Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

Abstract

Purpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors.Experimental Design: Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7-and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration-time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed.Results: Neutropenia and stomatitis were the most common DLTs. The MTD for the 7-and 21-day schedules was 50 mg twice daily and 50 mg once daily, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was approximately 19 hours. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposure-related increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity.Conclusions: The recommended phase II dose of MLN8237 is 50 mg twice daily on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase III trial in peripheral T-cell lymphoma.

Recent advances in the development of Aurora kinases inhibitors in hematological malignancies

“…The most common grade 3-4 adverse events reported were neutropenia in over half of the patients, anemia and thrombocytopenia in a third of the patients and a few with stomatitis, febrile neutropenia and fatigue. The toxicity profile was similar to that reported in early-phase trials of patients with solid tumors, in which neutropenia and stomatitis were the most commonly observed toxicities with a similar dose and schedule [Cervantes et al 2012;Dees et al 2012].…”

Targeted Delivery of Silver Nanoparticles and Alisertib: In Vitro and In Vivo Synergistic Effect Against Glioblastoma

“…Ali has been chosen as pharmacologic model for drug loading because of its effect as a selective AAK inhibitor and because its application against solid tumors (epi thelial ovarian, fallopian tube and primary peritoneal carcinoma) is well known [31][32][33]. In this work, we also studied the synergic effect of Ali and AgNPs.…”

Phase II Intergroup Trial of Alisertib in Relapsed and Refractory Peripheral T-Cell Lymphoma and Transformed Mycosis Fungoides: SWOG 1108

“…Additional toxicities, including mucositis and somnolence, related to ␥-aminobutyric acid A ␣-1 benzodiazepine receptor binding, were ameliorated with use of the recommended phase II dose of 50 mg twice a day for 7 of 21 days. 7,8 A phase II study using this dose and schedule of alisertib demonstrated clinical responses in a variety of aggressive B-and T-cell lymphomas. A 27% overall response rate was observed, including four of eight patients with T-cell histologies.…”