Lessons learned: Itacitinib in combination with nab-paclitaxel plus gemcitabine demonstrated an acceptable safety profile with clinical activity in patients with advanced solid tumors including pancreatic cancer.The results support future studies of itacitinib as a component of combination regimens with other immunologic and targeted small molecule anticancer agents.
Background: Cytokine-mediated signaling via JAK/STAT is central to tumor growth, survival, and systemic inflammation, which is associated with cancer cachexia, particularly in pancreatic cancer. Because of their centrality in the pathogenesis of cancer cachexia and progression, JAK isozymes have emerged as promising therapeutic targets. Preclinical studies have demonstrated antiproliferative effects of JAK/STAT pathway inhibition in both in vitro and in vivo models of cancer, including pancreatic cancer.
Methods: This phase Ib/II dose-optimization study assessed itacitinib, a selective JAK1 inhibitor, combined with nab-paclitaxel plus gemcitabine in adults with treatment-naïve advanced/metastatic disease (Part 1) or pancreatic adenocarcinoma (Parts 2/2A; NCT01858883). Starting doses (Part 1) were itacitinib 400 mg, nab-paclitaxel 125 mg/m2, and gemcitabine 1,000 mg/m2. Additional dose levels incorporated were granulocyte colony-stimulating factor, de-escalations of itacitinib to 300 mg once daily (QD), nab-paclitaxel to 100 mg/m2, and gemcitabine to 750 mg/m2.
Results: Among 55 patients in Part 1, 6 developed seven hematologic dose-limiting toxicities (Cycle 1). Itacitinib 300 mg plus nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 was tolerated and expanded in Part 2. Treatment discontinuation and grade 3/4 neutropenia rates prompted itacitinib de-escalation to 200 mg QD in Part 2A. The most common grade 3/4 toxicities were fatigue and neutropenia. Partial responses occurred across all itacitinib doses and several tumor types (overall response rate, 24%).
Conclusion: Itacitinib plus chemotherapy demonstrated acceptable safety and clinical activity in patients with advanced solid tumors including pancreatic cancers. This study was terminated early (sponsor's decision) based on negative phase III results for a JAK1/2 inhibitor in previously treated advanced pancreatic cancer.
经验获取
• Itacitinib 和白蛋白结合型紫杉醇及吉西他滨联合治疗在晚期实体肿瘤(包括胰腺癌)患者中显示出可接受的安全特性与临床活性。
• 研究结果支持将 Itacitinib 作为含有其他免疫和靶向小分子抗癌剂的联合治疗的组成部分开展未来研究。
摘要
背景。通过 JAK/STAT 的细胞因子介导信号传导对于肿瘤生长、生存以及与癌症恶病质(特别是胰腺癌)相关的系统性炎症而言,至关重要。由于 JAK 同工酶在癌症恶病质和癌症进展的致病机制中具有重要地位,它们现已成为有希望的治疗靶点。临床前研究已经证明 JAK/STAT 通路抑制在癌症(包括胰腺癌)的体外和体内模型中具有抗增殖作用。
方法。本次 Ib/II 期剂量优化研究对既往未接受治疗的晚期/转移性癌(第 1 部分)或胰腺癌(第 2/2A 部分;NCT01858883)成年患者的 Itacitinib(一种选择性的 JAK1 抑制剂)和白蛋白结合型紫杉醇及吉西他滨联合治疗进行了评估。初始剂量(第 1 部分)为 Itacitinib 400 mg,白蛋白结合型紫杉醇 125 mg/m2,吉西他滨 1 000 mg/m2。加入的额外剂量是粒细胞集落刺激因子,Itacitinib 降至 300 mg,每天给药一次 (QD),白蛋白结合型紫杉醇降至 100 mg/m2,吉西他滨降至 750 mg/m2。
结果。在第 1 部分中的 55 名患者中,有 6 名患者出现七次血液学剂量限制性毒性(第 1 周期)。在第 2 部分中,可以耐受和扩展 Itacitinib 300 mg 和白蛋白结合型紫杉醇 125 mg/m2 及吉西他滨 1 000 mg/m2 联合治疗。在第 2A 部分中,治疗终止以及 3/4 级嗜中性粒细胞减少症比率导致 Itacitinib 降至 200 mg QD。最常见的 3/4 级毒性为疲劳和嗜中性粒细胞减少症。部分缓解在所有 Itacitinib 剂量和几种肿瘤类型中均有出现(总缓解率为 24%)。
结论。Itacitinib 联合化疗在晚期实体肿瘤(包括胰腺癌)患者中显示出可接受的安全性与临床活性。基于 JAK1/2 抑制剂在经治的晚期胰腺癌中的阴性 III 期结果,本研究提前终止(由申办方决定)。
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