Phase II study of alisertib as a single agent for treating recurrent or progressive atypical teratoid/rhabdoid tumor.

Abstract

BACKGROUND:

Recurrent atypical teratoid/rhabdoid tumor (AT/RT) is, most often, a fatal pediatric malignancy with limited curative options.

METHODS:

We conducted a phase II study of Aurora kinase A inhibitor alisertib in patients aged <22 years with recurrent AT/RT. Patients received alisertib once daily (80 mg/m2 as enteric-coated tablets or 60 mg/m2 as liquid formulation) on Days 1-7 of a 21-day cycle until progressive disease (PD) occurred. Alisertib plasma concentrations were measured in cycle 1 on Days 1 (single dose) and 7 (steady state) and analyzed with noncompartmental pharmacokinetics. Trial efficacy end point was ≥10 participants with stable disease (SD) or better at 12 weeks.

RESULTS:

SD (n = 8) and partial response (PR) (n = 1) were observed among 30 evaluable patients. Progression-free survival (PFS) was 30.0% ± 7.9% at 6 months and 13.3% ± 5.6% at 1 year. One-year overall survival (OS) was 36.7% ± 8.4%. Two patients continued treatment for >12 months. PFS did not differ by AT/RT molecular groups. Neutropenia was the most common adverse effect (n = 23/30, 77%). The 22 patients who received liquid formulation had a higher mean maximum concentration (Cmax) of 10.1 ± 3.0 µM and faster time to Cmax (Tmax = 1.2 ± 0.7 h) than those who received tablets (Cmax = 5.7 ± 2.4 µM, Tmax = 3.4 ± 1.4 h).

CONCLUSIONS:

Although the study did not meet predetermined efficacy end point, single-agent alisertib was well tolerated by children with recurrent AT/RT, and SD or PR was observed in approximately a third of the patients.

• Authors: Santhosh A Upadhyaya, Olivia Campagne, Catherine A Billups, Brent A Orr, Arzu Onar-Thomas, Ruth G Tatevossian, Roya Mostafavi, Jason R Myers, Anna Vinitsky, Daniel C Moreira, Holly B Lindsay, Lindsay Kilburn, Patricia Baxter, Amy Smith, John R Crawford, Sonia Partap, Anne E Bendel, Dolly G Aguilera, Kim E Nichols, Evadnie Rampersaud, David W Ellison, Paul Klimo, Zoltan Patay, Giles W Robinson, Alberto Broniscer, Clinton F Stewart, Cynthia Wetmore, Amar Gajjar
• Journal: Neuro-oncology (Neuro Oncol) Vol. 25 Issue 2 Pg. 386-397 (02 14 2023) ISSN: 1523-5866 [Electronic] England
• PMID: 35652336 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Antineoplastic Agents
• MLN 8237
• Azepines
• Pyrimidines
• Aurora Kinase A
• Protein Kinase Inhibitors

Topics

• Child
• Humans
• Antineoplastic Agents (therapeutic use)
• Rhabdoid Tumor (drug therapy)
• Azepines (therapeutic use)
• Pyrimidines (therapeutic use)
• Central Nervous System Neoplasms (drug therapy)
• Aurora Kinase A
• Protein Kinase Inhibitors (therapeutic use, adverse effects)