Alvocidib (CDK9 Inhibitor)
Alvocidib is a cyclin-dependent kinase (CDK) inhibitor with selective activity against CDK9.1
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
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 study, in which alvocidib in combination with cytarabine and mitoxantrone (ACM) was compared to the standard-of-care 7+3 chemotherapy 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 study (TPI-ALV-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 study (TPI-ALV-101) is currently being conducted to evaluate the safety and tolerability 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.