RVU120 Shows Early Promise in R/R Metastatic or Advanced Solid Tumors

Treatment with the first-in-class CDK8/19 inhibitor RVU120 showcased early signs of clinical activity and a favorable toxicity profile in patients with relapsed/refractory metastatic or advanced solid tumors, according to data from part 2 of the phase 1/2 RVU120-SOL-021 (AMNYS-51) trial (NCT05052255) presented at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.^1,2

In part 2, patients received RVU120 at doses of 100 mg (n = 6) or 150 mg (n = 5) once daily; of the 11 total patients, 9 were determined to be evaluable for food-effect and 7 were evaluable for dose-limiting toxicities (DLTs). The most visible benefit was observed in patients with adenoid cystic carcinomas enrolled in parts 1 and 2 (n = 8). Five of these patients achieved a longer duration of treatment on RVU120 vs their most recent prior line of therapy. Additionally, a reduction of more than 10% of target lesion size was observed in 3 patients.

Among these patients, one with parotid adenoid cystic carcinoma (patient 4801-059) achieved an 11% reduction in target lesion size and remains on treatment for over 8 months. Another patient with nasopharyngeal adenoid cystic carcinoma (patient 3403-023) experienced a 20% reduction and discontinued treatment after more than 12 months. The last patient who had adenoid cystic carcinoma of the tongue (patient 3403-047) had a 14% reduction in lesion size and discontinued treatment after more than 5 months.

“RVU120 demonstrates a favorable safety profile in a heavily pretreated, unselected all-comer population of patients with solid tumors,” the lead study author Magdalena Błaszkowska, PhD, noted during a presentation of the data. “No [DLTs] or other safety signals were observed confirming CDK8/19 inhibition as a viable approach for cancer therapies.” For part 2, gastrointestinal-related events such as nausea and vomiting were the most common treatment-emergent adverse effects (AEs). These events were predominantly low-grade and manageable with supportive care.

Diving Into the Study Design and Patient Characteristics

The open-label, multicenter, multinational, single-group assignment, dose-escalation AMNYS-51 trial utilized a 3+3 design and enrolled patients with histologically confirmed and/or documented advanced or metastatic solid tumors who have exhausted all standard therapeutic options and or progressed on at least 1 prior systemic therapy and were not eligible to receive further available treatment.³ Patients needed to be at least 18 years of age, have measurable or evaluable disease by RECIST 1.1 criteria, an ECOG performance status ranging from 0 to 2, and an estimated life expectancy of at least 12 weeks.

The study was comprised of 2 parts. The first phase enrolled patients with relapsed/refractory solid tumor patients who have exhausted available standard of care.¹ The primary objective was to examine the safety and tolerability of RVU120 monotherapy; secondary objectives included evaluating preliminary antitumor response and the agent’s pharmacokinetic (PK) profile.

Part 2 of the trial further evaluated the safety and tolerability of RVU120. The drug was administered at a starting dose of 100 mg daily, with dose escalation up to 150 mg in a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or withdrawal from the study. Safety assessments were based on the incidence of serious AEs and DLTs.

Investigators also explored the pharmacokinetics of RVU120, specifically assessing the impact of food intake on drug absorption. Patients were evaluated under both fed and fasted conditions. Fed status was defined by consuming at least 50% of a standard high-calorie meal, whereas fasted status was defined as no food intake for at least 10 hours before and 4 hours after dosing.

Pharmacodynamic activity was assessed by monitoring changes in STAT5 phosphorylation levels using flow cytometry. This was measured through ex-vivo plasma inhibitory assays, where cancer cells were exposed to patient plasma samples at baseline and on day 13 of cycle 1, once steady-state levels of RVU120 were achieved.

At the data cutoff date of September 16, 2024, 11 patients had been treated with RVU120 in part 2 of the trial. Of the 11 patients, 4 had adenoid cystic carcinoma, 2 had pancreatic adenocarcinoma, 2 had hormone receptor–positive/HER2-negative breast cancer, 1 had non–small cell lung cancer adenocarcinoma, 1 had melanoma, and 1 had colon cancer. The median patient age was 58 years, and the median number of previous lines of therapy was 5, indicative of a heavily pretreated population.

Additional Safety Insights

“Continuous [daily] dosing of RVU120 at doses of 100 mg and 150 mg is considered safe and may improve tolerability of RVU120 compared [with] 250 mg every other day,” the study authors wrote. AEs reported with RVU120 included nausea (55%), increased aspartate aminotransferase levels (45%), increased alanine aminotransferase levels (45%), vomiting (36%), dyspepsia (36%), increased N-terminal pro-B-type natriuretic peptide (27%), increased blood alkaline phosphatase level (27%), thrombocytopenia (27%), anemia (27%), pyrexia (18%), increased Troponin T 18%), dizziness (18%), increased lipase (18%), reduced appetite (18%), QT prolongation (18%), asthenia (18%), fatigue (18%), increased amylase (18%), and headache (18%).

Shedding Light on RVU120’s PK Profile

PK data for RVU120 was characterized across the dosing interval on cycle 1, day 1, and after multiple doses on cycle 1, day 13. Plasma exposure of RVU120 increased with dose across the range investigated for evaluable patients. The median time to maximum concentration for RVU120 was observed approximately 6 hours after the agent was dosed, with a half-life of about 40 hours. Daily dosing at 100 mg and 150 mg resulted in similar plasma exposure to the equivalent every-other-day dose when measured after repeated dosing at cycle 1, day 13.

“Pharmacodynamic analyses support PK findings as 100 mg and 150 mg QD dosing led to the expected target engagement levels in relation to the equivalent RVU120 QOD dose at [cycle 1 day 13],” the study authors wrote.

Next Steps

A total of 4 ongoing phase 2 trials are further evaluating RVU120 as a monotherapy and in combinations for patients with hematological malignancies such as acute myeloid leukemia, high-risk myelodysplastic syndrome (MDS), low-risk MDS, and myelofibrosis.

References

1. Błaszkowska M, Jędrzejewski Ł, Dziadziuszko R, et al. Phase I/II trial of RVU120, a CDK8/CDK19 inhibitor, in patients with relapsed/refractory metastatic or advanced solid tumors (AMNYS-51). Presented at: 2024 ENA Symposium; October 23-October 25, 2024; Barcelona, Spain.
2. Ryvu Therapeutics presents clinical and preclinical data on RVU120, RVU305, and novel synthetic lethality programs at the 2024 EORTC-NCI-AACR Symposium. News release. Ryvu Therapeutics. October 23, 2024. Accessed October 28, 2024. https://ryvu.com/2024/10/23/ryvu-therapeutics-presents-clinical-and-preclinical-data-on-rvu120-rvu305-and-novel-synthetic-lethality-programs-at-the-2024-eortc-nci-aacr-symposium/
3. RVU120 (SEL120) in patients with relapse/refractory metastatic or advanced solid tumors. ClinicalTrials.gov. Updated October 28, 2024. Accessed October 28, 2024. https://clinicaltrials.gov/study/NCT05052255