R. A. Kudgus,1 E. Fox,2 R. M. McGovern,1 G. Moorthy,2 A. Marachelian,3 S. G. DuBois,4 J. M. Reid1; 1Mayo Clinic, Rochester, MN, 2Children’s Hospital of Philadelphia, Philadelphia, PA, 3Children’s Hospital Los Angeles, Los Angeles, CA, 4University of California, San Francisco, San Francisco, CA

BACKGROUND: Neuroblastoma is a rare cancer of the sympathetic nervous system. There are 700 new cases in the US each year. 40% of patients with high-risk disease relapse. Alisertib (MLN8237) is an investigational, oral Aurora A kinase inhibitor that has shown promise in preclinical and clinical studies in neuroblastoma. This study was the first to evaluate alisertib in combination with irinotecan (IRN) and temozolomide (TMZ). Metabolism of both alisertib and IRN includes glucuronidation via UGT1A1. We studied the pharmacokinetics (PK) of alisertib and IRN and performed genotyping for UGT1A1*28 and PBREM to study associations with PK.
METHODS: Subjects received IRN (50 mg/m2/day) and TMZ (100 mg/m2/day) on days 1-5 and alisertib enteric-coated tablets once daily on days 1-7. Three alisertib dose levels were investigated: 45; 60; and 80 mg/m2. In cycle 1, serial plasma samples were obtained following Day 4 dosing in all subjects. The PK of alisertib and IRN as well as active (SN-38) and inactive metabolites (APC, SN-38G) were determined using LC/MSMS and HPLC, respectively.
RESULTS: 22 Subjects, median (range) age of 8 (4-22) years, were evaluated. The mean alisertib half-life and apparent clearance were 8.7 ± 4.7 h, 0.094 ± 0.16 L/min/m2, respectively. Alisertib had overlapping AUC at each dose level. The AUC for IRN and SN-38 remained constant over all alisertib dose levels (3465 ± 516, 78 ± 17 h•ng/mL, respectively). No associations were observed between UGT1A1*28 and PBREM genotypes with alisertib or IRN PK in this small cohort.
CONCLUSION: There appears to be no effect of alisertib on IRN PK. PK is being studied further in patients enrolling to the Phase II portion of the study and in patients receiving alisertib oral solution.