672P Phase I/II trial of RVU120 (SEL120), CDK8/CDK19 inhibitor in patients with relapsed/refractory metastatic or advanced solid tumors

CDK8 and its paralog CDK19 are part of the mediator complex connecting enhancers and core promoters and regulating genes responsible for oncogenic transformation and differentiation. RVU120 is a selective CDK8/19 inhibitor, currently in phase 1 clinical development. RVU120 showed strong anticancer activity in non-clinical cancer models. In the ongoing phase I/II study (NCT05052255), patients with metastatic or locally advanced solid tumors receive RVU120 until disease progression or unacceptable toxicity. Primary objectives are safety, tolerability, and determination of the recommended phase 2 dose. Secondary objectives include ORR, pharmacokinetic and pharmacodynamics. Molecular response to RVU120 is assessed by genetic profiling of tumor biopsies and ctDNA. NanoString technology is used for transcriptional profiling of tumor biopsies. As of 01 May 2023, there were 30 patients treated across 7 cohorts (75 - 375 mg). The most frequent AEs were nausea and vomiting, all were G1 or 2. No patient experienced a DLT, 10 SAEs were reported in 6 patients (worsening of tumoral pain, urinary tract infection, medullary compression, lower GI bleeding, worsening of basal ataxia/dizziness, renal calculi, stroke). One patient died following an SAE of general physical health deterioration due to PD. No SAE was considered IMP related. A total of 15 patients had at least 1 RECIST assessment: 2 PD (21% and 26% increase in TL size), 13 radiologic SD (between -4% and +11% change in TL size). Out of these, a patient with refractory pancreatic cancer achieved a reduction of CA19.9 on 3 consecutive time points and radiologic SD after cycle 3. Pharmacodynamic profiling of all patients revealed target engagement of >70% at doses up to 375 mg. Data from genetic and transcriptomic profiling will be presented. After 7 dose levels with single agent RVU120 (up to 375 mg), a favorable safety profile was observed. Most TEAEs were mild/moderate, no DLTs nor IMP related SAEs were reported. RECIST assessments of 15 patients demonstrated radiologic SD in 13 patients. Dose escalation is currently ongoing with PK modeling indicating high target engagement.