On January 15, 2020 Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases, reported that the first patient has been dosed in a Phase 2 study evaluating the investigational agent alvocidib, a potent CDK9 inhibitor, in patients with acute myeloid leukemia (AML) who have either relapsed from or are refractory to venetoclax in combination with a hypomethylating agent (HMA) (Press release, Tolero Pharmaceuticals, JAN 15, 2020, View Source [SID1234553246]). The open-label, randomized study has two parts and will evaluate the safety and efficacy of alvocidib in monotherapy or in combination with low-dose cytarabine.

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"Patients with AML who are resistant to or progressed following treatment with the BCL-2 inhibitor venetoclax in combination with an HMA have limited treatment options, and it has been well established in the literature that a key potential mechanism of resistance to BCL-2 targeted therapy is the switch to a dependence on MCL-1," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero Pharmaceuticals, Inc. "The initiation of this study marks an important step toward understanding the potential of alvocidib as a monotherapy or in combination with low-dose cytarabine for these patients. We believe that patients whose cancers have progressed following treatment with venetoclax may be sensitive to alvocidib and this trial will help us to better understand this hypothesis."

The primary objective of the Phase 2 study is to determine the rate of combined complete remission (CR) and CR with incomplete hematological recovery (CRi), of alvocidib and alvocidib in combination with low-dose cytarabine in patients with AML. Secondary objectives include establishing the recommended treatment regimen for the second part of the study and evaluating the median overall survival (mOS) and CR rate. Additional secondary outcome measures include evaluating event-free survival (EFS), duration of composite CR (CRc), safety and tolerability of the regimen and mortality.

In the first part of the study, patients who are refractory to or have relapsed on venetoclax in combination with an HMA will be randomized into two arms. In Arm 1 of the study, patients will receive combination therapy of alvocidib and low-dose cytarabine. In Arm 2 of the study, patients will receive alvocidib monotherapy. In the second part of the study, patients will receive the regimen based on the outcome of the first part.

The trial is being conducted at sites in the United States. Additional information on this trial, including comprehensive inclusion and exclusion criteria, can be accessed at www.ClinicalTrials.gov (NCT03969420).

About Alvocidib
Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in the Phase 2 studies, Zella 202 in patients with acute myeloid leukemia (AML) who have either relapsed from or are refractory to venetoclax in combination with azacytidine or decitabine (NCT03969420) and Zella 201 in patients with relapsed or refractory MCL-1 dependent AML, in combination with cytarabine and mitoxantrone (NCT02520011). Alvocidib is also being evaluated in Zella 101, a Phase 1 clinical study evaluating the maximum tolerated dose, safety and clinical activity of alvocidib in combination with cytarabine and daunorubicin (7+3) in newly diagnosed patients with AML (NCT03298984), and Zella 102, a Phase 1b/2 study in patients with myelodysplastic syndromes (MDS) in combination with decitabine (NCT03593915). In addition, alvocidib is being evaluated in a Phase 1 study in patients with relapsed or refractory AML in combination with venetoclax (NCT03441555).

About CDK9 Inhibition and MCL-1
MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.1 In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.2 MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse or resistance to treatment.1,3 The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).4,5 Because of the short half-life of MCL-1 (2-4 hours), the effects of targeting upstream pathways are expected to reduce MCL-1 levels rapidly.4 Inhibition of CDK9 has been shown to block MCL-1 transcription, resulting in the rapid downregulation of MCL-1 protein, thus restoring the normal apoptotic regulation.1