Lessons learned: The combination of the antiangiogenic agent ziv-aflibercept and the heat shock protein 90 inhibitor ganetespib was associated with several serious and unexpected adverse events and was not tolerable on the dosing schedule tested.Studies such as these emphasize the importance of considering overlapping toxicities when designing novel treatment combination regimens.
Background: Although inhibition of angiogenesis is an effective strategy for cancer treatment, acquired resistance to antiangiogenic therapy is common. Heat shock protein 90 (Hsp90) is a molecular chaperone that regulates various oncogenic signaling pathways involved in acquired resistance and has been shown to play a role in angiogenesis. Combining an antiangiogenic agent with an Hsp90 inhibitor has therefore been proposed as a strategy for preventing resistance and improving antitumor activity. We conducted a single-arm phase I study evaluating the combination of ziv-aflibercept, an antiangiogenic drug, with the Hsp90 inhibitor ganetespib.
Methods: Adult patients were eligible if they had recurrent or metastatic gastrointestinal carcinomas, nonsquamous non-small cell lung carcinomas, urothelial carcinomas, or sarcomas that had progressed after at least one line of standard therapy. Ziv-aflibercept was administered intravenously on days 1 and 15, and ganetespib was administered intravenously on days 1, 8, and 15, of each 28-day cycle.
Results: Five patients were treated with the combination. Although three patients achieved stable disease, study treatment was associated with several serious and unexpected adverse events.
Conclusion: The dose escalation phase of this study was not completed, but the limited data obtained suggest that this combination may be too toxic when administered on this dosing schedule.
经验获取
• 抗血管生成剂阿柏西普与热休克蛋白90抑制剂 ganetespib 联合使用与一些严重及意外的不良事件有关,并且试验给药计划不耐受。
• 这些研究都强调了在设计新型治疗组合方案时考虑交叉毒性的重要性。
摘要
背景。虽然抑制血管生成是治疗癌症的有效策略,但血管生成治疗经常会造成获得性耐药。热休克蛋白 90(Hsp90) 是一种分子伴侣,可调节多种涉及获得性耐药的致癌信号通路,已被证明在血管生成中发挥重要作用。因此,抗血管生成剂与 Hsp90 抑制剂联合使用,被提出为一种预防耐药性和提高抗肿瘤活性的策略。我们开展了一项单组I期研究,评估抗血管生成药物阿柏西普与 Hsp90 抑制剂 ganetespib 联合使用的疗效。
方法. 符合条件的成年患者需患有复发或转移性胃肠道肿瘤、非鳞状非小细胞肺癌、尿路上皮癌或肉瘤经过至少一次标准治疗后出现进展。第1天和第15天静脉注射阿柏西普,第1天、第8天和第15天静脉注射 ganetespib,每28天为一疗程。
结果。 5例患者接受了联合治疗。虽然有3例患者病情稳定,但研究治疗与数种严重及意外的不良事件有关。
结论。本研究剂量递增阶段尚未完成,但所获得的有限数据表明,此剂量计划中的组合可能毒性过大。
Trial registration: ClinicalTrials.gov NCT02192541.
© AlphaMed Press; the data published online to support this summary are the property of the authors.