Interim analysis of promise, a clinical study combining the BET inhibitor OPN-2853 with ruxolitinib in patients with advanced myelofibrosis experiencing an inadequate response to ruxolitinib

Abstract

Abstract Background: Myelofibrosis (MF) a myeloproliferative neoplasm is characterised by progressive splenomegaly, cytopenia, debilitating symptoms, and leukemic progression. MF patients (pts) classified as Dynamic International Prognostic Scoring System (DIPSS) High or Intermediate-2 (Int-2) risk have median overall survival of 2-4 years (yrs). Ruxolitinib (rux) is approved for MF and effectively controls disease-related symptoms and splenomegaly in some pts; however, disease control is often inadequate and the disease eventually progresses, thus a major unmet medical need remains. In MF mouse models, the effects of rux are complemented by targeting BET (bromodomain and extra-terminal) proteins. BET and JAK inhibitor combinations have also demonstrated clinical activity in pts with MF, with reduction in spleen size, increase in hemoglobin levels, and alleviation of symptoms reported. Design and methods The Phase 1, multicentre, dose-finding PROMise trial (EudraCT 2019-000916-27) was designed to evaluate whether the BETi OPN-2853 could be safely combined with rux and restore or increase disease control in MF pts with inadequate response to single-agent rux. Eligible pts are ≥16 yrs, have primary or secondary DIPSS Int-2 or High MF, received ≥24 weeks (wks) of rux (stable dose prior 4 wks), and residual splenomegaly >5cm below costal margin. Two OPN-2853 doses (40 and 80mg QD) are evaluated with 2 rux dose groups (Low [5-20mg daily] and Mid/High [≥25mg daily]) in 21-day cycles. Spleen is assessed by ultrasound at Screening (SCR) and end Cycles 5 & 8, and by palpation at SCR, Day 1 every cycle, and end Cycle 8. Primary outcome measures are dose-limiting toxicities (DLTs) and >50% reduction in palpable spleen from SCR to end Cycle 8. Other key outcomes include adverse events (AEs), symptoms (MFSAF at SCR, Cycles 5 & 8), and molecular response. Current status Recruitment closed in June 2025. As of 05-March-2025, 24 pts have been treated (14 at 40 mg and 10 at 80 mg OPN-2853 QD, respectively; the majority [18/24] in Mid/High category for rux dosing). Median age was 70 yrs (range: 44 to 81) and 13/24 male. 54% of pts had primary MF, 46% secondary MF, 85% and 15% were Int-2 and high-risk respectively. The median baseline spleen length by ultrasound was 20.2 cm (IQR: 16.3 to 23). The median baseline spleen length by palpation was 9 cm (IQR: 6 to 15.3). At the time of analysis 16 pts had completed 8 cycles; with 11 of these continuing beyond that point. Two DLTs (thrombocytopenia and elevated ALT) have been reported; both were at 40 mg QD OPN-2853. AEs ≥ grade 3 include: platelet count decreased (6/24, 25%); anemia (2/24, 8.3%). The median (IQR) spleen size by palpation, calculated as the change from baseline to minimum post-baseline spleen size, reduced by 5.0 (4.8, 6.2) cm in 20 evaluable patients. Of the 9 evaluable pts with non-missing baseline and post baseline values, mean change from baseline to cycle 8 in Brief Fatigue Inventory score improved by 0.9 (95% CI: 0, 1.77). Conclusion Encouraging levels of spleen reduction and a manageable safety profile have been observed with combination OPN-2853 & rux treatment. Clinical activity observed is supported by symptom assessment and molecular data, and no patients experienced leukemic progression.