H. Lee Moffitt Cancer Center and Research Institute, Thoracic Oncology Program, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Br J Cancer. 2012 Feb 28;106(5):839-45. doi: 10.1038/bjc.2012.21. Epub 2012 Feb 14.
Bcl-2 family genes are frequently amplified in small cell lung cancer (SCLC). A phase I trial was conducted to evaluate the safety of obatoclax, a Bcl-2 family inhibitor, given in combination with standard chemotherapy.
Eligible patients (3-6 per cohort) had extensive-stage SCLC, measurable disease, ≤ 1 before therapy, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients were treated with escalating doses of obatoclax, either as a 3- or 24-h infusion, on days 1-3 of a 21-day cycle, in combination with carboplatin (area under the curve 5, day 1 only) and etoposide (100 mg m(-2), days 1-3). The primary endpoint was to determine the maximum tolerated dose of obatoclax.
Twenty-five patients (56% male; median age 66 years) were enrolled in three dose cohorts for each schedule. Maximum tolerated dose was established with the 3-h infusion at 30 mg per day and was not reached with the 24-h infusion. Compared with the 24-h cohorts, the 3-h cohorts had higher incidence of central nervous system (CNS) adverse events (AEs); dose-limiting toxicities were somnolence, euphoria, and disorientation. These CNS AEs were transient, resolving shortly after the end of infusion, and without sequelae. The response rate was 81% in the 3-h and 44% in the 24-h infusion cohorts.
Although associated with a higher incidence of transient CNS AEs than the 24-h infusion, 3-h obatoclax infusion combined with carboplatin-etoposide was generally well tolerated at doses of 30 mg per day. Though patient numbers were small, there was a suggestion of improved efficacy in the 3-h infusion group. Obatoclax 30 mg infused intravenously over 3 h on 3 consecutive days will be utilised in future SCLC studies.
Bcl-2 家族基因在小细胞肺癌（SCLC）中经常扩增。进行了一项 I 期试验，以评估 obatoclax（一种 Bcl-2 家族抑制剂）与标准化疗联合使用的安全性。
符合条件的患者（每个队列 3-6 人）患有广泛期 SCLC，可测量疾病，治疗前≤1，东部合作肿瘤学组表现状态 0 或 1，以及足够的器官功能。患者接受递增剂量的 obatoclax 治疗，3 小时或 24 小时输注，在 21 天周期的第 1-3 天，联合卡铂（第 1 天仅 AUC5）和依托泊苷（100mg/m²，第 1-3 天）。主要终点是确定 obatoclax 的最大耐受剂量。
每个方案的三个剂量队列中各招募了 25 名患者（56%为男性；中位年龄 66 岁）。3 小时输注的最大耐受剂量为 30mg/天，24 小时输注未达到。与 24 小时队列相比，3 小时队列的中枢神经系统（CNS）不良事件（AE）发生率更高；剂量限制毒性为嗜睡、欣快和定向障碍。这些 CNS AE 是短暂的，在输注结束后不久就会消退，且没有后遗症。3 小时组的缓解率为 81%，24 小时组为 44%。
尽管与 24 小时输注相比，3 小时 obatoclax 输注与更高的中枢神经系统 AE 发生率相关，但在 30mg/天的剂量下，与卡铂-依托泊苷联合使用通常耐受性良好。尽管患者人数较少，但 3 小时输注组的疗效有所提高。未来的 SCLC 研究将采用 3 小时静脉输注 30mg 奥巴妥克拉。
