Alvocidib (CDK9 Inhibitor)

Alvocidib is an investigational, intravenously administered, small molecule cyclin-dependent kinase 9 (CDK9) inhibitor.1

MECHANISM OF ACTION

Alvocidib is a potent inhibitor of CDK9.2 The primary function of CDK9 is to activate transcription elongation by phosphorylating the C-terminal domain of RNA polymerase II.3 By inhibiting CDK9, alvocidib downregulates the transcription of target genes, including MCL1.1 In MCL-1–dependent acute myeloid leukemia (AML), downregulation of MCL-1 protein expression can trigger apoptosis of leukemic blasts.4

diagram showing the relationship of CDK9 and MCL-1 expression

CLINICAL ACTIVITY

Alvocidib has shown clinical activity in multiple types of solid tumors and hematologic malignancies.2 Tolero’s initial focus is the development of alvocidib in MCL-1–dependent AML.

Proof of concept was shown in a multicenter, randomized, phase 2 clinical trial, in which alvocidib in combination with cytarabine and mitoxantrone (ACM) was compared to the standard-of-care cytarabine/daunorubicin (7+3) regimen in newly diagnosed, intermediate- and high-risk AML patients. ACM showed a significant improvement in the complete remission (CR) rate compared to 7+3.5

A phase 2, biomarker-driven, clinical trial (Zella 201) is currently being conducted to compare ACM with cytarabine and mitoxantrone in patients with MCL-1–dependent, relapsed or refractory AML.

A phase 1 trial (Zella 101) is currently being conducted to evaluate the maximum tolerated dose, safety and clinical activity of alvocidib and cytarabine/daunorubicin (7+3) in patients with newly diagnosed, intermediate- and high-risk AML.

Alvocidib is an investigational agent and is not approved by the US FDA or any other regulatory authorities.

References: 1. Yeh YY, Chen R, Hessler J, et al. Up-regulation of CDK9 kinase activity and Mcl-1 stability contributes to the acquired resistance to cyclin-dependent kinase inhibitors in leukemia. Oncotarget. 2015;6(5):2667-2679. 2. Morales F, Giordano A. Overview of CDK9 as a target in cancer research. Cell Cycle. 2016;15(4):519-527. 3. Ocana A, Pandiella A. Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies. Oncotarget. 2017;8(13):22218-22234. 4. Thomas D, Powell JA, Vergez F, et al. Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood. 2013;122(5):738-748. 5. Zeidner JF, Foster MC, Blackford AL, et al. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015;100(9):1172-1179

  


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