Trial in progress: A study of roginolisib in combination with ruxolitinib in patients with myelofibrosis who are unresponsive to JAK inhibitors (HEMA-MED)

Abstract Background and Significance. Inhibition of both the Phosphoinositide 3-kinase (PI3K) pathway and Janus kinase (JAK) signalling leads to decreased proliferation of cells from patients with myelofibrosis (MF) in clonogenic assays. In JAK2V617F knock-in mouse model of MF, the combined inhibition improved splenomegaly and survival (Bartalucci et al. 2013). In contrast to the first generation PI3K inhibitors, such as parsaclisib and umbralisib, roginolisib is a novel, oral, non-ATP competitive, allosteric small molecule inhibitor of PI3Kδ. Recent, we showed that roginolisib in combination with ruxolitinib inhibited proliferation of cells obtained from MF patients who were either naïve or resistant to ruxolitinib (Balliu M et al, this meeting, submitted). In its first-in-human (FiH) dose study (NCT04328844), 44 patients (36 with solid tumors and 8 with follicular lymphoma) received roginolisib with no drug-associated, PI3K inhibitor related, toxicities, nor needed dose modifications in the absence of a dose limiting toxicity (DLT). Study design and Methods. The HEMA-MED trial (NCT06887803) is prospective, multi-center, open-label Phase 1/2, single arm open - label study consisting of 2 parts. Part 1 (=Phase 1) will enroll 13 patients to assess the safety of the combination roginolisib+ruxolitinib, and Part 2 (=Phase 2) will expand to add 13 more patients to allow the assessment of benefit/risk for all 26 patients. The primary objective is to evaluate the safety and tolerability of roginolisib when administered in combination with ruxolitinib in patients with MF. Secondary objectives include: (a) changes in peripheral blood Tregs from baseline at Week 12 and continued reduction over time; (b) Splenic response rate (SRR), ie reduction in spleen volume of ≥15%, ≥25% and ≥35% at 12 and 24 weeks compared to baseline, as assessed by MRI/CT; (c) proportion of patients who have any reduction in Total Symptom Score (TSS) at 12 and 24 weeks compared to baseline as measured by Myelofibrosis Symptom Assessment Form (MFSAF). Exploratory measurements will assess endpoints associated with the mechanism of action of roginolisib. Key Inclusion criteria are (1) ≥18 years of age inclusive, at the time of signing the informed consent; (2) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; (3) Diagnosis of primary MF, Post-Polycythemia Vera Myelofibrosis MF (PPV-MF), or post-essential thrombocythemia MF (PET-MF); (4) Treated with ruxolitinib for ≥ 3 months with a stable dose ≥ 10 mg for a minimum of 8 weeks prior to Day 1. Furthermore, patients must show an unsatisfactory spleen reduction; (5) Independent of spleen size, active symptoms of MF at the screening visit, as demonstrated by the presence of a Total Symptom Score (TSS) of ≥ 10 using the Screening Symptom Form; (6) Peripheral blast count < 10%. Key exclusion criterion is a history of a prior Grade 3 or 4 AE which did not respond to therapy or resolved with treatment interruptions and returned to at least Grade 1. The dose of roginolisib will be 80 mg IOA-244 QD. The study will initially enroll 13 patients in Part 1 to assess the safety and benefit/risk profile of roginolisib when combined with ruxolitinib. Part 2 will enroll an additional 13 patients to better characterize the benefit/risk of the combination. The study is currently actively enrolling at 8 sites in Italy and Spain. Conclusions. Given the safety profile of roginolisib in patients of the FiH dose study, the combination of ruxolitinib and roginolisib is expected to provide a safe combination treatment in patients with MF who are no longer responding to JAK inhibition.