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


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 dose-limiting toxicity (DLT) was seen in patients treated at the 3 μg/kg dose level (DL) during the first 4 weeks. All 5 patients treated at the 4.5 μg/kg DL came off study or required dose reductions for behavioral toxicity or fatigue. Similar DLT on the 3 μg/kg DL became apparent over time. There was 1 DLT (myoclonus) in 12 patients enrolled at the 1.0 μg/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 μg/kg/wk. Clinical and radiographic improvement and cessation of growth can occur.


METHODS
This study provides Class III evidence that pegylated interferon-α-2b in patients with unresectable, progressive, symptomatic, or life-threatening PNs results in radiographic reduction or stabilization of PN size.
Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, USA. regina.jakacki@chp.edu
R I
RI
Jakacki
E
E
Dombi
D M
DM
Potter
S
S
Goldman
J C
JC
Allen
I F
IF
Pollack
B C
BC
Widemann
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D007279:Injections, Subcutaneous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects*; D008279:Magnetic Resonance Imaging; D008297:Male; D018318:Neurofibroma, Plexiform / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects*; D011859:Radiography; D011994:Recombinant Proteins; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C417083:peginterferon alfa-2b
Cancer Treat Rev. 2003 Aug;29(4):241-52
12927565
Med Pediatr Oncol. 1996 Mar;26(3):220-2
8544807
N Engl J Med. 2000 Dec 7;343(23):1666-72
11106715
Neurology. 2002 May 28;58(10):1461-70
12041525
Blood. 2004 Jun 15;103(12):4408-15
15010373
Pediatr Neurol. 2007 May;36(5):293-300
17509460
Neurology. 2009 Oct 20;73(16):1273-9
19841379
Proc Natl Acad Sci U S A. 1995 May 9;92(10):4562-6
7753843
Brain. 1988 Dec;111 ( Pt 6):1355-81
3145091
Comput Med Imaging Graph. 2004 Jul;28(5):257-65
15249071
Clin Cancer Res. 1999 Oct;5(10):2726-34
10537335
Neurology. 2007 Feb 27;68(9):643-7
17215493
Arch Dis Child. 1998 May;78(5):408-12
9659085
J Biol Chem. 1992 Mar 15;267(8):5017-20
1371992
Cancer. 1993 Dec 15;72(12):3549-52
8252467
J Pediatr. 1997 Nov;131(5):678-82
9403645
Neurology. 2003 Jan 14;60(1):130-2
12525736
N Engl J Med. 1992 May 28;326(22):1456-63
1489383
J Neurooncol. 1987;5(4):323-30
2964515
Clin Pediatr (Phila). 1996 Nov;35(11):545-61
8953130
Semin Oncol. 1997 Feb;24(1 Suppl 4):S24-31
9122731