mln-8237 and Multiple-Myeloma

Topics: Aged; Aurora Kinases; Azepines; Bortezomib; Female; Humans; Male; Middle Aged; Multiple Myeloma; Protein Kinase Inhibitors; Pyrimidines; Recurrence; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Aurora Kinase A; Azepines; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrimidines

Topics: Aminoglycosides; Aurora Kinase A; Azepines; Cell Cycle; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Multiple Myeloma; Protein Binding; Pyrimidines

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Aurora Kinase A; Azepines; Chimera; fms-Like Tyrosine Kinase 3; Fusion Proteins, bcr-abl; Hematology; Humans; Leukemia, Myeloid, Acute; Lymphoma, T-Cell, Peripheral; Multiple Myeloma; Pyrimidines; Societies, Medical; Staurosporine; T-Lymphocytes; United States

Aurora-A is a mitotic kinase that regulates mitotic spindle formation and segregation. In multiple myeloma (MM), high Aurora-A gene expression has been correlated with centrosome amplification and proliferation; thus, inhibition of Aurora-A in MM may prove to be therapeutically beneficial. Here we assess the in vitro and in vivo anti-MM activity of MLN8237, a small-molecule Aurora-A kinase inhibitor. Treatment of cultured MM cells with MLN8237 results in mitotic spindle abnormalities, mitotic accumulation, as well as inhibition of cell proliferation through apoptosis and senescence. In addition, MLN8237 up-regulates p53 and tumor suppressor genes p21 and p27. Combining MLN8237 with dexamethasone, doxorubicin, or bortezomib induces synergistic/additive anti-MM activity in vitro. In vivo anti-MM activity of MLN8237 was confirmed using a xenograft-murine model of human-MM. Tumor burden was significantly reduced (P = .007) and overall survival was significantly increased (P < .005) in animals treated with 30 mg/kg MLN8237 for 21 days. Induction of apoptosis and cell death by MLN8237 were confirmed in tumor cells excised from treated animals by TdT-mediated dUTP nick end labeling assay. MLN8237 is currently in phase 1 and phase 2 clinical trials in patients with advanced malignancies, and our preclinical results suggest that MLN8237 may be a promising novel targeted therapy in MM.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Aurora Kinase A; Aurora Kinases; Azepines; Boronic Acids; Bortezomib; Cell Cycle; Cell Line, Tumor; Cellular Senescence; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dexamethasone; Doxorubicin; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, SCID; Multiple Myeloma; Neoplasm Transplantation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrazines; Pyrimidines; Spindle Apparatus; Time Factors; Transplantation, Heterologous; Tumor Suppressor Proteins; Xenograft Model Antitumor Assays