Phase I trial of pegylated interferon-α-2b in young patients with plexiform neurofibromas

Abstract

Objective: Interferon has antiproliferative and antiangiogenic properties. We sought to evaluate preliminary efficacy and determine the recommended phase II dose (RP2D) for pegylated interferon-␣-2b (PI) in patients with unresectable progressive or symptomatic plexiform neurofibromas (PN).Methods: PI was administered weekly in cohorts of 3-6 patients during the dose-finding phase and continued for up to 2 years. Twelve patients were treated at the RP2D to further evaluate toxicity and activity.Results: Thirty patients (median age 9.3 years, range 1.9-34.7 years) were enrolled. No doselimiting toxicity (DLT) was seen in patients treated at the 3 g/kg dose level (DL) during the first 4 weeks. All 5 patients treated at the 4.5 g/kg DL came off study or required dose reductions for behavioral toxicity or fatigue. Similar DLT on the 3 g/kg DL became apparent over time. There was 1 DLT (myoclonus) in 12 patients enrolled at the 1.0 g/kg DL. Eleven of 16 patients with pain showed improvement and 13 of 14 patients with a palpable mass had a decrease in size. Five of 17 patients (29%) who underwent volumetric analysis had a 15%-22% decrease in volume. Three of 4 patients with documented radiographic progression prior to enrollment showed stabilization or shrinkage. Conclusions:The RP2D of PI for pediatric patients with PN is 1 g/kg/wk. Clinical and radiographic improvement and cessation of growth can occur. Classification of evidence:This study provides Class III evidence that pegylated interferon-␣-2b in patients with unresectable, progressive, symptomatic, or life-threatening PNs results in radiographic reduction or stabilization of PN size. Neurology ® 2011;76:265-272 GLOSSARY AUC ϭ area under the curve; DL ϭ dose level; DLT ϭ dose-limiting toxicity; FDA ϭ Food and Drug Administration; IFN ϭ interferon; MTD ϭ maximum tolerated dose; NF1 ϭ neurofibromatosis type 1; NHT ϭ nonhematologic toxicity; PEG ϭ polyethylene glycol; PI ϭ pegylated interferon-␣-2b; PN ϭ plexiform neurofibroma; RP2D ϭ recommended phase II dose; STIR ϭ short T1-inversion recovery; TSH ϭ thyroid-stimulating hormone; VA ϭ volumetric analyses.Neurofibromatosis type 1 (NF1) is a common autosomal dominant neurogenetic disorder characterized by a wide variety of progressive cutaneous, neurologic, skeletal, and neoplastic manifestations.1 PN are one of several types of neurofibromas that may occur in patients with NF1 and are characterized by a proliferation of Schwann cells, fibroblasts, and mast cells occurring along the length of a nerve. They occur in 25%-50% of adults and children with NF1, 2,3 and typically infiltrate adjacent normal tissue, making complete surgical resection usually impossible. As they grow, they frequently become disfiguring as well as disabling or even life-threatening. 4,5 Regrowth following subtotal resection is common.6 Standard chemotherapy is not effective and there is currently no standard medical treatment despite various clinical trials. [7][8][9] Interferons (IFNs) have both antiproliferative and antiangiogenic pr...

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

“…25 Behavioral issues, including attention-deficit hyperactivity disorder, are commonly seen in patients with NF1 26 and worsening of such and/or fatigue were dose-limiting toxicities in the phase I study. 17 Similarly, treatment-limiting behavioral issues and/or fatigue occurred in 12% and 14% of patients, respectively, in the current study; the majority of behavioral issues were preexisting and worsened on therapy. Four of the 14 patients (28.6%) enrolled in the pain stratum either came off study or required a dose reduction for mood/behavioral issues, most of which were preexisting, Fig.…”

“…A phase I study of PI in pediatric patients with unresectable PN showed both clinical and imaging responses by volumetric MRI analysis and established the recommended phase II dose of 1.0 mcg/kg/wk given by subcutaneous injection. 17 We therefore undertook a phase II trial evaluating the imaging (stratum 1) and/or clinical (stratum 2) response rates in patients with unresectable PN. Stratum 3 evaluated the impact of PI on growth rate in patients with documented progression on imaging at trial entry by comparing time to progression (TTP) with the actuarial curve of the placebo arm of the National Cancer Institute-coordinated tipifarnib trial (NCT00021541).…”

Recommendations for imaging tumor response in neurofibromatosis clinical trials

“…Therefore, more sensitive methods, such as volume segmentation, were developed for the analysis of PN and schwannomas. [10][11][12][13][14][15] These methods documented the feasibility of reproducibly measuring tumor volumes in natural history studies and treatment trials for PN and VS. 13,14,[16][17][18][19] Using the MEDx-based lesion detection method developed for PN, interobserver differences were less than 10% and intraobserver variation was #5%. 10 For VS measured using the Vitrea2 workstation, the coefficient of variation ranged from 0.6% to 6.8%.…”

Sleep and pulmonary outcomes for clinical trials of airway plexiform neurofibromas in NF1

“…12 In children, a normal AHI is ,1.5. In adults, a normal AHI is ,5; the degree of OSA can be classified as mild , moderate (AHI [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30], or severe (AHI .30). Treatment of OSA is directed at maintaining patency of the upper airway.…”

“…In recent years, shrinkage of PNs has been observed after treatment with PEG-intron, imatinib, and selumetinib. [15][16][17] Because clinical benefit may occur with minimal volume changes, sleep and pulmonary outcomes may be more sensitive than radiographic changes at detecting a meaningful response to treatment. Our objectives were to define reproducible and clinically meaningful measures of sleep and pulmonary function, which can be used as primary endpoints in clinical trials targeting airway PNs.…”