CDK 8/19 Kinase Inhibitor RVU120 in Patients with AML or Higher-Risk MDS: Safety and Efficacy Results from New Dose Escalation Cohorts

Abstract

Background: RVU120, a novel CDK8/19 kinase inhibitor has shown high anti-leukemic activity in AML cell lines and patient-derived cells mediated by inhibition of STAT 5 phosphorylation (Rzymski T et al. 2015). Clinical activity, including 1 Complete Remission (CR) in a patient with R/R AML has been shown in the currently ongoing First in Human (FiH) phase Ib dose escalation trial (NCT04021368). Preliminary safety, efficacy, and pharmacokinetic (PK) data from the first 16 patients have been disclosed (Abboud. C et al EHA 2022). Here, we present an update from patients treated at doses between 75 mg and 100 mg. Aims: The primary objective of the study is to determine the safety profile and the recommended phase 2 dose (RP2D) of RVU120 as a single agent in R/R AML and HR-MDS. Secondary objectives include the characterization of PK, antitumor activity, and exploratory pharmacodynamic (PD) effects. Methods: CLI120-001 is an open-label, multi-center, modified 3+3 dose escalation study currently enrolling at Cohort 7 (100 mg). Each decision related to dose escalation is made by a study data review committee (DRC). RVU120 is administered orally every other day, for a total of 7 doses, in a 3-week treatment cycle until disease progression or unacceptable toxicity. Adverse events are graded according to NCI-CTCAE v.5.0. DLTs are assessed at the completion of Cycle 1. Disease evaluation is performed according to Dohner 2017 and Cheson 2006 response criteria for AML and MDS respectively. Pharmacodynamic assessments (PD) include a flow cytometry assay to assess target engagement by evaluating changes from baseline of phosphorylated STAT5 in patients' leukemic cells. Results: Up to July 25, 2022, 17 patients have been treated with RVU120 at doses from 10 mg to 110 mg per day on day 1, 3, 5, 7, 9, 11 and 13 in a 21-day cycle. Three patients had HR-MDS and 14 had AML, relapsed/refractory to a median of 3 prior lines of therapy, median age was 71 years and ECOG PS was 0-1 in 10 patients and 2 in 7 patients. Most frequent all grade Adverse Events (AE) were nausea (in 55% of patients), thrombocytopenia (33%) and febrile neutropenia (33%), hypokalemia (27%) and vomiting (27%). Drug discontinuation due to AE occurred in 5 patients, Clinical benefit was observed in 11 evaluable patients. Best response was 1 CR and 10 disease stabilizations (SD), 2 of which associated with Hematological Improvement due to increased Erythroid differentiation and/or Platelet recovery, and 4 with BM blast reduction. At the dose level of 100 mg, one patient with AML, refractory to 4 prior lines of therapy and with GATA2 rearrangement, achieved SD and is ongoing at Cycle 4 with platelet recovery and RBC transfusion independence; 1 patient with HR-MDS, progressing after 5 lines of therapy, showed a SD with BM blasts clearance at flow cytometry in an unscheduled efficacy evaluation. The third patient dosed at 100 mg died due to SAE of pneumonia with no post treatment BM evaluation. 2 additional patients (1 treated at 75 mg and 1 at 85 mg) are still ongoing after nearly 6 months of treatment. Both achieved SD. All patients' CD34+ blasts were tested for relative STAT5 phosphorylation changes from baseline. Results showed a clear correlation between pSTAT5 inhibition and RVU120 exposure. Conclusion: In the dose-escalation phase of the study, RVU120 shows clinical activity in AML and HR-MDS with a tolerable safety profile. Relevant target inhibition is achieved at the current dose level and is expected to increase at higher doses. Currently available data warrant further testing of RVU120 in hematologic disorders, and dose escalation in the Phase Ib study continues.