Population Pharmacokinetics and Exposure‐Safety Relationships of Alisertib in Children and Adolescents With Advanced Malignancies

Abstract

Population pharmacokinetic (PK) and exposure‐safety analyses of alisertib were performed in children enrolled in 2 clinical trials: NCT02444884 and NCT01154816. NCT02444884 was a dose‐finding study in children with relapsed/refractory solid malignancies (phase 1) or neuroblastomas (phase 2). Patients received oral alisertib 45 to 100 mg/m2 as powder‐in‐capsule once daily or twice daily for 7 days in 21‐day cycles. Serial blood samples were collected up to 24 hours after dosing on cycle 1, day 1. NCT01154816 was a phase 2 single‐arm study evaluating efficacy in children with relapsed/refractory solid malignancies or acute leukemias. Patients received alisertib 80 mg/m2 as enteric‐coated tablets once daily for 7 days in 21‐day cycles. Sparse PK samples were collected up to 8 hours after dosing on cycle 1, day 1. Sources of alisertib PK variability were characterized and quantified using nonlinear mixed‐effects modeling to support dosing recommendations in children and adolescents. A 2‐compartment model with oral absorption described by 3 transit compartments was developed using data from 146 patients. Apparent oral clearance and central distribution volume were correlated with body surface area across the age range of 2 to 21 years, supporting the use of body surface area–based alisertib dosing in the pediatric population. The recommended dose of 80 mg/m2 once daily enteric‐coated tablets provided similar alisertib exposures across pediatric age groups and comparable exposure to that in adults receiving 50 mg twice daily (recommended adult dose). Statistically significant relationships (P < .01) were observed between alisertib exposures and incidence of grade ≥2 stomatitis and febrile neutropenia, consistent with antiproliferative mechanism‐related toxicities.

Knowledge mapping of AURKA in Oncology：An advanced Bibliometric analysis (1998–2023)

“… NCT No. Regimen Cancer Cohort Cases Phases End Year Ref NCT01154816 Alisertib Advanced Malignancies 118 II 2019 Ref [ 94 ] NCT01045421 Alisertib Advanced Solid Tumors 273 I|II 2014 Ref [ 12 ] NCT01512758 Alisertib Advanced Malignancies 36 I 2013 Ref [ 95 ] NCT01653028 Alisertib Advanced/Metastatic Sarcoma 72 II 2015 Ref [ 96 ] NCT02444884 Alisertib Relapsed/Refractory Solid Tumors 54 I 2011 Ref [ 97 ] NCT00807495 Alisertib Lymphoma 48 II 2013 Ref [ 98 ] NCT01466881 Alisertib Lymphoma …”

Development and therapeutic evaluation of 5D3(CC-MLN8237)3.2 antibody-theranostic conjugates for PSMA-positive prostate cancer therapy

“…The deregulation of Aurora A kinase is shown to induce mitotic arrest followed by apoptosis as well as severe mitotic abnormalities that result in selective lethality for many types of solid and hematological malignancies ( Du and Hannon, 2004 ; Harrington et al, 2004 ; Cheung et al, 2009 ; Perez Fidalgo et al, 2009 ; Moore et al, 2010 ; Malumbres and Perez de Castro, 2014 ). Because of its significant role in mitotic progression and tumor proliferation ( Cheung et al, 2009 ), Aurora A kinase inhibition would be expected to have an antitumor effect across a broad range of human tumors ( Zhou et al, 2022 ). Alisertib (MLN8237) is a selective small molecular Aurora-A kinase inhibitor that is investigated for treatment as a single agent or in combination with other agents across a range of solid and hematologic malignancies ( Manfredi et al, 2011 ; Venkatakrishnan et al, 2015 ; Tayyar et al, 2017 ).…”