On June 14, 2019 Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases, reported data for the first time from the ongoing Phase 1 Zella 101 study evaluating the safety and clinical activity of alvocidib, a potent CDK9 inhibitor, in combination with cytarabine and daunorubicin in patients with newly diagnosed acute myeloid leukemia (AML) (Press release, Tolero Pharmaceuticals, JUN 14, 2019, View Source [SID1234537097]). These results were presented in a poster presentation at the 24th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper), being held June 13-16, 2019 in Amsterdam, The Netherlands.

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Preliminary data from the study indicated that alvocidib in combination with cytarabine and daunorubicin has shown clinical activity with acceptable safety in patients with newly diagnosed AML. Of the 18 evaluable patients, more than three-quarters (78%, n=14) achieved a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi). Of these patients attaining a CR/CRi, 78% (n=11) reached the 30-day post-study evaluation, per the study protocol. A subset of these patients, 27% (n=3 of 11) proceeded to stem cell transplant. Additionally, among adverse cytogenic risk patients (n=9) who generally respond poorly to induction therapy, two-thirds (67%, n=6 of 9), achieved a CR/CRi.1

Of the patients that attained a CR/CRi (n=14), 10 (71%) are still in remission with a median follow-up of 76 days. In addition, 21 of 22 (95%) enrolled patients are still alive, with a median follow-up of 70 days.

Adverse events (AEs) in the study include diarrhea, tumor lysis syndrome, infections and elevated AST levels and were consistent with those noted in previous alvocidib studies.1

"These preliminary data from the Zella 101 study in patients with newly diagnosed AML are encouraging, as they add to the growing body of evidence from the alvocidib clinical program," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero Pharmaceuticals. "We look forward to continuing this study to further our understanding of how the combination of alvocidib with cytarabine and daunorubicin may benefit this patient population."

Additional data from Tolero’s pipeline will also be presented in an oral presentation at the meeting, highlighting the impact of investigational agent TP-0903, an oral AXL receptor tyrosine kinase (RTK) inhibitor, on Axl-RTK inhibition in patients with several tumors, including chronic lymphocytic leukemia (CLL).

Below are the details for the presentations:

Abstract Title

Details

Zella 101: Phase 1 Study of Alvocidib
Followed by 7+3 Induction in Newly
Diagnosed AML Patients

Abstract # PF285

June 14, 5:30-7 p.m. CEST

Poster Presentation

AXL-RTK Inhibition Directs the
Functional Phenotype of Chimeric
Antigen Receptor T Cells

Abstract # S909

June 15, 4-4:15 p.m. CEST

Oral Presentation

About Alvocidib
Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in a Phase II study, Zella 201, in patients with relapsed or refractory MCL-1 dependent acute myeloid leukemia, AML, in combination with cytarabine and mitoxantrone (NCT02520011). Alvocidib is also being evaluated in Zella 101, a Phase I clinical study evaluating the maximum tolerated dose, safety and clinical activity of alvocidib in combination with (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.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 In MCL-1–dependent AML, 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