Falcón Alejandro, Ponce Santiago, Cote Gregory M, Gil Ana, Lin Jessica J, Bockorny Bruno, Martínez Julia, Kahatt Carmen, Martinez Sara, Zubiaur Pablo, Siguero Mariano, Cullell-Young Martin, Jiménez Javier, Zugazagoitia Jon, Paz-Ares Luis
Servicio de Oncología Médica, Hospital Universitario Virgen del Rocio, Av. Manuel Siurot, S/N, 41013, Seville, Spain.
Hospital Universitario, 12 de Octubre, Madrid, Spain.
Invest New Drugs. 2025 Sep 18. doi: 10.1007/s10637-025-01583-y.
Lurbinectedin and irinotecan showed synergistic antitumor activity when combined in preclinical studies, and have non-completely overlapping toxicity profiles. A two-stage phase I/II trial was designed to evaluate the combination. The first (dose escalation) stage of the trial assessed two schedules, lurbinectedin on Day (D)1 plus irinotecan on D1,D8 or D1 every three weeks in 83 patients with relapsed advanced solid tumors. Two recommended doses (RDs) were defined for lurbinectedin on D1 plus irinotecan on D1,D8: lurbinectedin 2.0 mg/m plus irinotecan 75 mg/m, and lurbinectedin 3.0 mg/m plus irinotecan 40 mg/m, both with primary growth factor prophylaxis. No RD was defined for lurbinectedin on D1 plus irinotecan on D1. Lurbinectedin on D1 plus irinotecan on D1,D8 q3wk showed a manageable safety profile at the RDs, with most common toxicities being myelosuppression, fatigue and gastrointestinal disorders. No toxic deaths occurred. Thirteen confirmed partial responses and 24 disease stabilizations ≥ 4 months were found at all dose levels, including the RDs. Compared to other tumor types, antitumor activity was higher in small cell lung cancer (SCLC), soft tissue sarcoma (synovial), endometrial carcinoma, glioblastoma and pancreatic adenocarcinoma. No major pharmacokinetic interaction was found between lurbinectedin and irinotecan. The second (expansion) stage of the trial is evaluating the RD of lurbinectedin 2.0 mg/m plus irinotecan 75 mg/m with primary growth factor prophylaxis in selected advanced solid tumors. An ongoing phase III trial is also evaluating the combination in second-line SCLC after prior platinum-containing chemotherapy. Trial registration number: NCT02611024 (Nov 20, 2015).
在临床临床临床临床前研究中，鲁比卡丁与伊立替康联合使用时显示出协同抗肿瘤活性，且毒性特征并非完全重叠。一项两阶段的I/II期试验旨在评估该联合用药方案。试验的第一阶段（剂量递增阶段）评估了两种给药方案：在83例复发的晚期实体瘤患者中，第1天给予鲁比卡丁加第1天、第8天或每三周第1天给予伊立替康。确定了第1天给予鲁比卡丁加第1天、第8天给予伊立替康的两个推荐剂量（RDs）：鲁比卡丁2.0mg/m²加伊立替康75mg/m²，以及鲁比卡丁3.0mg/m²加伊立替康40mg/m²，两者均采用主要生长因子预防措施。未确定第1天给予鲁比卡丁加第1天给予伊立替康的推荐剂量。第1天给予鲁比卡丁加第1天、第8天每三周给予伊立替康在推荐剂量下显示出可控的安全性，最常见的毒性为骨髓抑制、疲劳和胃肠道疾病。未发生毒性死亡。在所有剂量水平，包括推荐剂量水平，发现13例确认的部分缓解和24例疾病稳定≥4个月。与其他肿瘤类型相比，小细胞肺癌（SCLC）、软组织肉瘤（滑膜）、子宫内膜癌、胶质母细胞瘤和胰腺腺癌的抗肿瘤活性更高。未发现鲁比卡丁与伊立替康之间存在主要的药代动力学相互作用。试验的第二阶段（扩展阶段）正在评估鲁比卡丁2.0mg/m²加伊立替康75mg/m²并采用主要生长因子预防措施在选定的晚期实体瘤中的推荐剂量。一项正在进行的III期试验也在评估该联合用药方案在含铂化疗后的二线小细胞肺癌中的疗效。试验注册号：NCT02611024（2015年11月20日）。
