Phase II trial of pegylated interferon alfa-2b in young patients with neurofibromatosis type 1 and unresectable plexiform neurofibromas

Abstract

Background: There is no proven medical therapy for plexiform neurofibromas (PNs). We undertook a phase II trial of pegylated interferon (PI) to evaluate response and time to progression (TTP).

Methods: PI was administered as a subcutaneous injection to patients with neurofibromatosis type 1‒related PN, stratified by the presence of symptoms (asymptomatic: stratum 1, symptomatic: stratum 2) or documented imaging progression (stratum 3). Patients in strata 1 and 2 received PI for up to one year if stable, 2 years for those with clinical (stratum 2) or imaging response (≥20% decrease in volume). Patients on stratum 3 continued PI until progression. PI was considered active in stratum 3 if TTP doubled compared with the placebo arm of a previous randomized trial using tipifarnib.

Results: Enrolled were 82 evaluable patients (median age 10 y; range 1.6 to 21.4). Fatigue and/or worsening of behavioral issues were the most common toxicities requiring dose modification. Across all strata, imaging responses were seen in 4 patients (5%). Three of 26 symptomatic patients on stratum 2 met the criteria for clinical response without corresponding imaging changes. In stratum 3, median TTP was 29.4 months versus 11.8 for the placebo arm of the previous trial (P=.031). The slope of tumor growth on PI slowed significantly compared with the slope before starting PI (P=.044).

Conclusions: In patients with active PN, PI results in more than doubling of the TTP compared with placebo. Imaging changes in symptomatic patients were not associated with changes in clinical status.

Keywords: clinical trials; interferon; neurofibromatosis type 1; pediatrics; plexiform neurofibromas.

© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Figures

Fig. 1

A, B, C and D: Panel A shows the slope of tumor growth after starting PI for 20 patients on stratum 3 with available pretreatment volume data comparable to the data obtained on study, highlighting 3 patient examples in bold. The growth rate is represented on the y-axis in Figure 1A. Panels B, C and D are the corresponding tumor growth curves, B with minor shrinkage and unconfirmed response, C with prolonged stable disease over 5 years, and D with no change in growth trajectory. Where the top horizontal line meets the points on the graph represents the time when PI was started.

Fig. 2

Comparison of TTP between patients on stratum 3 (median TTP 29.4 mo) and the placebo arm from the tipifarnib trial (median TTP 11.8 mo); P=.031 by 2-tailed log-rank test.