3-week cycles: lurbinectedin (3.2 mg/m2 day 1) and two doxorubicin levels (DL1: 25 mg/m2 day 1; DL2 25 mg/m2 days 1 and 8). The primary objectives were to identify the maximum tolerated dose (MTD) and recommended dose for subsequent randomized trials. Results: Ten patients were enrolled in a 6-month period. The most common treatment-emergent adverse events (TEAE) were grade (G) 2 fatigue and nausea, and G2 cytopenias with no febrile neutropenia events. There were 2 dose-limiting toxicities (DLTs) at DL2 (day 8 [G2 ALT/AST increase, G3 neutropenia]), and 1 DLT in DL1 (G3 ALT increase). These were reversible and all patients continued the study. DL1 was chosen for further study. At the time of data cutoff, the estimated median PFS is 16.5 months (95%CI 6.0-ND). The ORR was 60% (6/10 confirmed partial responses [PR]). Conclusions: In this phase 1b study, the recommended dose is lurbinectedin 3.2 mg/m2 in combination with doxorubicin 25 mg/m2 every 3 weeks. The study combination was well-tolerated and demonstrated intriguing clinical activity.

中文翻译：

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Lurbinectedin 加阿霉素组合治疗晚期/转移性软组织肉瘤患者的 1b 期试验的安全性和有效性

目的：虽然细胞毒性化疗是转移性软组织肉瘤 (STS) 患者的标准一线治疗，但临床结果仍然不理想。我们之前的研究表明 lurbinectedin 联合阿霉素具有良好的耐受性，在 STS 中具有良好的临床活性。我们设计这项 1b 期试验是为了优化剂量，作为平滑肌肉瘤 (LMS) 随机试验的基础，并进一步探索安全性和疗效信号。患者和方法：患者患有晚期/转移性 STS，且既往未接受过蒽环类/鲁比奈定/曲贝替定治疗。升级遵循 3+3 设计，周期为 3 周：lurbinectedin（第 1 天 3.2 mg/m2）和两个多柔比星水平（DL1：第 1 天 25 mg/m2；DL2 25 mg/m2 第 1 天和第 8 天）。主要目标是确定后续随机试验的最大耐受剂量 (MTD) 和推荐剂量。结果：6 个月期间招募了 10 名患者。最常见的治疗引起的不良事件 (TEAE) 是 (G) 2 级疲劳和恶心，以及 G2 血细胞减少症，无发热性中性粒细胞减少症事件。 DL2（第 8 天[G2 ALT/AST 增加，G3 中性粒细胞减少]）有 2 种剂量限制性毒性 (DLT)，DL1 中有 1 种 DLT（G3 ALT 增加）。这些都是可逆的，所有患者都继续研究。选择DL1进行进一步研究。截至数据截止时，估计中位 PFS 为 16.5 个月 (95% CI 6.0-ND)。 ORR 为 60%（6/10 确认部分缓解 [PR]）。结论：在这项 1b 期研究中，推荐剂量为 lurbinectedin 3.2 mg/m2 联合阿霉素 25 mg/m2，每 3 周一次。该研究组合具有良好的耐受性，并表现出令人感兴趣的临床活性。