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Introduction: CDK8 and its paralog CDK19 have central roles in the maintenance of cancer cell viability and undifferentiated state for a variety of tumor type.1,2RVU120 (SEL120), a first-in-class selective CDK8/CDK19 kinase inhibitor with significant anti-leukemic activity in preclinical AML models, has shown clinical efficacy in a currently ongoing phase 1b trial in patients with relapsed/refractory (R/R) AML or HR-MDS (NCT04021368). Objectives: Primary objective of the study is to determine the preliminary safety profile, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and the recommended phase 2 dose of RVU120 as a single agent. Secondary objectives include pharmacokinetic and pharmacodynamic profile, including in STAT5 phosphorylation changes and pattern of gene expression. Material and methods: CLI120-001 is an open-label dose-escalation study with 3 + 3 design, currently enrolling R/R AML or HR-MDS patients at 5 sites in the US and 2 sites in Poland. RVU120 is administered orally every other day, total of 7 doses, in a 3-week treatment cycle, until disease progression or unacceptable toxicity. Pharmacokinetic (PK) parameters are calculated by non-compartmental analysis. Pharmacodynamic (PD) activity is assessed by flow cytometry measure of pSTAT5 Ser725 levels, (highly dependent on the activity of CDK8 and CDK19 in AML/MDS cells). Results: As per May 26th 2022, 16 pts have been dosed (5 pts ongoing), median age 72 years, median 3 prior lines of therapy, 10/16 received Ven combo prior study entry. RVU120 treatment resulted in notable clinical benefits in some patients: 103-001: U2AF1/DNMT3A/RUNX1//BCOR/STAG2-positive HR-MDS, failing both azacytidine and venetoclax-decitabine remained on trial for more than 18 months with SD and significant reduction of transfusion requirement at different timepoints. 103-002: FLT3//NPM1/DNMT3A-positive AML, relapsing after chemotherapy + midostaurin, gilteritinib, and progressing under venetoclax-decitabine, with skin leukemia and ≥50% of BM blasts at study entry, showed complete clearance of BM blasts by the end of C1, hematologic recovery on C2 and CR (due to resolution of skin leukemia) on C7. 106-002: JAK2 V617F positive AML secondary to PV, progressing on prior venetoclax-azacytidine, showed a 36% decrease of BM blasts from C1 to C6 and is ongoing. 107-002: AML MRC, relapsing after 2 prior intensive chemotherapies, is ongoing with SD for more than 3 months 107-005: TP53 positive AML, relapsing after 2 prior intensive chemotherapy regimens, experienced a 37% reduction of BM blasts at the end of C2 and is currently ongoing at C3. As dose escalation continues, RVU120 showed a favorable safety profile with no DLTs and no drug-related SAEs. In addition, RVU120 was not associated with QT prolongation or myelosuppression. Conclusions: Clinically meaningful benefit of RVU120 monotherapy has been observed, with one CR and disease stabilizations with blast reductions in several ongoing patients who failed multiple prior therapy lines. Initial PD assessments of pSTAT5 inhibition indicate less than complete target inhibition at doses of up to 85 mg. Dose escalation is continuing, and assessment of the 100 mg cohort is currently ongoing. [ABSTRACT FROM AUTHOR]