A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus nab-Paclitaxel and Gemcitabine in Advanced Solid Tumors
Abstract
Training learned: Itacitinib in conjunction with nab-paclitaxel plus gemcitabine shown a suitable safety profile with clinical activity in patients with advanced solid tumors including pancreatic cancer.The outcomes support future studies of itacitinib as a part of combination regimens along 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, that is connected with cancer cachexia, specifically in pancreatic cancer. Due to their centrality within the pathogenesis of cancer cachexia and progression, JAK isozymes emerged as promising therapeutic targets. Preclinical research has shown antiproliferative results of JAK/STAT path inhibition both in in vitro as well as in vivo types of cancer, including pancreatic cancer.
Methods: This phase Ib/II dose-optimization study assessed itacitinib, a selective JAK1 inhibitor, coupled with nab-paclitaxel plus gemcitabine in grown-ups with treatment-naïve advanced/metastatic disease (Part 1) or pancreatic adenocarcinoma (Parts 2/2A NCT01858883). Beginning 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 partly 1, 6 developed seven hematologic dose-restricting toxicities (Cycle 1). Itacitinib 300 mg plus nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 was tolerated and expanded partly 2. Treatment stopping and grade 3/4 neutropenia rates motivated itacitinib de-escalation to 200 mg QD partly 2A. The most typical grade 3/4 toxicities were fatigue and neutropenia. Partial responses happened across all itacitinib doses and many tumor types (overall response rate, 24%).
Conclusion: Itacitinib plus chemotherapy shown acceptable safety and clinical activity in patients with advanced solid tumors including pancreatic cancers. This research was ended early (sponsor’s decision) according to negative phase III recent results for a JAK1/2 inhibitor in formerly treated advanced pancreatic cancer.