River-52: A Multicenter, Open-Label Clinical Trial of RVU120 in Patients with Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia
Authors: Papayannidis Cristina , Mądry Krzysztof , Centkowski Piotr , Prejzner Witold , Butrym Aleksandra , Chraniuk Dominik , Saba Chadi , Angelosanto Noemi , Curley Ruth , Nogai Hendrik , Dudziak Renata , Moybenko Oleksandr , Rzymski Tomasz , Mazan Milena , Sroka-Porada Agnieszka , Wilkinson Gary , Stein Eytan M. 
Published: December 2024

Background: RVU120 is a first-in-class orally bioavailable CDK8/19 kinase inhibitor. RVU120 showed robust anti-cancer activity in acute myeloid leukemia (AML) cell lines and patient-derived models, reducing viability of blasts and number of leukemic stem cells (LSC), promoting differentiation into red blood cells and overcoming resistance to cancer drugs (Rzymski et al., Oncotarget, 2017; Mazan et al., Blood, 2019). Patient-derived cells with recurrent NPM1 and/or DNMT3A mutations showed vulnerability to RVU120 treatment, paving the way for clinical development of the drug in molecularly defined AML populations (Mazan et al., Blood, 2003; Pakulska et al., HemaSphere, 2022). Moreover, encouraging clinical activity was observed in the phase I CLI120-001 study (NCT04021368) including one complete response in an NPM1/DNMT3A mutated patient, as well as several blast reductions and hematologic improvement in 50% of the evaluable patients. We report initial data investigating RVU120 in adult participants with R/R high-risk myelodysplastic syndrome (HR-MDS) or AML.
Methods: RIVER-52 (NCT06268574) is an ongoing phase II multicenter, open-label study. This trial is evaluating the clinical activity of RVU120 in participants with AML or HR-MDS who have failed at least one line of previous therapy and have no available alternative standard options, based on their mutation status for NPM1 and DNMT3A. Participants received RVU120 250 mg monotherapy every other day (EOD) on Days 1, 3, 5, 7, 9, 11, and 13 in consecutive 21-day treatment cycles. The clinical trial is conducted in 2 parts. In Part 1, participants with AML are assigned to one of three cohorts based on the presence or absence of NPM1 and DNMT3A mutations. Participants with HR-MDS are assigned to Cohort 4. If there are signs of anti-tumor or clinical activity of RVU120 as evidenced by the observed CR rate and/or signs of clinical benefit (e.g., hematologic improvement), the clinical trial may proceed to Part 2 in the selected population(s).
The primary objective of RIVER-52 is to evaluate the efficacy of RVU120 focusing on genetically defined subsets of patients with AML and HR-MDS and to confirm the drug's safety profile. Secondary and exploratory objectives include pharmacokinetics (PK), Quality of Life (QoL) and pharmacodynamic (PD) effects.
Results: At the time of abstract submission, 12 patients received RVU120, out of them 9 had AML including 6 patients not harboring the alterations of interest, 1 patient with NPM1 mutation, and 2 patients with DNMT3A mutation, and 3 patients with HR-MDS. 8 patients discontinued the study treatment (4 for progressive disease, 3 for death following fatal pneumonia in 2 cases and 1 following febrile neutropenia that occurred after study drug discontinuation, and 1 for withdrawal of consent), while 4 pts are ongoing, one of them a 59-year-old female with NPM1 mutation showing promising evidence of 50% blast reduction at C2D13 on cytomorphology and flow cytometry. A total of 58 treatment-emergent AEs have been reported. The most common TEAEs were nausea in 6 pts and asthenia in 5 pts, followed by pneumonia, febrile neutropenia, abdominal pain, and anemia, in 3 pts each. The majority of AEs are of grade 1 or 2. Preliminary pharmacokinetic data showed systemic exposure consistent with that seen in previous RVU120 studies, sufficient for robust target engagement.
Conclusions: While the study is ongoing, preliminary results of RIVER-52 study demonstrate that RVU120 monotherapy has an acceptable safety profile, encouraging antileukemic activity, and emerging biologic activity consistent with the proposed mechanism of action in pts with R/R acute leukemia harboring NPM1 alterations.