Phase I Study of Aurora A Kinase Inhibitor Alisertib (MLN8237) in Combination With Selective VEGFR Inhibitor Pazopanib for Therapy of Advanced Solid Tumors.

OBJECTIVES

Pazopanib is a multikinase angiogenesis inhibitor. Alisertib is a highly selective inhibitor of mitotic Aurora A kinase. There is preclinical evidence that mitosis-targeting agents exhibit antiangiogenic effects. Thus, the combination of these 2 agents may have a synergistic effect on tumor vasculature. The primary objective of this study is to determine the optimal tolerated dose (OTD) for alisertib and pazopanib.

MATERIALS AND METHODS

This phase 1b study evaluated the OTD of alisertib twice a day, on days 1 to 7 with pazopanib, once a day, continuously in a 21-day cycle, both taken orally. Disease response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 every 2 cycles. OTD cohort was expanded to assure safety and perform pharmacokinetics analysis.

RESULTS

A total of 27 patients received treatment. Seventy-seven percent of the patients had received at least 3 prior chemotherapy regimens. Dose-limiting toxicities occurred in dose level (DL) 2+ (grade 4 thrombocytopenia and grade 3 mucositis) and DL 3 (grade 3 liver transaminases elevation and grade 3 abdominal pain). The OTD was determined to be DL 2: alisertib 20 mg twice daily and pazopanib 600 mg daily. Pharmacokinetic analysis revealed that clearance of alisertib was reduced by ∼40% in the presence of pazopanib compared with clearance in the absence of pazopanib. Fourteen patients had stable disease and 2 patients had a partial response.

CONCLUSIONS

The combination of alisertib with pazopanib demonstrates manageable safety and early clinical evidence of antitumor activity in patients with advanced malignancies (NCT01639911).