An open-label, Phase I/II clinical trial of romaciclib (RVU120) as monotherapy and in combination with ruxolitinib in patients with intermediate or high-risk, primary or secondary myelofibrosis (POTAMI-61)

Abstract Background Myelofibrosis (MF) is associated with dysregulated JAK1/2 signaling. Ruxolitinib (RUX, JAK1/2 inhibitor) was the first targeted agent approved by FDA for MF treatment. JAK signaling involves recruitment of STATs to cytokine receptors, followed by their activation and nuclear translocation leading to gene expression modulation. Romaciclib is the first-in-class, highly selective and orally bioavailable CDK8/19 small molecule inhibitor showing potent anti-proliferative and pro-apoptotic effects in JAK2-mutant cell lines, as well as synergistic activity with RUX. In murine MF models, romaciclib reduced burden of mutant cells, decreased WBC counts, reduced spleen size, and modulated megakaryocyte differentiation. Combination of romaciclib with RUX further enhanced therapeutic efficacy. These results suggest that romaciclib, alone or in combination with JAK1/2 inhibitor, may offer a novel treatment option for MF patients. Methods POTAMI-61 (NCT06397313) is an ongoing 2-part, open-label clinical trial assessing romaciclib as monotherapy and in combination with RUX. In Part A, approximately 20 patients were treated with either romaciclib as single agent (cohort 1, comprising patients who failed or were ineligible for JAKi treatment) or in combination with RUX (cohort 2, consisting of patients with suboptimal response to JAKi). Part B will further assess efficacy in larger patient population. Study treatment is administered in 21-day cycles until treatment discontinuation, withdrawal, or trial termination. Romaciclib PK will be characterized to confirm systemic exposure and support dose proportionality assessments. All patients provided informed consent. Aims Primary endpoint is to evaluate romaciclib activity, both as monotherapy and in combination with RUX, by assessing spleen volume reduction (SVR) of ≥35% at Week 24, as measured by MRI/CT. Secondary and exploratory endpoints include safety determined by (S)AEs incidence, further evaluation of antitumor activity, and/or clinical benefit of romaciclib (as mono/combo), including proportion of patients achieving ≥50% reduction in total symptom score (TSS), improvement of BM fibrosis by ≥1 grade after 24 weeks of treatment, SVR duration (time from initial ≥35% SVR by MRI/CT until PD/death), incidence of leukemic transformation (BM/PB blasts count ≥20% lasting for ≥2 weeks), changes in proinflammatory cytokines, PFS/OS, and PK of romaciclib in combination with RUX. Results As of 25 July 2025, 31 patients were evaluated for participation in trial Part A. Eight patients failed screening, 23 patients started treatment (12 in cohort 1, 11 in cohort 2). Enrollment in Part B is open at the cutoff date. Median time on treatment in Part A was 8 weeks; 11 patients are ongoing. Four patients completed 24-week assessment (1 in cohort 1, 3 in cohort 2), and additional 6 patients completed 12-week assessment (3 in each cohort). At 24 weeks, SVR20 rate was 25% (1/4), and 75% of patients (3/4) achieved any SVR. Notably, all patients with SVR had an improved outcome at 24 weeks compared to 12-week assessment. 50% of patients (2/4) achieved 50% TSS reduction, 1 patient showed complete resolution of symptoms. In 6 patients who only completed 12-week assessment, SVR20 rate was 17% (1/6), and SVR10 rate was 50% (3/6). Reduction of BM fibrosis was seen after 12 weeks of treatment in a patient who failed prior lines of RUX and fedratinib; reduction of TSS of 50% was not observed in these 6 patients after 12 weeks. The most common AEs were nausea and vomiting, reported in 52% and 43% of patients, respectively. Majority of AEs were G1-2. The most common G3 AEs regardless of relationship were anemia, thrombocytopenia, nausea (3 pts each), vomiting, UTI, and fatigue (2 pts each). Safety profiles in cohorts 1 and 2 were comparable. PK analyses confirm that PK is consistent with expectations from prior studies, with no unexpected deviations from model-predicted exposure targets, supporting expected lack of DDI between RUX and romaciclib. No death was reported as of cutoff date. Conclusions Based on early data cut with median treatment duration of 8 weeks, romaciclib was found to be tolerated by patients with MF. Initial signs of clinical activity were observed, as demonstrated by SVR, TSS improvements, and BM fibrosis reduction in some patients while data continue to mature. Initial evidence from POTAMI-61 study supports further investigation of romaciclib in patients with MF.