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

Background

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm causing progressive splenomegaly, cytopenias, systemic symptoms and mortality. Ruxolitinib (rux), a JAK 1/2 inhibitor, is an approved treatment for MF which effectively controls disease related symptoms and splenomegaly in some patients. However, disease control is often inadequate and there is eventual disease progression. A major unmet medical need remains.

In mouse models of MF, the effects of rux are complemented by epigenetic inhibitors targeting BET (bromodomain and extra-terminal motif) proteins and combinations of BET and JAK inhibitors have shown promising initial clinical results. The PROMise clinical study was designed to test the hypothesis that the short-acting BET inhibitor OPN-2853 (previously called PLX2853) (T_1/2 = 1.3 hrs) would combine with rux to restore disease control in patients with inadequate disease control with single agent rux. Preclinical studies of OPN-2853 revealed potent ability to inhibit splenomegaly in a Ba/F3 model, and combinability with rux to delay disease in a SET-2 MF model.

Design and Methods

PROMise is a phase I, multicentre, dose finding trial being conducted in the UK to identify a safe and tolerable recommended Phase II Dose (RP2D) of OPN-2853 in combination with rux and to assess the efficacy of this combination in reducing spleen size in patients with high or intermediate-2 risk MF who are not adequately responding to rux alone. PROMise investigates three potential daily dose levels of OPN-2853: 20 mg, 40 mg and 80 mg. Eligible patients must be ≥ 16 years, have been on rux for at least 24 weeks, with a stable dose for at least 4 weeks, and must have persistent splenomegaly extending at least 5cm below the costal margin.

A maximum of 60 patients will be recruited across three rux dose groups: Low-Dose (5-20 mg daily), Mid-Dose (25-45 mg daily), and High-Dose (≥50 mg daily). Each rux group is evaluated separately, with dose recommendations made using the continual reassessment method, once 2 to 4 evaluable patients in the group have completed the first 21-day cycle. A co-primary outcome for the trial is a >50% reduction in palpable spleen size from screening at the end of 8 cycles. Spleen size is also evaluated by serial ultrasound. Serial blood and bone marrow samples are collected to measure molecular response, on-target transcriptional/epigenetic responses in myeloid and stem cells and other translational research exploratory endpoints. Additionally, pharmacokinetic samples are taken at specified time points to establish the PK properties of OPN-2853 in combination with rux.

Current Status

The PROMise trial is currently ongoing and open to recruitment. As of 12-Feb-2024, 16 patients have been evaluated; 6 were on low-dose rux, 8 on mid-dose and 2 on high-dose. Median age was 71 years with a median spleen size of 9 cm at screening. Median haemoglobin was 102 g/L. 56% of patients have primary myelofibrosis, 44% secondary myelofibrosis, 18% and 82% with MF-2 and MF-3, respectively. Whilst the RP2D is still being determined, early findings indicate that the combination therapy is well-tolerated with the majority of patients (10 of 16) completing 8 cycles of combination treatment. Two dose limiting toxicities have occurred to date (thrombocytopenia and raised liver transaminases) and all study arms are now recruiting at 80 mg dose level. Notably, grade 3 or above adverse events were infrequent with platelet count reduction (n=5, 31%) and anemia (n=2, 12.5%) the most common in patients receiving combination treatment. The median(range) spleen size, calculated as the change from baseline to minimum post-baseline spleen size, has reduced by 5 (0, 10) cm.

Conclusion

The ongoing PROMise study (EudraCT 2019-000916-27) combines a daily dose of OPN-2853 with standard of care ruxolitinib to test the hypothesis that a continuous daily dosing regimen of oral agents will improve disease burden. Encouraging levels of spleen reduction have been observed in the context of a well tolerated agent.