River-81: A Multicenter, Open-Label, Dose-Finding Clinical Trial to Assess Safety, PK, PD, Clinical Efficacy of RVU120 in Combination with Venetoclax in Patients with AML Failing Prior Venetoclax Plus Hypomethylating Agent Therapy
Authors: Giannini Maria Benedetta , De la Fuente Burguera Adolfo , Venditti Adriano , Prejzner Witold , García Sara , Angelosanto Noemi , Nogai Hendrik , Dudziak Renata , Mohanty Vakul , Baran Natalia , Obacz Marta , Pakulska Urszula , Woźnicki Jerzy , Wiklik Katarzyna , Micek Marta , Rzymski Tomasz , Mazan Milena , Sroka-Porada Agnieszka , Wilkinson Gary , Butrym Aleksandra , Borlenghi Erika , Mądry Krzysztof , Kulis Jan , Coelho Diego , Grzywczak Daniel 
Published: December 2024

Introduction:
RVU120, an orally bioavailable small molecule inhibits the mediator complex kinases CDK8 and CDK19. Previous research on AML cell lines and patient-derived cells showed the synergistic effects of RVU120 and venetoclax (Ven), suggesting RVU120 potential mechanism of action characterized by repression of inflammation and AML oncogenic pathways at transcriptomic level. Of note, RVU120 + Ven combination is able to overcome Ven resistance by downregulating MCL-1 protein expression (Pakulska et al., EHA2024 Hybrid Congress). Furthermore, this combination leads to eradication of leukemic stem cells (LSCs) in a hierarchical model of AML, providing further evidence of its potential anti-leukemic activity in AML patients. Clinical efficacy from a phase 1 trial of RVU120 (NCT NCT04021368) in patients failing prior Ven therapy further supported the design of the phase 2 study, RIVER-81.
Methods:
RIVER 81 (NCT 06191263) is a phase 2 study with a dose-finding escalation phase (part 1) followed by part 2 and 3, which will enroll approximately 94 pts to test the efficacy of RVU120 in combination with Ven in patients failing first line treatment with Ven and HMA. Patients will receive 21-day cycles of increasing doses of RVU120 and Ven in part 1. Part 2 and 3 will be conducted at doses selected based on data in part 1. The primary endpoints include rate of CR, CRh, CRi, with and without MRD according to ELN 2022. The secondary endpoints include transfusion independence, DoR, PFS, RFS, EFS, overall survival, and percentage of participants bridged to HSCT. Safety assessments include the incidence and severity of AEs as per CTCAE v5.1; DLT evaluation for part 1 of the study is performed during cycle 1. Exploratory endpoints of the study include measures of PK, pSTAT5 and other biomarkers. Finally, patient-reported outcomes are assessed by changes in summary scores of the HM-PRO. Preclinical mechanistic studies include efficacy and RNAseq analysis of the combination's effects in a panel of AML cell lines representing various resistance mechanisms to Ven.
Results:
At the time of the abstract submission, 10 patients, median age 76.5 years, relapsing or refractory to VEN+HMA first line, with 2 patients further relapsing after transplant, received RVU120 in combination with Ven, 5 in cohort 1 (RVU120 125 mg + Ven 200 mg) and 5 in cohort 2 (RVU120 250 mg + Ven 200 mg). 8 patients discontinued the study (7 pts for infection, and 1 for progressive disease) while 2 patients are currently ongoing in Cohort 2 with one of them, an 82 YO female patient with AML with DNMT3A mutation, showing CRi at C1D13. No DLTs in any of the evaluable pts were observed, nor adverse events related to RVU120 and Ven leading to drug interruption. A grade 1 SUSAR of nausea was reported in a patient dosed in cohort 2 that resolved with appropriate antiemetic treatment. Preclinical research testing the combination of RVU120 with Ven across a broad panel of AML cell lines demonstrated drug synergy in cell lines representing 2 out of 4 distinct Ven resistant clusters, according to Mohanty et al., bioRxiv, 2024. The ongoing analysis of transcriptomic profiles and treatment-induced changes will be presented in the poster to enable further patient stratification in the RIVER-81 study.
Conclusions: Preliminary evidence of activity in a Ven-refractory AML population comes from the first evaluable patient treated in cohort 2 of RIVER-81 trial that achieved a CRi in Cycle 1.In the studies population, infections occur frequently with poor outcome.The safety and tolerability of RVU120 in combination with Ven allows further exploration.The current data warrant continuation of enrollment into the study.