Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia.

Abstract

Alvocidib is a cyclin-dependent kinase 9 inhibitor leading to downregulation of the antiapoptotic BCL-2 family member, MCL-1. Alvocidib has shown clinical activity in a timed sequential regimen with cytarabine and mitoxantrone in relapsed/refractory and newly diagnosed acute myeloid leukemia (AML) but has not been studied in combination with traditional 7+3 induction therapy. A multiinstitutional phase I dose-escalation study of alvocidib on days 1-3 followed by 7+3 (cytarabine 100 mg/m²/day i.v. infusion days 5-12 and daunorubicin 60 mg/m² i.v. days 5-7) was performed in newly diagnosed AML ≤65 years. Core-binding factor AML was excluded. There was no MTD on this study; the recommended phase II dose of alvocidib was 30 mg/m² i.v. over 30 minutes followed by 60 mg/m² i.v. infusion over 4 hours. There was one dose-limiting toxicity of cytokine release syndrome. The most common grade ≥3 nonhematologic toxicities were diarrhea (44%) and tumor lysis syndrome (34%). Overall, 69% (22/32) of patients achieved complete remission (CR). In an exploratory cohort, eight of nine (89%) patients in complete remission had no measurable residual disease, as determined by a centralized flow cytometric assay. Clinical activity was seen in patients with secondary AML, AML with myelodysplastic syndrome-related changes, and a genomic signature of secondary AML (50%, 50%, and 92% CR rates, respectively). Alvocidib can be safely administered prior to 7+3 induction with encouraging clinical activity. These findings warrant further investigation of alvocidib combinations in newly diagnosed AML. This study was registered at clinicaltrials.gov identifier NCT03298984.