On June 12, 2020 Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases, reported that data from the completed Phase 1 Zella 101 study evaluating the investigational agent alvocidib, a potent CDK9 inhibitor, in adult patients with newly diagnosed acute myeloid leukemia (AML) (Press release, Tolero Pharmaceuticals, JUN 12, 2020, View Source [SID1234561070]). These results were presented in a poster presentation at the 25th European Hematology Association (EHA) (Free EHA Whitepaper) Virtual Congress, being held June 11-14, 2020.

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Updated findings from the Phase 1, dose-escalation, safety and biomarker study of alvocidib followed by cytarabine and daunorubicin (7+3) induction therapy showed encouraging clinical activity and a tolerable safety profile in adults with newly diagnosed AML. In the study, 71% (n=22 of 31) of evaluable patients achieved complete remission (CR), with an overall response rate (ORR) of 77% (n=24 of 31). Additionally, an exploratory cohort of the study found that 89% (n=8 of 9) of patients achieved measurable residual disease (MRD)-negativity. At a median of 9.2 months follow-up, overall survival was not reached, with 62% of patients alive at data cut-off.1

The maximum tolerated dose of alvocidib was determined to be 30 mg/m2 IV bolus followed by 60 mg/m2 IV over 4 hours and no dose-limiting toxicities (DLTs) were observed. The most frequently observed treatment-emergent, nonhematologic adverse events of Grade 3 or higher were diarrhea, tumor lysis syndrome and hypocalcemia, which all resolved with supportive care.1

"AML is an aggressive blood cancer which can progress rapidly and remains difficult to treat. We are pleased with the clinical responses, including overall survival, observed in newly diagnosed AML patients treated with alvocidib followed by standard induction therapy. In addition, the high level of MRD-negativity, a meaningful indicator of durable response, is particularly encouraging," said David J. Bearss, Ph.D., Chief Executive Officer, Tolero Pharmaceuticals, and Chief Scientific Officer and Global Head of Research, Global Oncology. "We are excited to continue the advancement of this program and further investigate the potential role of alvocidib in contributing to a durable complete remission and achievement of MRD-negativity."

Below are the details for the presentation:

Abstract Title

Details

Author

Alvocidib Followed by 7+3 Induction in
Newly Diagnosed AML Achieves High
Rates of MRD-Negative CR: Results of a
Phase 1 Dose Escalation Study

Poster# 551

June 12, 2020

8:30 a.m. CEST

e-Poster Presentation

Joshua F. Zeidner, M.D.,
University of
North Carolina

About Alvocidib

Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in the ongoing Phase 2 Zella 202 study in patients with acute myeloid leukemia (AML) who have either relapsed from or are refractory to venetoclax in combination with azacitidine or decitabine (NCT03969420). Alvocidib is also being evaluated in Zella 102, a Phase 1b/2 study in patients with myelodysplastic syndromes (MDS) in combination with azacitidine or decitabine (NCT03593915) and 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.2 In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.3 MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse or resistance to treatment.2,4 The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).5,6 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.5 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.2