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

ABSTRACT: 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).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.Thirty patients (median age 9.3 years, range 1.9-34.7 years) were enrolled. No dose-limiting 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.The RP2D of PI for pediatric patients with PN is 1 ?g/kg/wk. Clinical and radiographic improvement and cessation of growth can occur.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.

SUBMITTER: Jakacki RI

PROVIDER: S-EPMC3034394 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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

Jakacki R I RI Dombi E E Potter D M DM Goldman S S Allen J C JC Pollack I F IF Widemann B C BC

Neurology 20110101 3

<h4>Objective</h4>Interferon has antiproliferative and antiangiogenic properties. We sought to evaluate preliminary efficacy and determine the recommended phase II dose (RP2D) for pegylated interferon-α-2b (PI) in patients with unresectable progressive or symptomatic plexiform neurofibromas (PN).<h4>Methods</h4>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 ...[more]

PMID: 21242495

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Project description:BackgroundPlexiform 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.MethodsEligible 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/m(2) 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.FindingsSix 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).InterpretationImatinib mesylate could be used to treat plexiform neurofibromas in patients with NF1. A multi-institutional clinical trial is warranted to confirm these results.FundingNovartis Pharmaceuticals, the Indiana University Simon Cancer Centre, and the Indiana University Herman B Wells Center for Pediatric Research.

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

Publications

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

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