Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia
| Autor: | Kathryn Kolibaba, Daniel J. Lee, Joshua F. Zeidner, Stephen P. Anthony, David J. Bearss, Judy Costas, Gil Fine, Mark G. Frattini, B. Douglas Smith |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Oncology
Adult Male Cancer Research medicine.medical_specialty Daunorubicin Disease-Free Survival Drug Administration Schedule 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Piperidines hemic and lymphatic diseases Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Aged Flavonoids Mitoxantrone Dose-Response Relationship Drug business.industry Remission Induction Cytarabine Myeloid leukemia Alvocidib Middle Aged medicine.disease Progression-Free Survival Tumor lysis syndrome Cytokine release syndrome Regimen Leukemia Myeloid Acute chemistry 030220 oncology & carcinogenesis Female Neoplasm Recurrence Local business 030215 immunology medicine.drug |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 27(1) |
| ISSN: | 1557-3265 |
| Popis: | Purpose: 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. Patients and Methods: 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. Results: 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). Conclusions: 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. |
| Databáze: | OpenAIRE |
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