The FDA has lifted a partial clinical hold on the phase 1b trial (NCT04021368) evaluating RVU120 (SEL120) in patients with relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). The decision follows a review of safety data and implementation of a revised study protocol. The trial aims to determine the safety, tolerability, and preliminary efficacy of RVU120, a novel CDK8/CDK19 inhibitor, in this patient population with limited treatment options.
The partial hold was initiated after a report of a serious adverse event potentially related to RVU120, resulting in a patient death. Enrollment was suspended, but patients already receiving the drug were allowed to continue treatment.
Revised Protocol and Dose Escalation
Based on FDA recommendations, the trial will resume enrollment with a 75-mg dose of RVU120 administered every other day, following a standard 3+3 design. This approach is part of a revised protocol designed to enhance patient safety. After the 75-mg cohort is completed, the FDA will assess the data to determine further dose escalation strategies.
"We are thankful to the FDA for working with us in a swift and interactive manner to review the data from the trial and introduce modifications to the study protocol," said Pawel Przewiezlikowski, chief executive officer of Ryvu Therapeutics, in a press release. "We believe that the initially demonstrated benefit of treatment with RVU120 as a single agent for [patients with] AML and MDS, coupled with the amended study protocol, will lead to a safe, timely, and successful completion of the clinical trial."
Ryvu Therapeutics anticipates working closely with investigators and clinical sites to obtain IRB approvals for the revised protocol and resume patient enrollment in Q3 2021.
RVU120: A Novel CDK8/CDK19 Inhibitor
RVU120 is a novel CDK8/CDK19 kinase inhibitor that has shown significant activity in preclinical AML models. The phase 1b dose-escalation plan initially comprised 8 cohorts of patients receiving RVU120 at dose levels ranging from 10 mg to 225 mg. Cohorts 1 to 4 followed an accelerated dose-escalation scheme, enrolling one patient per cohort, while cohorts 5 through 8 were to receive dose escalation according to the modified Fibonacci 3+3 design.
The drug was administered orally, every other day, for a total of 7 doses per treatment cycle, within a 3-week cycle. Treatment continued until progressive disease or intolerable toxicity.
Trial Objectives and Endpoints
The primary objective of the trial is to determine the preliminary toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose, and recommended phase 2 dose of single-agent RVU120. Secondary endpoints include characterization of pharmacokinetics, antitumor activity, and exploratory pharmacodynamic effects.
Preliminary Data from EHA 2021
Preliminary safety, efficacy, and pharmacokinetic data from the first 4 dose-escalation cohorts were presented at the EHA 2021 Annual Congress. A study data review committee assessed findings from each cohort, applying Cheson 2006 and Dohner 2017 criteria for MDS and AML response evaluation. DLTs were evaluated at the end of the first treatment cycle.
Across the first four cohorts, patients had relapsed/refractory AML or high-risk MDS and had received multiple prior lines of therapy. One patient in cohort 3 experienced an erythroid response at cycle 5 day 8 and remained on treatment at cycle 12. The patient in cohort 4 achieved a complete response to treatment at cycle 2, except for skin leukemia, which resolved at cycle 7; however, the patient progressed at the bone marrow level at the end of cycle 8 and discontinued treatment.
Pharmacokinetic analysis showed relatively rapid absorption of RVU120, with Tmax at 4 to 8 hours post-administration. Exposure, based on Cmax and AUC, appeared linear between 10 mg and 75 mg. The elimination half-life ranged from 22 to 40 hours, with low accumulation.
Notably, no DLTs were reported. Four patients experienced serious adverse events, but investigators deemed them unrelated to the drug. As of July 14, 2021, only one patient remained on treatment with RVU120.
