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

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.

• Authors: 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
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 3 Pg. 489-99 (Jun 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 24352795 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Azepines
• MLN 8237
• Protein Kinase Inhibitors
• Pyrimidines
• AURKA protein, human
• Aurora Kinase A

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Aurora Kinase A (antagonists & inhibitors, genetics, metabolism)
• Azepines (administration & dosage, adverse effects, pharmacokinetics)
• Female
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, genetics, metabolism)
• Lymphoma, Non-Hodgkin (drug therapy, genetics, metabolism)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Multiple Myeloma (drug therapy, genetics, metabolism)
• Neoplasm Recurrence, Local (drug therapy, genetics, metabolism)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics)