Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Cancer Chemother Pharmacol. 2010 Nov;66(6):1079-85. doi: 10.1007/s00280-010-1265-5. Epub 2010 Feb 18.
To establish the safety, maximum tolerated dose (MTD), recommended phase II dose, and preliminary antitumor activity of obatoclax mesylate (GX15-070MS), a Bcl-2 antagonist, in combination with topotecan in patients with solid tumor malignancies.
Patients with solid tumor malignancies for whom topotecan was an appropriate treatment were administered obatoclax mesylate and topotecan on a 3-week cycle in a pre-defined, standard 3 + 3 dose escalation scheme. The starting dose for obatoclax mesylate was 14 mg/m(2) by 3-h intravenous (IV) infusion. Topotecan 1.25 mg/m(2) was given concurrently as an IV infusion on days 1-5 of each cycle.
Fourteen patients received 40 cycles of obatoclax mesylate at the following doses: 14 mg/m(2) on day 1, 14 mg/m(2) on days 1 and 3, and 20 mg/m(2) on day 1. The most common toxicities related to obatoclax were neurologic, including ataxia, mood alterations, somnolence, and cognitive dysfunction. The majority of these were grades 1 and 2 (88%). Two of five patients experienced dose-limiting grade 3 neurologic toxicity at a dose of 20 mg/m(2); no patients experienced grade 4 neurologic toxicities, and no other patients experienced grade 3 neurologic toxicity. Of the patients who experienced grade 3 neurologic events, one later developed febrile neutropenia, which was also a dose-limiting toxicity (DLT). After an additional three patients were treated without DLT at the previously tolerated dose of 14 mg/m(2) on day 1, the level was escalated to 14 mg/m(2) on days 1 and 3. Three patients were treated at this dose and, with none experiencing a DLT, 14 mg/m(2) on days 1 and 3 was defined as the recommended phase II dose. Two patients with small-cell lung cancer (SCLC) achieved partial responses and four patients had stable disease. Median time to progression (TTP) was 12 weeks.
Obatoclax mesylate administered at 14 mg/m(2) IV on days 1 and 3 is safe and well tolerated when given in combination with topotecan 1.25 mg/m(2) IV on days 1-5 of an every 3-week cycle. A phase II trial to assess the efficacy of this combination for patients with relapsed SCLC is currently accruing patients.
评估 Obatoclax 甲磺酸盐（GX15-070MS）与拓扑替康联合用于治疗固体肿瘤恶性肿瘤患者的安全性、最大耐受剂量（MTD）、推荐的 II 期剂量和初步抗肿瘤活性。
对于接受拓扑替康治疗的固体肿瘤恶性肿瘤患者，采用预定义的标准 3+3 剂量递增方案，每 3 周为一个周期，给予 Obatoclax 甲磺酸盐和拓扑替康治疗。Obatoclax 甲磺酸盐的起始剂量为 14mg/m2，静脉输注 3 小时。每个周期的第 1-5 天，同时给予拓扑替康 1.25mg/m2 静脉输注。
14 名患者接受了 40 个周期的 Obatoclax 甲磺酸盐治疗，剂量如下：第 1 天 14mg/m2，第 1 天和第 3 天 14mg/m2，第 1 天 20mg/m2。与 Obatoclax 相关的最常见毒性为神经毒性，包括共济失调、情绪改变、嗜睡和认知功能障碍。这些毒性大多数为 1 级和 2 级（88%）。5 名患者中有 2 名发生剂量限制性 3 级神经毒性，剂量为 20mg/m2；无患者发生 4 级神经毒性，也无其他患者发生 3 级神经毒性。发生 3 级神经事件的患者中，有 1 例随后发生发热性中性粒细胞减少症，也是剂量限制性毒性（DLT）。在另外 3 名患者以先前耐受的 14mg/m2 剂量（第 1 天）接受治疗而无 DLT 后，剂量水平提高至第 1 天和第 3 天的 14mg/m2。3 名患者接受了该剂量治疗，无 1 例发生 DLT，因此将第 1 天和第 3 天的 14mg/m2 定义为推荐的 II 期剂量。2 名小细胞肺癌（SCLC）患者获得部分缓解，4 名患者病情稳定。中位无进展生存期（TTP）为 12 周。
Obatoclax 甲磺酸盐在第 1 天和第 3 天静脉注射 14mg/m2，与拓扑替康 1.25mg/m2 联合应用，每 3 周 1 次，在第 1-5 天静脉注射，是安全且耐受良好的。目前正在进行一项评估该联合方案用于复发性 SCLC 患者疗效的 II 期试验。
