Study of Parsaclisib Plus Ruxolitinib in Myelofibrosis Discontinued

The phase 3 LIMBER-304 study (NCT04551053) has been discontinued because it was unlikely to meet its primary end point of spleen reduction in patients with myelofibrosis, according to a press release from Incyte.¹

At a preplanned interim analysis, an independent data monitoring committee determined the combination trial investigating ruxolitinib (Jakafi) and parsaclisib was not expected to meet the primary end point, leading the company to discontinue the trial. They also stated that safety was not a reason for the study’s termination.

In the double-blind phase 3 LIMBER-304 trial, patients who were already receiving ruxolitinib to manage symptoms of myelofibrosis but had a suboptimal response were randomly assigned on a 1:1 basis to receive ruxolitinib with parsaclisib versus ruxolitinib with placebo.

Ruxolitinib, an oral Janus kinase inhibitor, is a standard-of-care treatment for higher-risk myelofibrosis in patients with platelet count of at least 50 × 109/L. Parsaclisib is a next-generation, investigational oral PI3Kδ inhibitor. Its New Drug Application for use in relapsed or refractory follicular lymphoma, marginal zone lymphoma, and mantle cell lymphoma was withdrawn in January 2022; however, the company stated that this was due to business reasons rather than changes in efficacy or safety results, and it would not impact other clinical trials.²

Suboptimal response was determined if after at least 3 months on ruxolitinib, patients had palpable spleen at least 5 cm below the left subcostal margin. Patients in the LIMBER-304 study received parsaclisib for 8 weeks in combination with stable-dose ruxolitinib. Patients were stratified by platelet count of 50 × 109/L to 100 × 109/L versus above 100 × 109/L, as well as DIPSS (Dynamic International Prognostic Scoring System) scores of high versus intermediate-2 versus intermediate-1.

The primary end point was the proportion of patients achieving a targeted reduction in spleen volume from baseline to week 24 as determined by MRI or CT scan. Key secondary end points included the proportion of patients with a targeted reduction in Total Symptom Score, change in Total Symptom Score, overall survival, time to targeted reduction in spleen volume, and number of treatment-emergent adverse events.¹ The estimated enrollment was 212 patients.

In a completed phase 2 trial of the combination (NCT02718300), patients with a suboptimal response to ruxolitinib showed a median 15.4% reduction in spleen volume at 12 weeks and a 19.3% reduction at 24 weeks after receiving 8 weeks of parsaclisib added to ruxolitinib, followed by a continued daily dose of parsaclisib.³ Those who changed to a weekly dose of parsaclisib after 8 weeks of the daily dose had a 1.6% median spleen volume reduction at 12 weeks and 2.5% reduction at 24 weeks. The most frequent grade 3 and 4 adverse event observed was thrombocytopenia.

The phase 3 randomized LIMBER-313 trial (NCT04551066), investigating this combination in patients who have not received prior ruxolitinib, has not yet reported its outcomes. Incyte stated that data from the LIMBER-304 trial would be presented at an upcoming scientific meeting.¹

_References:

_{1. Incyte provides update on interim analysis of phase 3 LIMBER-304 study of parsaclisib and ruxolitinib in patients with myelofibrosis. News release. Incyte. March 3, 2023. Accessed March 6, 2023. https://bit.ly/3yeLpYd}

_{2. Incyte provides update on parsaclisib and MCLA-145. News release. Incyte; January 25, 2022. Accessed March 7, 2023. https://bwnews.pr/3JhH10G}

_{3. Yacoub A, Borate U, Rampal RK, et al. Efficacy and safety of add-on parsaclisib to ruxolitinib therapy in myelofibrosis patients with suboptimal response to ruxolitinib: final results from a phase 2 study. Blood. 2022;140(supplement 1):579-582. doi:10.1182/blood-2022-160384}