Background: Ruxolitinib (JAK1/JAK2 inhibitor) and fedratinib (JAK2/FLT3 inhibitor) are indicated in the US for myelofibrosis (MF); however, some patients fail to achieve adequate/sustained response to initial JAK-inhibitor therapy. Itacitinib is a potent JAK inhibitor selective for JAK1 over JAK2 when administered as a once-daily sustained-release (SR) formulation. In prior clinical trials, the SR formulation improved MF-related symptoms but had less effect with respect to spleen volume reduction. When dosed as a twice-daily (BID) immediate release (IR) formulation, itacitinib may offer increased JAK2 inhibition (in addition to JAK1 inhibition) to better address the JAK2-mediated myeloproliferative features of MF. This open-label phase 2 study is designed to determine a tolerable and safe dose of itacitinib IR that results in clinically significant reductions in symptoms and spleen volume in patients with MF who have previously received ruxolitinib and/or fedratinib monotherapy (INCB 39110-213; NCT04629508). Methods: Eligible patients are aged ≥18 years, diagnosed with at least INT-1 risk (Dynamic International Prognostic Scoring System [Passamonti. Blood. 2010;115:1703-1708]) primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF and have received ruxolitinib and/or fedratinib monotherapy. Patients must also have palpable splenomegaly and platelets ≥50×109/L at screening. Exclusion criteria include receipt of a JAK inhibitor other than ruxolitinib or fedratinib, ≥10% myeloid blasts in peripheral blood or bone marrow, or inability to taper ruxolitinib/fedratinib over 14 days without use of other agents. Two itacitinib IR dose levels (DLs) will be evaluated in part 1 following a Bayesian optimal interval design algorithm: 3-9 patients will be enrolled at DL1 (300 mg BID) and observed for 28 days for dose-limiting toxicity before enrollment at DL2 (600 mg BID). Part 2 will enroll ~55 patients at the recommended phase 2 dose (RP2D) determined in part 1. Patients may remain on treatment until week 48 if they are receiving clinical benefit and have not met study withdrawal criteria. A safety follow-up will occur 30 days after treatment completion. Primary objectives: part 1 - evaluate safety and tolerability of itacitinib IR and select the RP2D; part 2 - evaluate efficacy of itacitinib IR at the RP2D based on spleen volume reduction at week 24. Secondary objectives (part 2 only): evaluate safety and tolerability of itacitinib IR; evaluate efficacy of itacitinib IR with respect to MF symptom improvement at week 24 in patients with baseline total symptom score ≥10, quality-of-life improvement, and patient global impression of change. Sites are opening in the US and EU.

Citation Format: Andrew T. Kuykendall, Lea Burke, Mani Lakshminarayanan, Philomena Colucci. A Two-Part Phase 2 Study of Itacitinib Immediate Release in Patients with Primary or Secondary Myelofibrosis Who Have Received Prior Ruxolitinib and/or Fedratinib Monotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT236.