A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus nab‐Paclitaxel and Gemcitabine in Advanced Solid Tumors

• Published in: The oncologist (Dayton, Ohio) Ohio), 2019-01, Vol.24 (1), p.14-e10
• Main Authors: Beatty, Gregory L, Shahda, Safi, Beck, Thaddeus, Uppal, Nikhil, Cohen, Steven J, Donehower, Ross, Gabayan, Afshin Eli, Assad, Albert, Switzky, Julie, Zhen, Huiling, Von Hoff, Daniel D
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Clinical Trial Results; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Female; Humans; Janus Kinase 1 - antagonists & inhibitors; Male; Neoplasms - drug therapy; Neoplasms - pathology; Treatment Outcome
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2017-0665

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