Single-agent erlotinib versus oral etoposide in patients with recurrent or refractory pediatric ependymoma: a randomized open-label study
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Overexpression of human epidermal growth factor receptor (HER/EGFR) is associated with various tumors, including ependymomas. To investigate whether EGFR inhibition was of benefit in pediatric patients with recurrent ependymoma, a multi-center, randomized, open-label, phase 2 study of oral erlotinib versus oral etoposide was undertaken. Twenty-five patients were randomized to receive erlotinib 85 mg/m2 daily or etoposide 50 mg/m2/day for 21 consecutive days followed by a 7-day rest period. Courses were repeated every 28 days. In the erlotinib arm, no patient achieved a complete, partial, or minor response, and only 2 (15.4 %) patients showed stable disease as their best response. In the etoposide arm, 2 patients (16.7 %) demonstrated partial responses, 1 (8.3 %) patient demonstrated a minor response, and 2 (16.7 %) showed prolonged stable disease, for a prolonged disease control rate of 41.7 %. Three patients received at least nine cycles of etoposide (range 9–24 cycles) before discontinuing at the request of the physician and/or family. Four patients who failed etoposide in this study received erlotinib in a companion single arm study; none had a response. The futility criteria were met at the second interim analysis, and both studies were discontinued. Pharmacokinetics of erlotinib were similar to previous observations in pediatric patients. Overall, erlotinib was well tolerated and safety was consistent with its established profile in adults. The overall risk–benefit profile does not support the use of erlotinib in pediatric patients with recurrent ependymoma, whereas single-agent etoposide appears to have efficacy in a subset of patients.
KeywordsEpendymoma Epidermal growth factor receptor EGFR Pediatrics Etoposide Erlotinib
The authors would like to acknowledge all of the investigators who participated in this study, the patients and their families.
This study was funded by Astellas Pharma, Inc. Medical writing support was provided by Tara N. Miller, PhD, and Sarah J. Knott, medical writers at Envision Scientific Solutions, and funded by Astellas.
Compliance with ethical standards
Conflict of interest
Regina I. Jakacki is now at Astra-Zeneca; Margaret A. Foley, Jiuzhou Wang, and Stan C. Gill are full-time employees of Astellas; Mark W. Kieran, Daniel C. Bowers, Eric Bouffet, and Stergios Zacharoulis have no conflicts to report. Julie Horan was an employee of OSI Pharmaceuticals, Inc. during the development of the protocol and Novella Clinical Inc. during the study.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
- 1.Central Brain Tumor Registry of the United States (2004) Statistical report: primary brain tumors in the United States, 1997–2001. http://www.cbtrus.org/reports//2004-2005/2005report.pdf. Accessed 28 July 2014
- 3.Garvin JH Jr, Selch MT, Holmes E, Berger MS, Finlay JL, Flannery A, Goldwein JW, Packer RJ, Rorke-Adams LB, Shiminski-Maher T, Sposto R, Stanley P, Tannous R, Pollack IF (2012) Phase II study of pre-irradiation chemotherapy for childhood intracranial ependymoma. Children’s Cancer Group protocol 9942: a report from the Children’s Oncology Group. Pediatr Blood Cancer 59(7):1183–1189. doi: 10.1002/pbc.24274 CrossRefPubMedGoogle Scholar
- 8.Bouffet E, Hawkins CE, Ballourah W, Taylor MD, Bartels UK, Schoenhoff N, Tsangaris E, Huang A, Kulkarni A, Mabbot DJ, Laperriere N, Tabori U (2012) Survival benefit for pediatric patients with recurrent ependymoma treated with reirradiation. Int J Radiat Oncol Biol Phys 83(5):1541–1548. doi: 10.1016/j.ijrobp.2011.10.039 CrossRefPubMedGoogle Scholar
- 11.Sandri A, Massimino M, Mastrodicasa L, Sardi N, Bertin D, Basso ME, Todisco L, Paglino A, Perilongo G, Genitori L, Valentini L, Ricardi U, Gandola L, Giangaspero F, Madon E (2005) Treatment with oral etoposide for childhood recurrent ependymomas. J Pediatr Hematol Oncol 27(9):486–490CrossRefPubMedGoogle Scholar
- 12.Robison NJ, Campigotto F, Chi SN, Manley PE, Turner CD, Zimmerman MA, Chordas CA, Werger AM, Allen JC, Goldman S, Rubin JB, Isakoff MS, Pan WJ, Khatib ZA, Comito MA, Bendel AE, Pietrantonio JB, Kondrat L, Hubbs SM, Neuberg DS, Kieran MW (2014) A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer. Pediatr Blood Cancer 61(4):636–642. doi: 10.1002/pbc.24794 CrossRefPubMedGoogle Scholar
- 15.Mendrzyk F, Korshunov A, Benner A, Toedt G, Pfister S, Radlwimmer B, Lichter P (2006) Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma. Clin Cancer Res 12(7 Pt 1):2070–2079. doi: 10.1158/1078-0432.CCR-05-2363
- 17.OSI Pharmaceuticals LLC, an affiliate of Astellas Pharma US, Inc. (2012) Tarceva (erlotinib) Prescribing Information. http://www.gene.com/download/pdf/tarceva_prescribing.pdf. Accessed 28 July 2014
- 19.Kieran MW, Turner CD, Rubin JB, Chi SN, Zimmerman MA, Chordas C, Klement G, Laforme A, Gordon A, Thomas A, Neuberg D, Browder T, Folkman J (2005) A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer. J Pediatr Hematol Oncol 27(11):573–581CrossRefPubMedGoogle Scholar
- 20.Jakacki RI, Hamilton M, Gilbertson RJ, Blaney SM, Tersak J, Krailo MD, Ingle AM, Voss SD, Dancey JE, Adamson PC (2008) Pediatric phase I and pharmacokinetic study of erlotinib followed by the combination of erlotinib and temozolomide: a Children’s Oncology Group Phase I Consortium Study. J Clin Oncol 26(30):4921–4927. doi: 10.1200/JCO.2007.15.2306 CrossRefPubMedPubMedCentralGoogle Scholar