Population Pharmacokinetics and Exposure-Safety Relationships of Alisertib in Children and Adolescents With Advanced Malignancies
Xiaofei Zhou, Diane R Mould, Ying Yuan, Elizabeth Fox, Emily Greengard, Douglas V Faller, Karthik Venkatakrishnan, Xiaofei Zhou, Diane R Mould, Ying Yuan, Elizabeth Fox, Emily Greengard, Douglas V Faller, Karthik Venkatakrishnan
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.
Keywords: Aurora A kinase; alisertib; exposure-safety; pediatric; population pharmacokinetics.
Conflict of interest statement
X.Z., Y.Y., and D.V.F. disclose employment by Millennium Pharmaceuticals, Inc, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. D.R.M. is a paid consultant for Millennium Pharmaceuticals, Inc, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. K. V. discloses previous employment by Millennium Pharmaceuticals, Inc. E.F. and E.G. have no disclosures to report.
© 2021 Millennium Pharmaceuticals Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.
Figures
References
- Bolanos‐Garcia VM. Aurora kinases. Int J Biochem Cell Biol. 2005;37(8):1572‐1577.
- Venkatakrishnan K, Zhou X, Ecsedy J, et al. Dose selection for the investigational anticancer agent alisertib (MLN8237): pharmacokinetics, pharmacodynamics, and exposure‐safety relationships. J Clin Pharmacol. 2015;55(3):336‐347.
- Zullo KM, Guo Y, Cooke L, et al. Aurora A kinase inhibition selectively synergizes with histone deacetylase inhibitor through cytokinesis failure in T‐cell lymphoma. Clin Cancer Res. 2015;21(18):4097‐4109.
- Nikonova AS, Astsaturov I, Serebriiskii IG, Dunbrack RL Jr, Golemis EA. Aurora A kinase (AURKA) in normal and pathological cell division. Cell Mol Life Sci. 2013;70(4):661‐687.
- Ikezoe T, Yang J, Nishioka C, et al. A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia. Mol Cancer Ther. 2007;6(6):1851‐1857.
- Dar AA, Zaika A, Piazuelo MB, et al. Frequent overexpression of Aurora kinase A in upper gastrointestinal adenocarcinomas correlates with potent antiapoptotic functions. Cancer. 2008;112(8):1688‐1698.
- Mazumdar A, Henderson YC, El‐Naggar AK, Sen S, Clayman GL. Aurora kinase A inhibition and paclitaxel as targeted combination therapy for head and neck squamous cell carcinoma. Head Neck. 2009;31(5):625‐634.
- Manfredi MG, Ecsedy JA, Chakravarty A, et al. Characterization of alisertib (MLN8237), an investigational small‐molecule inhibitor of Aurora A kinase using novel in vivo pharmacodynamic assays. Clin Cancer Res. 2011;17(24):7614‐7624.
- Ding YH, Zhou ZW, Ha CF, et al. Alisertib, an Aurora kinase A inhibitor, induces apoptosis and autophagy but inhibits epithelial to mesenchymal transition in human epithelial ovarian cancer cells. Drug Des Devel Ther. 2015;9:425‐464.
- Wang F, Li H, Yan XG, et al. Alisertib induces cell cycle arrest and autophagy and suppresses epithelial‐to‐mesenchymal transition involving PI3K/Akt/mTOR and sirtuin 1‐mediated signaling pathways in human pancreatic cancer cells. Drug Des Devel Ther. 2015;9:575‐601.
- Goldberg SL, Fenaux P, Craig MD, et al. An exploratory phase 2 study of investigational Aurora A kinase inhibitor alisertib (MLN8237) in acute myelogenous leukemia and myelodysplastic syndromes. Leuk Res Rep. 2014;3(2):58‐61.
- Melichar B, Adenis A, Lockhart AC, et al. Safety and activity of alisertib, an investigational Aurora kinase A inhibitor, in patients with breast cancer, small‐cell lung cancer, non‐small‐cell lung cancer, head and neck squamous‐cell carcinoma, and gastro‐oesophageal adenocarcinoma: a five‐arm phase 2 study. Lancet Oncol. 2015;16(4):395‐405.
- Zhou X, Mould DR, Takubo T, et al. Global population pharmacokinetics of the investigational Aurora A kinase inhibitor alisertib in cancer patients: rationale for lower dosage in Asia. Br J Clin Pharmacol. 2018;84(1):35‐51.
- Carol H, Boehm I, Reynolds CP, et al. Efficacy and pharmacokinetic/pharmacodynamic evaluation of the Aurora kinase A inhibitor MLN8237 against preclinical models of pediatric cancer. Cancer Chemother Pharmacol. 2011;68(5):1291‐1304.
- Maris JM, Morton CL, Gorlick R, et al. Initial testing of the Aurora kinase A inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP). Pediatr Blood Cancer. 2010;55(1):26‐34.
- Muscal JA, Scorsone KA, Zhang L, Ecsedy JA, Berg SL. Additive effects of vorinostat and MLN8237 in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines. Invest New Drugs. 2013;31(1):39‐45.
- Lipsitz EG, Nguyen V, Zhao H, et al. Modeling MLN8237, an Aurora kinase A inhibitor, with irinotecan (IRN) and temozolomide (TMZ) in neuroblastoma (NB). J Clin Oncol. 2010;28(15_suppl):10593‐10593.
- Zhou X, Pant S, Nemunaitis J, et al. Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of alisertib, an investigational Aurora A kinase inhibitor in patients with advanced malignancies. Invest New Drugs. 2018;36(2):248‐258.
- Zhou X, Pusalkar S, Chowdhury SK, et al. Mass balance, routes of excretion, and pharmacokinetics of investigational oral [14C]‐alisertib (MLN8237), an Aurora A kinase inhibitor in patients with advanced solid tumors. Invest New Drugs. 2019;37(4):666‐673.
- Pusalkar S, Zhou X, Li Y, et al. Biotransformation pathways and metabolite profiles of oral [14C]alisertib (MLN8237), an investigational Aurora A kinase inhibitor, in patients with advanced solid tumors. Drug Metab Dispos. 2020;48(3):217‐229.
- Zhou X, Lockhart AC, Fu S, et al. Pharmacokinetics of the investigational Aurora A kinase inhibitor alisertib in adult patients with advanced solid tumors or relapsed/refractory lymphoma with varying degrees of hepatic dysfunction. J Clin Pharmacol. 2019;59(9):1204‐1215.
- Mosse YP, Lipsitz E, Fox E, et al. Pediatric phase I trial and pharmacokinetic study of MLN8237, an investigational oral selective small‐molecule inhibitor of Aurora kinase A: a children's oncology group phase I consortium study. Clin Cancer Res. 2012;18(21):6058‐6064.
- Mosse YP, Fox E, Teachey DT, et al. A phase II study of alisertib in children with recurrent/refractory solid tumors or leukemia: Children's Oncology Group phase I and pilot consortium (ADVL0921). Clin Cancer Res. 2019;25(11):3229‐3238.
- Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC. Shortening the timeline of pediatric phase I trials: the rolling six design. J Clin Oncol. 2008;26(2):190‐195.
- Lipsitz E, Moorthy G, Mosse Y, Fox E, Adamson PC. A sensitive and selective liquid chromatography/tandem mass spectrometry method for determination of MLN8237 in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878(25):2369‐2373.
- Dees EC, Cohen RB, von Mehren M, et al. Phase I study of Aurora A kinase inhibitor MLN8237 in advanced solid tumors: safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations. Clin Cancer Res. 2012;18(17):4775‐4784.
- Cervantes A, Elez E, Roda D, et al. Phase I pharmacokinetic/pharmacodynamic study of MLN8237, an investigational, oral, selective Aurora A kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2012;18(17):4764‐4774.
- Kelly KR, Shea TC, Goy A, et al. Phase I study of MLN8237–investigational Aurora A kinase inhibitor–in relapsed/refractory multiple myeloma, non‐Hodgkin lymphoma and chronic lymphocytic leukemia. Invest New Drugs. 2014;32(3):489‐499.
- Falchook G, Kurzrock R, Gouw L, et al. Investigational Aurora A kinase inhibitor alisertib (MLN8237) as an enteric‐coated tablet formulation in non‐hematologic malignancies: phase 1 dose‐escalation study. Invest New Drugs. 2014;32(6):1181‐1187.
- Fernandez E, Perez R, Hernandez A, Tejada P, Arteta M, Ramos JT. Factors and mechanisms for pharmacokinetic differences between pediatric population and adults. Pharmaceutics. 2011;3(1):53‐72.
- O'Connor OA, Özcan M, Jacobsen ED, et al. Randomized phase III study of alisertib or investigator's choice (selected single agent) in patients with relapsed or refractory peripheral T‐cell lymphoma. J Clin Oncol. 2019;37(8):613‐623.
- Battisti WP, Wager E, Baltzer L, et al. Good publication practice for communicating company‐sponsored medical research: GPP3. Ann Intern Med. 2015;163:461‐464.
Source: PubMed