A phase 1 study of the CDK9 inhibitor voruciclib in relapsed/refractory acute myeloid leukemia and B-cell malignancies
The anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Dependence on Mcl-1 is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase (CDK) inhibitor targeting CDK9, indirectly decreases Mcl-1 protein expression and synergizes with venetoclax in preclinical models. This dose escalation study evaluated voruciclib in patients with previously treated hematologic malignancies (registered as NCT03547115). Initially, voruciclib was administered daily continuously on a 28-day cycle (Group I). After two patients with prior allogeneic stem cell transplantation had a dose limiting toxicity (DLT) of interstitial pneumonitis at 100 mg, voruciclib administration was changed to days 1-14 of a 28-day cycle (Group II). Forty patients, 21 with AML and 19 with B-cell malignancies, were enrolled. Patients had a median of 3 prior lines of therapyies (range, 1-8). Dose escalation in Group II was stopped at 200 mg, a dose that achieved plasma concentrations sufficient for target inhibition, without DLTs observed.  The most common adverse events were diarrhea (30%), nausea (25%), anemia (22%), fatigue (22%), constipation (17%), dizziness (15%) and dyspnea (15%). In AML, one patient achieved a morphologic leukemia-free state and two had stable disease. There was a Voruciclib treatment led to a decrease in MCL1 mRNA expression, downregulation of MYC and NF-?B transcriptional gene sets, and reduced phosphorylation of RNA polymerase II . Voruciclib on intermittent dosing was well tolerated, with no DLTs, paving the way for evaluation of the combination of voruciclib with venetoclax in patients with previously treated AML. Overall design: Patients = 18 years of age with a diagnosis of AML, CLL, or B-cell NHL (DLBCL, mantle cell lymphoma, follicular lymphoma and marginal zone lymphoma) were eligible if they had disease progression after = 2 prior standard therapies, no prior CDK9 inhibitor exposure, ECOG performance status of 0 or 1, and adequate renal and hepatic function. To identify gene expression changes in response to voruciclib, transcriptomics analysis was conducted by bulk RNA-Seq on pre- and post-treatment PBMC samples from AML, DLBCL, and CLL patients who were dosed with voruciclib.