Trial in Progress: An Open-Label Clinical Trial of RVU120 As Monotherapy and in Combination with Ruxolitinib in Patients with Intermediate or High-Risk, Primary or Secondary Myelofibrosis (POTAMI-61)
Authors: Kuklík Rostislav , Falkowski Adam , Zaroogian Zachary , Mazan Milena , Szymula Agnieszka , Wilkinson Gary , Adamczyk Elżbieta , Woźnicki Jerzy , Micek Marta , Coelho Diego , Wiklik Katarzyna , Grzywczak Daniel , Nogai Hendrik , Rzymski Tomasz , Rampal Raajit 
Published: December 2024

Background
Myelofibrosis (MF) is characterized by clonal proliferation of stem cells with common symptoms including splenomegaly, hepatomegaly, anemia and thrombopenia. MF results from aberrant activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. Ruxolitinib (RUX) is JAK1/2 inhibitor used to treat MF and hydroxyurea-resistant/intolerant polycythemia vera. While RUX demonstrated important clinical benefits, a large proportion of patients have persistent disease manifestations despite therapy.
Cyclin-dependent kinases 8 and 19 (CDK8/19) regulate phosphorylation of STAT proteins in a RUX-independent manner. RVU120 is highly selective and potent CDK8/19 inhibitor. Analysis of the combinatorial effect of tested drug candidates on viability demonstrated synergy between RVU120 and all of the JAK inhibitors in RUX-naïve and RUX-resistant JAK2-mutated cell lines (Zaroogian et al., EHA 2024). Treatment with RVU120 alone or in combination with RUX in a murine model of MF resulted in significant reductions in disease manifestations (splenomegaly, fibrosis scoring, hematopoiesis) (Zaroogian et al., HemaSphere, 2023). RVU120 also has erythroid-stimulating activity and demonstrates a favorable safety profile with normal hematopoiesis (Rzymski et al., EHA 2021), making it potential candidate for widespread clinical use in treating MPNs. This data supports rationale that RVU120, given alone or in combination with RUX, may offer new treatment option for MF patients.
Study design (methods)
POTAMI-61 (NCT06397313; 2024-511688-27) is the study consisting of screening of up to 28 days, treatment (RVU120 given orally at 250 mg on days 1, 3, 5, 7, 9, 11, and 13 of 21-day treatment cycles until patient treatment discontinuation or study termination), end of treatment visit (30 days after the last RVU120 dose), and 1-year follow-up).
The primary objective evaluates RVU120 clinical activity, by measuring proportion of patients achieving SVR of ≥ 35% after 24 weeks of commencing study treatment by MRI/CT if given as monotherapy or in combination with RUX.
The secondary objectives evaluate anti-tumor activity (proportion of participants achieving grade ≥1 bone marrow (BM) fibrosis improvement after 24 weeks, DoR (time from initial SVR of ≥35% by MRI/CT until PD or death), leukemic transformation evidenced by BM or peripheral blood (PB) blast count of ≥20% lasting for 2 weeks) and/or clinical benefit (PFS/OS). Safety, PK and changes in symptom burden as monotherapy or in combination with RUX will be evaluated too.
Major inclusion criteria: diagnosis of primary or secondary MF according to revised WHO criteria; intermediate or high-risk MF according to DIPSS; measurable splenomegaly (spleen volume of &gt; 450 cm3 after at least 6 months of JAKi treatment); active symptoms (presence of 1 symptom score ≥5 or 2 symptom scores ≥3); ECOG performance score of 0-2.
Major exclusion criteria: PB or BM blast count of ≥10%; history of hematopoietic stem cell transplant; active known second malignancy; significant cardiac dysfunction including history of ventricular arrhythmia or QTc ≥470 ms.
Part A will enroll up to 2 cohorts, with expected 10 evaluable patients per cohort. Cohort 1 will assess RVU120 in MF patients who were previously treated with or are ineligible for treatment with a JAKi. Cohort 2 will assess RVU120 in combination with RUX in MF patients experiencing suboptimal response to JAKi therapy.
Part B is an enrichment phase to establish RVU120 efficacy and will enroll up to 210 patients across 3 cohorts (up to 70 patients in each). Cohorts 1 and 2 will enroll the same patient populations as in part A. In cohort 3, patients with untreated primary or secondary MF may be enrolled. Part A will start recruiting patients in Poland and Italy.
Recruitment for this study will begin in September 2024.