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Phase I study of MLN8237—investigational Aurora A kinase inhibitor—in relapsed/refractory multiple myeloma, Non-Hodgkin lymphoma and chronic lymphocytic leukemia
- Source :
- Investigational New Drugs
- Publisher :
- Springer Nature
-
Abstract
- SummaryPurpose 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.
- Subjects :
- Adult
Male
medicine.medical_specialty
Maximum Tolerated Dose
Chronic lymphocytic leukemia
Aurora A kinase
Antineoplastic Agents
Pharmacology
Neutropenia
Cell cycle mechanisms of anticancer drug action
Gastroenterology
Aurora A kinase inhibitor
Phase I-III Leukemia and lymphomas
chemistry.chemical_compound
Refractory
Phase I Studies
Internal medicine
medicine
Humans
Pharmacology (medical)
Protein Kinase Inhibitors
Multiple myeloma
Aged
Aurora Kinase A
Aged, 80 and over
Leukopenia
MLN8237
business.industry
Lymphoma, Non-Hodgkin
Azepines
Middle Aged
medicine.disease
Leukemia, Lymphocytic, Chronic, B-Cell
Novel antitumor agent
Pyrimidines
Tolerability
chemistry
Oncology
Alisertib
Female
Neoplasm Recurrence, Local
medicine.symptom
Multiple Myeloma
business
Subjects
Details
- Language :
- English
- ISSN :
- 01676997
- Volume :
- 32
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Investigational New Drugs
- Accession number :
- edsair.doi.dedup.....f071212ad92943915d1a90c2583f71ee
- Full Text :
- https://doi.org/10.1007/s10637-013-0050-9