Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: A phase 2 trial

Kent Robertson, Grzegorz Nalepa, Feng Chun Yang, Daniel C. Bowers, Chang Ho, Gary Hutchins, James Croop, Terry Vik, Scott Denne, Luis F. Parada, Cynthia M. Hingtgen, Larry Walsh, Menggang Yu, Kamnesh Pradhan, Mary K. Edwards-Brown, Mervyn D. Cohen, James Fletcher, Jeffrey Travers, Karl W. Staser, Melissa W. LeeMarcie R. Sherman, Cynthia J. Davis, Lucy C. Miller, David Ingram, D. Clapp

Research output: Contribution to journalArticle

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Abstract

Background: Plexiform neurofibromas are slow-growing chemoradiotherapy-resistant tumours arising in patients with neurofibromatosis type 1 (NF1). Currently, there are no viable therapeutic options for patients with plexiform neurofibromas that cannot be surgically removed because of their proximity to vital body structures. We undertook an open-label phase 2 trial to test whether treatment with imatinib mesylate can decrease the volume burden of clinically significant plexiform neurofibromas in patients with NF1. Methods: Eligible patients had to be aged 3-65 years, and to have NF1 and a clinically significant plexiform neurofibroma. Patients were treated with daily oral imatinib mesylate at 220 mg/m2 twice a day for children and 400 mg twice a day for adults for 6 months. The primary endpoint was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data were analysed on an intention-to-treat basis; a secondary analysis was also done for those patients able to take imatinib mesylate for 6 months. This trial is registered with ClinicalTrials.gov, number NCT01673009. Findings: Six of 36 patients (17%, 95% CI 6-33), enrolled on an intention-to-treat basis, had an objective response to imatinib mesylate, with a 20% or more decrease in tumour volume. Of the 23 patients who received imatinib mesylate for at least 6 months, six (26%, 95% CI 10-48) had a 20% or more decrease in volume of one or more plexiform tumours. The most common adverse events were skin rash (five patients) and oedema with weight gain (six). More serious adverse events included reversible grade 3 neutropenia (two), grade 4 hyperglycaemia (one), and grade 4 increases in aminotransferase concentrations (one). Interpretation: Imatinib mesylate could be used to treat plexiform neurofibromas in patients with NF1. A multi-institutional clinical trial is warranted to confirm these results. Funding: Novartis Pharmaceuticals, the Indiana University Simon Cancer Centre, and the Indiana University Herman B Wells Center for Pediatric Research.

Original languageEnglish
Pages (from-to)1218-1224
Number of pages7
JournalThe Lancet Oncology
Volume13
Issue number12
DOIs
StatePublished - Dec 2012

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Plexiform Neurofibroma
Neurofibromatosis 1
Imatinib Mesylate
Neoplasms
Chemoradiotherapy
Transaminases
Exanthema
Neutropenia
Tumor Burden
Hyperglycemia
Weight Gain
Edema

ASJC Scopus subject areas

  • Oncology

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Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1 : A phase 2 trial. / Robertson, Kent; Nalepa, Grzegorz; Yang, Feng Chun; Bowers, Daniel C.; Ho, Chang; Hutchins, Gary; Croop, James; Vik, Terry; Denne, Scott; Parada, Luis F.; Hingtgen, Cynthia M.; Walsh, Larry; Yu, Menggang; Pradhan, Kamnesh; Edwards-Brown, Mary K.; Cohen, Mervyn D.; Fletcher, James; Travers, Jeffrey; Staser, Karl W.; Lee, Melissa W.; Sherman, Marcie R.; Davis, Cynthia J.; Miller, Lucy C.; Ingram, David; Clapp, D.

In: The Lancet Oncology, Vol. 13, No. 12, 12.2012, p. 1218-1224.

Research output: Contribution to journalArticle

Robertson, K, Nalepa, G, Yang, FC, Bowers, DC, Ho, C, Hutchins, G, Croop, J, Vik, T, Denne, S, Parada, LF, Hingtgen, CM, Walsh, L, Yu, M, Pradhan, K, Edwards-Brown, MK, Cohen, MD, Fletcher, J, Travers, J, Staser, KW, Lee, MW, Sherman, MR, Davis, CJ, Miller, LC, Ingram, D & Clapp, D 2012, 'Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: A phase 2 trial', The Lancet Oncology, vol. 13, no. 12, pp. 1218-1224. https://doi.org/10.1016/S1470-2045(12)70414-X
Robertson, Kent ; Nalepa, Grzegorz ; Yang, Feng Chun ; Bowers, Daniel C. ; Ho, Chang ; Hutchins, Gary ; Croop, James ; Vik, Terry ; Denne, Scott ; Parada, Luis F. ; Hingtgen, Cynthia M. ; Walsh, Larry ; Yu, Menggang ; Pradhan, Kamnesh ; Edwards-Brown, Mary K. ; Cohen, Mervyn D. ; Fletcher, James ; Travers, Jeffrey ; Staser, Karl W. ; Lee, Melissa W. ; Sherman, Marcie R. ; Davis, Cynthia J. ; Miller, Lucy C. ; Ingram, David ; Clapp, D. / Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1 : A phase 2 trial. In: The Lancet Oncology. 2012 ; Vol. 13, No. 12. pp. 1218-1224.
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T1 - Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1

T2 - A phase 2 trial

AU - Robertson, Kent

AU - Nalepa, Grzegorz

AU - Yang, Feng Chun

AU - Bowers, Daniel C.

AU - Ho, Chang

AU - Hutchins, Gary

AU - Croop, James

AU - Vik, Terry

AU - Denne, Scott

AU - Parada, Luis F.

AU - Hingtgen, Cynthia M.

AU - Walsh, Larry

AU - Yu, Menggang

AU - Pradhan, Kamnesh

AU - Edwards-Brown, Mary K.

AU - Cohen, Mervyn D.

AU - Fletcher, James

AU - Travers, Jeffrey

AU - Staser, Karl W.

AU - Lee, Melissa W.

AU - Sherman, Marcie R.

AU - Davis, Cynthia J.

AU - Miller, Lucy C.

AU - Ingram, David

AU - Clapp, D.

PY - 2012/12

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N2 - Background: Plexiform neurofibromas are slow-growing chemoradiotherapy-resistant tumours arising in patients with neurofibromatosis type 1 (NF1). Currently, there are no viable therapeutic options for patients with plexiform neurofibromas that cannot be surgically removed because of their proximity to vital body structures. We undertook an open-label phase 2 trial to test whether treatment with imatinib mesylate can decrease the volume burden of clinically significant plexiform neurofibromas in patients with NF1. Methods: Eligible patients had to be aged 3-65 years, and to have NF1 and a clinically significant plexiform neurofibroma. Patients were treated with daily oral imatinib mesylate at 220 mg/m2 twice a day for children and 400 mg twice a day for adults for 6 months. The primary endpoint was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data were analysed on an intention-to-treat basis; a secondary analysis was also done for those patients able to take imatinib mesylate for 6 months. This trial is registered with ClinicalTrials.gov, number NCT01673009. Findings: Six of 36 patients (17%, 95% CI 6-33), enrolled on an intention-to-treat basis, had an objective response to imatinib mesylate, with a 20% or more decrease in tumour volume. Of the 23 patients who received imatinib mesylate for at least 6 months, six (26%, 95% CI 10-48) had a 20% or more decrease in volume of one or more plexiform tumours. The most common adverse events were skin rash (five patients) and oedema with weight gain (six). More serious adverse events included reversible grade 3 neutropenia (two), grade 4 hyperglycaemia (one), and grade 4 increases in aminotransferase concentrations (one). Interpretation: Imatinib mesylate could be used to treat plexiform neurofibromas in patients with NF1. A multi-institutional clinical trial is warranted to confirm these results. Funding: Novartis Pharmaceuticals, the Indiana University Simon Cancer Centre, and the Indiana University Herman B Wells Center for Pediatric Research.

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