SEL120 - a First-in-Class CDK8/19 Inhibitor As a Novel Option for the Treatment of Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome - Data from Preclinical Studies and Introduction to a Phase Ib Clinical Trial

Deregulated transcription, one of the key features of acute myelogenous leukemia (AML), remains largely unactionable by recently approved therapies. Preclinical studies indicate that targeting Cyclin Dependent Kinase 8 (CDK8) may be a novel therapeutic strategy for AML. CDK8 and its paralog CDK19, restrain activation of super-enhancer-associated tumor suppressors and lineage commitment genes in AML cells. SEL120 is a first-in-class, specific and selective inhibitor of CDK8/CDK19 and has shown activity in preclinical AML models.

Preclinical characterization of SEL120 demonstrated a unique mechanism of action, related to known functions of CDK8 in the regulation of transcription. Cells sensitive to SEL120 show enrichment for leukemia stem cells (LSCs) signatures and higher signal transducer and activator of transcription 5 (STAT5) levels. Treatment with SEL120 reduced STAT5 phosphorylation in sensitive cell lines both in vitro and in vivo. Transcriptomic analysis of AML cells revealed that SEL120 regulated genes involved in lineage controlling functions. Specifically, trimethylation of lysine 27 on histone H3 (H3K27me3) by the polycomb repressive complex 2 (PRC2), was proposed to maintain the stemness of LSCs by preventing differentiation. Derepression of lineage commitment genes marked with H3K27me3, was one of the earliest transcriptional events in sensitive cells treated with SEL120. Consistent with its transcriptional effects, SEL120 induced differentiation of AML cells. Additionally SEL120 significantly repressed the MYC Proto-Oncogene-dependent transcriptomic signatures.

Efficacy of SEL120 in AML was confirmed in models with high translational potential, including patient-derived AML cells (PDC) in vitro and in vivo. PDCs treated with SEL120 showed reduced viability, induction of apoptotic cell death and differentiation commitment. Administration of SEL120 in orthotopic AML patient-derived xenograft models reduced tumor burden to the level undetectable by flow cytometry, decreased splenomegaly and resulted in partial bone marrow recovery.

CLI120-001 is a first-in-human, open-label, multi-center, modified 3+3 dose escalation phase Ib study of SEL120 with a dose-escalation cohort (DC) followed by an enrichment cohort (EC) in adult patients with AML or high-risk myelodysplastic syndrome who have relapsed or refractory disease and have received no more than 3 prior lines of therapy. Other key inclusion criteria are Eastern Cooperative Oncology Group performance status of 0-2, white blood cell (WBC) count <10000/µL (prior hydroxyurea is permitted to reduce WBC), platelet count >10000/µL, adequate organ function defined as: aspartate aminotransferase and alanine aminotransferase ≤3x the upper limit of normal (ULN), total bilirubin ≤1.5x ULN, creatinine clearance ≥60 ml/min, left ventricular ejection fraction ≥40%. Major exclusion criteria include Q to T wave interval corrected for heart rate (QTc) ≥450 ms, taking concomitant medications that are known to be strong inhibitors or inducers of cytochrome P450 1A2 or that can prolong QTc and/or cause torsade de pointes.

The primary objective of the study is to assess safety and tolerability of SEL120 and to establish the recommended dose (RD) for further clinical development. Secondary objectives include evaluation of preliminary anti-leukemic activity and characterization of the pharmacokinetic profile of SEL120. The exploratory objective is to assess pharmacodynamics of SEL120 by using relevant biomarkers, including STAT5 pS726, transcriptional profiling by RNAseq and immunophenotypic changes related to stemness and differentiation of AML cells. SEL120 is administered as a single oral dose every other day for a total of 7 doses i.e. on days 1, 3, 5, 7, 9, 11 and 13, in a 21-day treatment cycle. Patients receive SEL120 until disease progression, unacceptable toxicity, or withdrawal of consent. The DC is now enrolling patients who are treated at dose levels defined by a modified Fibonacci sequence, and will end with selection of the RD based on all available study data. In the EC, additional patients will be treated at the RD to further support the evaluation of the RD of SEL120 monotherapy.

The study is currently running in the United States and is planned to be completed in 2020. The ClinicalTrials.gov Identifier: NCT04021368.