FDA Lifts Partial Clinical Hold on Trial Examining CDK8/CDK19 Inhibitor RVU120 in AML, MDS

The FDA has lifted a partial clinical hold that was placed on a first-in-human, phase 1b trial (NCT04021368) evaluating RVU120 (SEL120) in patients with relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).¹

The decision to issue the partial hold on the trial followed a recent report to the FDA that detailed a serious adverse effect that was potentially related to the agent and resulted in a patient death. In response, the regulatory agency suspended enrollment to the trial, but allowed participants who were already receiving the agent to continue treatment.

Based on recommendations issued by the FDA, the study will resume enrollment for patients to receive a 75-mg dose of the agent every other day as part of a standard 3+3 design in accordance with a revised protocol that was put in place to improve safety. After the 75-mg cohort is completed, the data yielded from those patients will be assessed by the FDA and a further dose-escalation approach will be determined.

“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,” Pawel Przewiezlikowski, chief executive officer of Ryvu Therapeutics, stated 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.”

We will be working closely with investigators and the clinical sites to obtain IRBs’ approvals on the revised protocol and resume patient enrollment in Q3 2021.”

RVU120 is a novel CDK8/CDK19 kinase inhibitor that has previously demonstrated significant activity in preclinical AML models.²

The phase 1b dose-escalation plan comprised 8 cohorts of patients who would receive RVU120 at dose levels ranging from 10 mg to 225 mg. Cohorts 1 to 4 would be part of the dose-escalated, accelerated scheme, and 1 patient would be enrolled to each cohort. Cohorts 5 through 8 would receive dose escalation according to the modified Fibonacci 3+3 design.

The investigative agent was given orally, every other day, for a total of 7 doses per treatment cycle as part of a 3-week cycle. Participants would receive the agent until progressive disease or intolerable toxicity.

The primary objective of the research was to determine the preliminary toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose, and recommended phase 2 dose of single-agent RVU120. Important secondary end points were focused on the characterization of pharmacokinetics, antitumor activity, and exploratory pharmacodynamic effects with the agent.

Preliminary safety, efficacy, and pharmacokinetic data from the first 4 dose-escalation, single-patient cohorts of the trial were presented during the EHA 2021 Annual Congress.³ A study data review committee reviewed findings from each cohort and Cheson 2006 and Dohner 2017 criteria for MDS and AML response evaluation were applied. DLTs were evaluated at the end of the first treatment cycle.

A total of 2 patients were enrolled to cohort 1. One of these patients was aged 78 years, had high-risk MDS that fell into the poor-risk category, an IPSS-R of 8.5, and an ECOG performance status of 1. The patient had previously received 2 lines of therapy, which included azacitidine and a CD33/CD3 bispecific antibody.

The other patient was aged 74 years, had AML that fell into the adverse risk category, a complex karyotype, and a tumor that harbored a TP53 mutation. The patient had an ECOG performance status of 1 and received 3 prior lines of treatment, which included cytarabine/decitabine, cytarabine/cladribine, and a CD33/CD3 bispecific antibody. Both patients received RVU120 at a 10-mg dose level. One of these patients were not evaluable for DLTs.

Cohorts 2 through 4 enrolled 1 patient each. The patient in cohort 2 was 54 years of age, had AML that fell into an adverse risk category, had Inv3+14 trisomy, and an ECOG performance status of 2. This patient previously received 3 lines of therapy that consisted of fludarabine plus high-dose cytarabine, idarubicin, and granulocyte-colony stimulating factor, as well as venetoclax (Venclexta). This patient received the investigative agent at a dose of 25 mg.

The patient in cohort 3 of the trial was older, 81 years of age, had high-risk MDS that fell into the normal risk category, had an IPSS-R of 6, and an ECOG performance status of 2. This patient received 2 previous lines of therapy that consisted of azacitidine plus decitabine and venetoclax. The patient received the agent at a dose of 50 mg.

Lastly, the patient enrolled to cohort 4 was aged 62 years, had persistent AML and skin leukemia that was intermediate risk, a normal karyotype and harbored NPM1 and FLT3-ITD mutations. The patient had an ECOG performance status of 0 and had previously received 3 lines of treatment that included cytarabine; idarubicin; midostaurin (Rydapt), gilteritinib (Xospata), and decitabine; and venetoclax. This patient received the agent at the highest dose examined, which was 75 mg.

Data showed that the evaluable patient in cohort 1 achieved stable disease with RVU120, and the patient in cohort 2 experienced progressive disease at cycle 1. The patient in cohort 3 experienced an erythroid response at cycle 5 day 8. At the time of the presentation, the patient was on cycle 12 of treatment, receiving 75 mg of the agent, after having been dose-escalated during cycle 7. The patient in cohort 4 achieved a complete response to treatment at cycle 2, except for skin leukemia which completely resolved at cycle 7. At the end of cycle 8, this patient was found to progress at the bone marrow level and thus, discontinued treatment.

A pharmacokinetic analysis was conducted based on plasma samples that had been collected on day 1 of cycle 1 and day 13 of cycle 1. Results revealed RVU120 absorption to be relatively rapid at Tmax 4 to 8 hours following treatment administration.

Moreover, exposure, based on Cmax and area under the curve (AUC), appeared to be linear with doses that fell between 10 mg and 75 mg. RVU120 elimination half-life in plasma ranged from 22 hours to 40 hours. Accumulation, which was based on half-life or the ratio of AUC D13/D1 was reported to be low.

Notably, no DLTs were reported with the agent. However, 4 patients experienced serious adverse effects and they were determined by investigators not to be associated with the drug; these included grade 3 pseudomonas sepsis, urinary tract infection, febrile neutropenia, and lung infection.

As of July 14, 2021, only 1 patient remains on treatment with RVU120.

References

1. FDA lifts partial clinical hold on phase 1b clinical trial of RVU120 (SEL120) in acute myeloid leukemia and myelodysplastic syndrome. News release. Ryvu Therapeutics. July 14, 2021. Accessed July 14, 2021. https://prn.to/3egqRoE
2. Rzymski T, Mikula M, Zylkiewicz E, et al. SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains. Oncotarget. 2017;8(20):33779-33795. doi:10.18632/oncotarget.16810
3. Angelosanto N, Abboud C, Borthakur G, et al. CLI120-001 phase 1b study of SEL20 (RVU120) in patients with AML or high-risk MDS: preliminary clinical and PK results from initial dose escalation cohorts. Presented at: EHA 2021 Virtual Congress; June 9-17, 2021. Abstract EP480. https://bit.ly/36PXhSR