A phase 1 study of the CDK9 inhibitor voruciclib in relapsed/refractory acute myeloid leukemia and B-cell malignancies

The antiapoptotic protein, myeloid cell leukemia-1 (Mcl-1), contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Tumor 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. Initially, voruciclib was administered daily, continuously, on a 28-day cycle (group 1). After 2 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 to 14 of a 28-day cycle (group 2). Forty patients, 21 with AML and 19 with B-cell malignancies, were enrolled. Patients had a median of 3 prior lines of therapy (range, 1-8). Dose escalation in group 2 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, 1 patient achieved a morphologic leukemia-free state, and 2 had stable disease. Voruciclib treatment led to a decrease in MCL1 messenger RNA expression, downregulation of myelocytomatosis (MYC) and NF-κB transcriptional gene sets, and reduced phosphorylation of RNA polymerase 2. Voruciclib on intermittent dosing was well tolerated, with no DLTs, paving the way for evaluation of the combination of voruciclib with venetoclax for patients with previously treated AML. This trial was registered at www.clinicaltrials.gov as #NCT03547115.

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Publication Details

Journal
Blood Advances
Published
2024-12-20
DOI
https://doi.org/10.1182/bloodadvances.2024014633
Citations
7
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
Field-Weighted Citation Impact
3.07

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article

A phase 1 study of the CDK9 inhibitor voruciclib in relapsed/refractory acute myeloid leukemia and B-cell malignancies

Rachel C. Cook, Catherine Diefenbach, Sameem Abedin, Richard Ghalie et al.
7 citations
Blood Advances
Chronic Lymphocytic Leukemia Research
3.07
article

A phase 1 study of the CDK9 inhibitor voruciclib in relapsed/refractory acute myeloid leukemia and B-cell malignancies

Rachel C. Cook, Catherine Diefenbach, Sameem Abedin, Richard Ghalie, Carly Roleder, Sandra E. Wiley, Mary C. Collins, Danielle M. Brander, Monzr M. Al Malki, Vijaya Raj Bhatt, Nathalie Javidi‐Sharifi, Edward C. Dominguez, Matthew Steven Davids, Shira Naomi Dinner, Yesid Alvarado, Kebede H. Begna, Prabhu Rajagopalan, Daniel Nathan Egan, Alexey V. Danilov
article en
7 citations

Abstract

The antiapoptotic protein, myeloid cell leukemia-1 (Mcl-1), contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Tumor 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. Initially, voruciclib was administered daily, continuously, on a 28-day cycle (group 1). After 2 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 to 14 of a 28-day cycle (group 2). Forty patients, 21 with AML and 19 with B-cell malignancies, were enrolled. Patients had a median of 3 prior lines of therapy (range, 1-8). Dose escalation in group 2 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, 1 patient achieved a morphologic leukemia-free state, and 2 had stable disease. Voruciclib treatment led to a decrease in MCL1 messenger RNA expression, downregulation of myelocytomatosis (MYC) and NF-κB transcriptional gene sets, and reduced phosphorylation of RNA polymerase 2. Voruciclib on intermittent dosing was well tolerated, with no DLTs, paving the way for evaluation of the combination of voruciclib with venetoclax for patients with previously treated AML. This trial was registered at www.clinicaltrials.gov as #NCT03547115.

Blood AdvancesVol. 9(4)
Northwestern University (US), City Of Hope National Medical Center (US), Mayo Clinic (US), The University of Texas MD Anderson Cancer Center (US), Oregon Health & Science University (US), Medical College of Wisconsin (US), Mountain Lakes High School (US), WinnMed (US), NYU Langone Health (US), Swedish Medical Center (US), Swedish Medical Center (US), City of Hope (US), MEI Pharma (United States) (US), Dana-Farber Cancer Institute (US), Duke Medical Center (US), Duke University Health System (US), Robert H. Lurie Comprehensive Cancer Center of Northwestern University, OHSU Knight Cancer Institute, University of Nebraska Medical Center (US)
Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, Sanofi, Gilead Sciences, Celgene, FibroGen, Regeneron Pharmaceuticals, TG Therapeutics, Astex Pharmaceuticals, MEI Pharma, CareDx, BeiGene, Incyte, Ascentage Pharma, Daiichi-Sankyo, Servier, MorphoSys, Sun Pharma, National Institutes of Health, Genentech, Pharmacyclics
Good health and well-being
Openalex Percentile: Top 8%
Chronic Lymphocytic Leukemia Research
3.07
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