Phase I Assessment of New Mechanism-Based Pharmacodynamic Biomarkers for MLN8054, a Small-Molecule Inhibitor of Aurora A Kinase

Abstract

The mitotic kinase Aurora A is an important therapeutic target for cancer therapy. This study evaluated new mechanism-based pharmacodynamic biomarkers in cancer patients in two phase I studies of MLN8054, a small-molecule inhibitor of Aurora A kinase. Patients with advanced solid tumors received MLN8054 orally for 7 consecutive days in escalating dose cohorts, with skin and tumor biopsies obtained before and after dosing. Skin biopsies were evaluated for increased mitotic cells within the basal epithelium. Tumor biopsies were assessed for accumulation of mitotic cells within proliferative tumor regions. Several patients in the highest dose cohorts showed marked increases in the skin mitotic index after dosing. Although some tumors exhibited increases in mitotic cells after dosing, others displayed decreases, a variable outcome consistent with dual mechanisms of mitotic arrest and mitotic slippage induced by antimitotics in tumors. To provide a clearer picture, mitotic cell chromosome alignment and spindle bipolarity, new biomarkers of Aurora A inhibition that act independently of mitotic arrest or slippage, were assessed in the tumor biopsies. Several patients, primarily in the highest dose cohorts, had marked decreases in the percentage of mitotic cells with aligned chromosomes and bipolar spindles after dosing. Evidence existed for an exposure-effect relationship for mitotic cells with defects in chromosome alignment and spindle bipolarity that indicated a biologically active dose range. Outcomes of pharmacodynamic assays from skin and tumor biopsies were concordant in several patients. Together, these new pharmacodynamic assays provide evidence for Aurora A inhibition by MLN8054 in patient skin and tumor tissues. Cancer Res; 71(3); 675-85. Ó2010 AACR.

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

“…MLN8054 showed sustained growth inhibition in multiple human tumor xenografts, with phenotypes consistent with AAK inhibition, in preclinical studies (25). In clinical studies, similar pharmacodynamic effects were reported, indicating AAK inhibition in skin and tumor tissues (34)(35)(36); however, dose escalation was stopped, and the MLN8054 development program discontinued, based on benzodiazepine-like somnolence and neurocognitive changes (34). Consistent with the expected activity of an AAK inhibitor, treatment with the second-generation agent MLN8237 has been shown to be associated with an accumulation of cells with abnormal mitotic spindles, leading to decreased proliferation and apoptosis in a range of human tumor cell lines (37)(38)(39)(40)(41)(42)(43).…”

“…Tumor biopsies were collected before dosing on day 1 and 6 to 8 hours postdose on days 1, 7, 14, and 21. Immunolabeling of skin and tumor biopsies for the quantification of mitotic cells and of tumor biopsies for the assessment of chromosome alignment and spindle bipolarity were conducted as previously described (36). For detection of apoptotic cells, 5-mm sections of formalin-fixed, paraffin-embedded skin punch biopsies were deparaffinized and stained by standard methods with hematoxylin and eosin using a Leica Autostainer XL (Meyer Instruments, Inc.).…”

“…MLN8237 (alisertib) is an investigational, orally administered, small-molecule inhibitor that is selective for AAK (32,33). MLN8237 was developed, in part, on the basis of preclinical (25) and clinical studies (34)(35)(36) with a firstgeneration agent, MLN8054. MLN8054 showed sustained growth inhibition in multiple human tumor xenografts, with phenotypes consistent with AAK inhibition, in preclinical studies (25).…”

Evaluation of the Aurora Kinase Inhibitor, ZM447439, in Canine Malignant Lymphoid Cells <i>in Vitro</i>

“…A number of small-molecule aurora kinase inhibitors have recently been developed and intensively investigated both experimentally and in numerous clinical trials in human medicine [16,[21][22][23]. However, there are no published data showing the effect of aurora kinase inhibitors in veterinary medicine at the time of this writing.…”

“…ZM447439 does not interfere with the activities of regular cell cycles in normal cells, and does not affect important regulators such as cdc2, cdc25, MAPK (Mitogen-Activated Protein Kinase) or cyclin B [18]. Aurora kinases are now an attractive target in human cancer therapy, and intensive research including preclinical and clinical trials have been reported [19][20][21][22][23]; however, to our knowledge, scant information exists on the efficacy of aurora kinase inhibition in veterinary medicine.…”