Vlahovic Gordana, Karantza Vassiliki, Wang Ding, Cosgrove David, Rudersdorf Nikita, Yang Jianning, Xiong Hao, Busman Todd, Mabry Mack
Duke University Medical Center, Rm. 047 Baker House, Trent Drive, DUMC 3624, Durham, NC, 27710, USA,
Invest New Drugs. 2014 Oct;32(5):976-84. doi: 10.1007/s10637-014-0116-3. Epub 2014 Jun 5.
Bcl-2 family proteins are the key regulators of the intrinsic apoptotic pathway, controlling the point-of no-return and setting the threshold to engage the death machinery in response to chemical damage. Bcl-2 proteins have emerged as attractive targets for anti-cancer drug development. Navitoclax is a selective, potent, orally bioavailable, small molecule Bcl-2 inhibitor. Primary endpoints assessed the safety and pharmacokinetic (PK) interactions between navitoclax in combination with carboplatin/paclitaxel or paclitaxel alone in patients with solid tumors The study comprised two arms, one a combination of navitoclax with paclitaxel and carboplatin, the second with navitoclax and paclitaxel alone. Nineteen patients were enrolled in this study. The most frequently reported treatment-emergent AEs were alopecia (57.9 %), anemia (52.6 %), nausea (52.6 %), constipation (42.1 %), diarrhea (42.1 %), fatigue (42.1 %), neutropenia (36.8 %), thrombocytopenia (36.8 %), vomiting (31.6 %), decreased appetite (31.6 %), dehydration (26.3 %), and hypomagnesaemia (26.3 %). In the light of significant hematological and non-hematological toxicity the study was ended before de-escalation of navitoclax. Only one partial response was obtained at any dose tested, thus lowering doses could not have increased efficacy. It is the combination of toxicity with modest efficacy that led to discontinuation. No apparent PK interaction was observed between navitoclax and carboplatin or paclitaxel and the combination of navitoclax and paclitaxel had modest anti-tumor activity.
Bcl-2家族蛋白是内源性凋亡途径的关键调节因子，控制着细胞凋亡的不可逆转点，并设定了响应化学损伤而启动死亡机制的阈值。Bcl-2蛋白已成为抗癌药物开发的有吸引力的靶点。维托克拉克斯是一种选择性、强效、口服生物可利用的小分子Bcl-2抑制剂。主要终点评估了维托克拉克斯与卡铂/紫杉醇联合使用或单独使用紫杉醇在实体瘤患者中的安全性和药代动力学（PK）相互作用。该研究包括两个组，一组是维托克拉克斯与紫杉醇和卡铂联合使用，另一组是维托克拉克斯与紫杉醇单独使用。19名患者参加了这项研究。最常报告的治疗中出现的不良事件是脱发（57.9%）、贫血（52.6%）、恶心（52.6%）、便秘（42.1%）、腹泻（42.1%）、疲劳（42.1%）、中性粒细胞减少（36.8%）、血小板减少（36.8%）、呕吐（31.6%）、食欲下降（31.6%）、脱水（26.3%）和低镁血症（26.3%）。鉴于显著的血液学和非血液学毒性，该研究在维托克拉克斯剂量递减前结束。在任何测试剂量下仅获得一例部分缓解，因此降低剂量不可能提高疗效。正是毒性与适度疗效的结合导致了试验的终止。未观察到维托克拉克斯与卡铂或紫杉醇之间有明显的PK相互作用，维托克拉克斯与紫杉醇联合使用具有适度的抗肿瘤活性。
