MEI Pharma Announces Acceptance of Abstract for Presentation at ASH 2023
Presentation Title: A Phase 1 Study of the Oral CDK9 Inhibitor Voruciclib in Relapsed/Refractory (R/R) B-Cell Lymphoma (NHL) or Acute Myeloid Leukemia (AML)
Session Title: Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster III (616)
Publication Number: 4286
About the Phase 1 Study
The Phase 1 study is a two stage, open-label, 3+3 dose escalation and expansion study evaluating voruciclib, a CDK9 inhibitor, as a monotherapy and in combination with venetoclax (marketed as Venclexta®), a BCL2 inhibitor. Inhibition of CDK9 blocks the production of Mcl-1, which is an established resistance mechanism to the BCL2 inhibitor venetoclax. The primary objectives of the study are to determine the safety and biologic effective dose of voruciclib monotherapy or voruciclib in combination with venetoclax. Secondary objectives of the study include assessing the preliminary efficacy, pharmacokinetics, pharmacodynamics, and biomarkers of voruciclib monotherapy or voruciclib in combination with venetoclax.
The first stage of the study, evaluating the dose and schedule of voruciclib as a single-agent in patients with relapsed and refractory (“R/R”) acute myeloid leukemia (“AML”) or B-cell malignances after failure of standard therapies, is now completed and the final results presented in the abstract. Stage 2 of the study is evaluating voruciclib in combination with standard dose venetoclax in patients with R/R AML.
Voruciclib is an orally administered cyclin-dependent kinase 9 (“CDK9”) inhibitor with potential to treat both hematological malignancies and solid tumors. It is in clinical development for acute myeloid leukemia and B-cell malignancies. Applications in solid tumors are also being considered.
The CDK family of proteins are important cell cycle regulators responsible for the control of cell proliferation, differentiation, apoptosis, and DNA repair. CDK9, one of several members of the CDK family of proteins, functions as a gene transcription controller and is also involved in regulating protein degradation. Specifically, CDK9 is a promising target to treat a range of cancers because of its role in controlling two other proteins often dysregulated in cancerous cells: myeloid leukemia cell differentiation protein ("Mcl-1") and the MYC proto-oncogene protein ("MYC")
Mcl-1 is a member of the family of anti-apoptotic proteins which, when elevated, may prevent the cell from undergoing cell death. Inhibition of CDK9 blocks the production of Mcl-1, which is an established resistance mechanism to the B-cell lymphoma 2 ("BCL2") inhibitor venetoclax (marketed as Venclexta®).
MYC regulates cell proliferation and growth. Upregulation of MYC is implicated in many human cancers and is frequently associated with poor prognosis and unfavorable patient survival. CDK9, in addition to being a transcription factor for MYC, also decreases phosphorylation of MYC protein that is implicated in stabilizing MYC in KRAS mutant cancers. Targeting MYC directly has historically been difficult, but CDK9 is a promising approach to target this oncogene.
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