Phase I study of MLN8237 - Investigational Aurora A kinase inhibitor - In relapsed/refractory multiple myeloma, non-Hodgkin lymphoma and chronic lymphocytic leukemia

Kevin R. Kelly, Thomas C. Shea, André Goy, Jesus G. Berdeja, Craig B. Reeder, Kevin T. McDonagh, Xiaofei Zhou, Hadi Danaee, Hua Liu, Jeffrey A. Ecsedy, Huifeng Niu, Ely Benaim, Swaminathan Padmanabhan Iyer

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Purpose: Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported in several heme-lymphatic malignancies. MLN8237 (alisertib) is a novel inhibitor of AAK that is being developed for the treatment of advanced malignancies. The objectives of this phase I study were to establish the safety, tolerability, and pharmacokinetic profiles of escalating doses of MLN8237 in patients with relapsed or refractory heme-lymphatic malignancies. Methods: Sequential cohorts of patients received MLN8237 orally as either a powder-in-capsule (PIC) or enteric-coated tablet (ECT) formulation. Patients received MLN8237 PIC 25-90 mg for 14 or 21 consecutive days plus 14 or 7 days' rest, respectively, or MLN8237 ECT, at a starting dose of 40 mg/day once-daily (QD) for 14 days plus 14 days' rest, all in 28-day cycles. Subsequent cohorts received MLN8237 ECT 30-50 mg twice-daily (BID) for 7 days plus 14 days' rest in 21-day cycles. Results: Fifty-eight patients were enrolled (PIC n=28, ECT n=30). The most frequent grade ≥3 drug-related toxicities were neutropenia (45 %), thrombocytopenia (28 %), anemia (19 %), and leukopenia (19 %). The maximum tolerated dose on the ECT 7-day schedule was 50 mg BID. The terminal half-life of MLN8237 was approximately 19 h. Six (13 %) patients achieved partial responses and 13 (28 %) stable disease. Conclusion: The recommended phase II dose of MLN8237 ECT is 50 mg BID for 7 days in 21-day cycles, which is currently being evaluated as a single agent in phase II/III trials in patients with peripheral T-cell lymphoma.

Original languageEnglish (US)
Pages (from-to)489-499
Number of pages11
JournalInvestigational New Drugs
Volume32
Issue number3
DOIs
StatePublished - Jun 2014

Keywords

  • Aurora A kinase inhibitor
  • Cell cycle mechanisms of anticancer drug action
  • MLN8237
  • Novel antitumor agent
  • Phase I-III Leukemia and lymphomas

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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    Kelly, K. R., Shea, T. C., Goy, A., Berdeja, J. G., Reeder, C. B., McDonagh, K. T., Zhou, X., Danaee, H., Liu, H., Ecsedy, J. A., Niu, H., Benaim, E., & Padmanabhan Iyer, S. (2014). Phase I study of MLN8237 - Investigational Aurora A kinase inhibitor - In relapsed/refractory multiple myeloma, non-Hodgkin lymphoma and chronic lymphocytic leukemia. Investigational New Drugs, 32(3), 489-499. https://doi.org/10.1007/s10637-013-0050-9