TY - JOUR
T1 - Phase I study of MLN8237 - Investigational Aurora A kinase inhibitor - In relapsed/refractory multiple myeloma, non-Hodgkin lymphoma and chronic lymphocytic leukemia
AU - Kelly, Kevin R.
AU - Shea, Thomas C.
AU - Goy, André
AU - Berdeja, Jesus G.
AU - Reeder, Craig B.
AU - McDonagh, Kevin T.
AU - Zhou, Xiaofei
AU - Danaee, Hadi
AU - Liu, Hua
AU - Ecsedy, Jeffrey A.
AU - Niu, Huifeng
AU - Benaim, Ely
AU - Padmanabhan Iyer, Swaminathan
N1 - Funding Information:
The authors would also like to acknowledge Nadia Korfali of FireKite for writing assistance in the development of this manuscript, which was funded by Millennium: The Takeda Oncology Company.
PY - 2014/6
Y1 - 2014/6
N2 - 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.
AB - 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.
KW - Aurora A kinase inhibitor
KW - Cell cycle mechanisms of anticancer drug action
KW - MLN8237
KW - Novel antitumor agent
KW - Phase I-III Leukemia and lymphomas
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U2 - 10.1007/s10637-013-0050-9
DO - 10.1007/s10637-013-0050-9
M3 - Article
C2 - 24352795
AN - SCOPUS:84904579971
SN - 0167-6997
VL - 32
SP - 489
EP - 499
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 3
ER -