A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Ruxolitinib Plus Parsaclisib in Patients with JAK- and PI3K-Inhibitor Treatment–Naive Myelofibrosis

Background: Ruxolitinib is a Janus kinase (JAK)1/JAK2 inhibitor that significantly improves outcomes in patients with myelofibrosis (MF). However, a subset of patients may experience a suboptimal response to ruxolitinib alone; deeper and more durable responses in these patients may potentially be achieved by combining ruxolitinib with agents that target other signaling pathways that mediate MF pathogenesis. Consistent with this, recent phase 2 data showed that the addition of the phosphatidylinositol 3 kinase (PI3K) δ inhibitor parsaclisib to ruxolitinib monotherapy resulted in additional alleviation of MF symptoms and splenomegaly in patients with MF (Yacoub A. EHA2021. PB1716).

Aims: This phase 3, randomized, double-blind study (INCB 50465-313, NCT04551066) evaluates the combination of ruxolitinib and parsaclisib in patients with MF who are naive to JAK and PI3K inhibitor therapies.

Methods: Eligible patients are ≥18 years of age with a diagnosis of primary MF, post–polycythemia vera MF, or post-essential thrombocythemia MF, have a Dynamic International Prognostic Scoring System (DIPSS; Passamonti F. Blood. 2010;115:1703–8) risk of at least intermediate (INT)-1, palpable spleen ≥5 cm below left subcostal margin, total symptom score ≥10 at screening on the Screening Symptom Form, Eastern Cooperative Oncology Group performance status of 0–2, and a life expectancy ≥24 weeks. Patients will be excluded if they previously received therapy with any JAK inhibitor, any PI3K inhibitor, any experimental or standard drug therapy for MF ≤3 months of first study dose, have recent history of inadequate bone marrow reserve (eg, platelet count <50×10⁹/L), or have inadequate liver or renal function at screening. Approximately 440 patients will be randomized (1:1) to ruxolitinib plus parsaclisib 5 mg once daily or ruxolitinib plus matching placebo, with stratification at randomization by DIPSS risk category (high vs INT-2 vs INT-1) and platelet count (≥100×10⁹/L vs 50 to <100×10⁹/L inclusive) (Figure 1). Treatment will begin on day 1, with starting ruxolitinib dose level determined by baseline platelet count and will continue as long as treatment is tolerated and discontinuation criteria are not met. When the last enrolled patient has completed 24 weeks of treatment, the study will be unblinded and patients randomized to ruxolitinib plus placebo who have adequate hematology parameters will be able to cross over to receive parsaclisib together with continued ruxolitinib. The primary objective is the evaluation and comparison of spleen volume at week 24 for patients who received ruxolitinib plus parsaclisib vs ruxolitinib plus placebo. Secondary objectives include evaluation and comparison of patient-reported MF symptoms, overall survival, time to onset and duration of response in spleen volume, and safety and tolerability of ruxolitinib plus parsaclisib vs ruxolitinib plus placebo. Sites are open across the United States, Europe, United Kingdom, and Asia.