Abstract CT236: 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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2021-07, Vol.81 (13_Supplement), p.CT236-CT236
• Main Authors: Kuykendall, Andrew T., Burke, Lea, Lakshminarayanan, Mani, Colucci, Philomena
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2021-CT236

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; eva