A Phase I Study of FOLFIRINOX Plus IPI-926, a Hedgehog Pathway Inhibitor, for Advanced Pancreatic Adenocarcinoma.
A Phase I Study of FOLFIRINOX Plus IPI-926, a Hedgehog Pathway Inhibitor, for Advanced Pancreatic Adenocarcinoma.
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DOI：
10.1097/mpa.0000000000000458
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发表时间：
2016-03
期刊：
影响因子：
2.9
通讯作者：
Kindler HL
中科院分区：
文献类型：
--
作者：
Ko AH;LoConte N;Tempero MA;Walker EJ;Kate Kelley R;Lewis S;Chang WC;Kantoff E;Vannier MW;Catenacci DV;Venook AP;Kindler HL
在胰腺癌小鼠模型中，IPI-926（一种口服 Hedgehog 抑制剂）通过消耗肿瘤相关基质来增加化疗的递送。这项多中心 Ib 期研究评估了 IPI-926 联合 FOLFIRINOX（5-氟尿嘧啶、亚叶酸、伊立替康、奥沙利铂）治疗晚期胰腺癌患者的情况。患者接受每日一次的 IPI-926 加 FOLFIRINOX 治疗。采用 3 + 3 剂量递增设计，以最大耐受剂量进行队列扩展。一部分患者接受灌注计算机断层扫描以评估肿瘤灌注的变化。确定最大耐受剂量比标准 FOLFIRINOX 低 1 个剂量水平。常见的治疗相关不良事件包括肝功能测试异常、神经病变、恶心/呕吐和腹泻。客观缓解率很高（67%），接受 IPI-926 维持治疗的患者即使在 FOLFIRINOX 停药后，CA19-9 水平仍进一步下降。治疗并未导致肿瘤灌注持续增加。当 IPI-926 加吉西他滨的单独 II 期试验表明该组合存在有害影响时，该研究提前结束。这是第一项证明在临床试验设计中使用 FOLFIRINOX 作为化疗骨干的可行性的研究。尽管在该方案中添加 IPI-926 观察到强大的抗肿瘤活性和可接受的安全性，但未来在胰腺癌中开发 Hedgehog 抑制剂似乎不太可能。
In mouse models of pancreatic cancer, IPI-926, an oral Hedgehog inhibitor, increases chemotherapy delivery by depleting tumor-associated stroma. This multicenter phase Ib study evaluated IPI-926 in combination with FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) in patients with advanced pancreatic cancer. Patients were treated with once-daily IPI-926 plus FOLFIRINOX. A 3 + 3 dose escalation design was used, with cohort expansion at the maximum tolerated dose. A subset of patients underwent perfusion computed tomography to assess changes in tumor perfusion. The maximum tolerated dose was identified 1 dose level below standard FOLFIRINOX. Common treatment-related adverse events included liver function test abnormalities, neuropathy, nausea/vomiting, and diarrhea. Objective response rate was high (67%), and patients receiving IPI-926 maintenance showed further declines in CA19-9 levels even after FOLFIRINOX discontinuation. Treatment did not result in consistent increases in tumor perfusion. The study closed early when a separate phase II trial of IPI-926 plus gemcitabine indicated detrimental effects of this combination. This is the first study to demonstrate the feasibility of using FOLFIRINOX as the chemotherapeutic backbone in a clinical trial design. Although robust antitumor activity and acceptable safety were observed with the addition of IPI-926 to this regimen, future development of Hedgehog inhibitors in pancreatic cancer seems unlikely.