P526: safety and efficacy update from cli120-001: a phase1b dose escalation study in relapse-refractory acute myeloid leukemia and high-risk myelodysplasia

Background: RVU120 is a novel CDK8/CDK19 kinase inhibitor currently under clinical investigation in a phase 1b dose escalation study for relapsed/refractory AML and high-risk MDS (NCT04021368). Complete remission in 1 patient with NPM1 mutation dosed at 75 mg, and clinically significant erythroid and/or platelet improvement in 4 patients treated at doses between 75 and 100 mg, have already been published (Angelosanto N et al EP480, EHA 2021;Abboud C et al abs.2771, ASH 2022), showing consistency of clinical observation with the preclinical antileukemic and differentiating effect of the drug (Pakulska U et al, abs.1518, ASH2021). This abstract provides an update from ongoing patients at higher dose levels. Aims: Primary Objective of this trial is to define the safety profile, dose-limiting toxicities (DLTs), maximum tolerated dose(MTD) and the recommended phase 2 dose of RVU120 as single agent. Secondary objectives include the characterization of PK, antileukemic activity and pharmacodynamic effects. Methods: All pts consented to the study participation. Dose escalation followed a 3 + 3 approach from Cohort 4 onwards and will continue up to RP2D which will be determined by an assessment of PD, PK and safety data. RVU120 is given orally EOD for 7 doses in a 21-day cycle until disease progression or unacceptable toxicity. Adverse events are graded according to NCI-CTCAE v5.0. DLTs are assessed at the completion of C1.Disease evaluation is performed according to Dohner 2017 and Cheson 2006 response criteria for AML and MDS respectively. PD is assessed by flow cytometric determination of PSTA5 inhibition in blasts (direct method) and ex vivo in cells treated with patients’ plasma (indirect method). Results: At the data cut off of 28th Feb 23, 22 pts have been enrolled, median age 72.5 years and median of 3 prior lines of therapy, ECOG PS was 2 in 6 pts, 1 in 13, 0 in 3. No DLTs were observed, no study drug interruptions due to adverse drug reactions occurred. Among the 39 serious adverse events that occurred, 3 were deemed related to the study drug: febrile neutropenia and enterocolitis in a patient treated at 100 mg and viral pneumonia in a patient treated at 110 mg. No trend for increased toxicity during the dose escalation phase. G1-G2 nausea was the most common treatment emergent adverse event (72% of prevalence). 10 out of 19 evaluable patients showed clinical benefit: 1 pt with AML treated at 75 mg with CR, 3 pts with AML treated at 100 mg and 1 pt with HR-MDS treated at 75 mg with significant increase of hemoglobin and platelets, 4 pts with adverse cytogenetics treated between 10 and 100 mg with a BM blast reduction and 1 pt with AML, dosed at 110 mg, showing a BM blasts reduction of 70% at the beginning of C4. This patient, with TP 53 double hit and monosomal karyotype is currently ongoing in C4 of therapy with a good drug tolerability. A second ongoing patient, treated at 100 mg is currently in C21 with hemoglobin in normal range and platelets above 90X109/L.A third patient, affected by AML refractory to 4 prior lines of therapy is currently ongoing at a dose of 110 mg with SD in C5. The next dose level of 135 mg is now open for enrolment. Summary/Conclusion: Results from patients dosed up to 110 mg have shown a favorable safety profile of RVU120. Clinically significant signs of efficacy were observed above 100 mg indicating that higher exposure may result in more pronounced anti-leukemic activity of RVU120. Currently available data warrant further exploration of RVU120 in AML and HR-MDS and enrollment is ongoing at 135 mg. Keywords: Kinase inhibitor, Myelodysplasia, Acute myeloid leukemia