A Phase II Trial of Peginterferon Alpha-2b (PEG-Intron) for Neurofibromatosis Type 1 Related Unresectable, Symptomatic or Life-Threatening Plexiform Neurofibromas
Neurofibromatosis 1 (NF1) is a common autosomal dominant neurogenetic disorder characterized
by diverse cutaneous, neurological, skeletal and neoplastic manifestations. Approximately
25 percent of individuals with NF1 develop plexiform neurofibromas (PN), which are benign
nerve sheath tumors that are among the most debilitating complications of NF1. Plexiform
neurofibromas may be congenital and appear to have the fastest growth rate in young
children. There are no standard treatment options for PN other than surgery, which is often
difficult due to the extensive growth and invasion of surrounding tissues. Interferon-alpha
has shown immune modulatory and antiproliferative effects in a variety of malignancies, and
also inhibits angiogenesis. The pegylated preparation, peginterferon alfa-2beta (Pegintron)
lengthens the plasma half-life and allows for administration once a week. A phase I trial
of Pegintron for children and young adults with NF1and PN was completed, and defined the
maximum tolerated dose (MTD) as 1 microgram/kg by subcutaneous (SC) injection once weekly
for a maximum duration of 2 years. At this dose level, Pegintron was well tolerated, and
disease stabilization and minor PN shrinkage by volumetric MRI analysis were observed in
several patients. At doses exceeding the MTD fatigue and behavioral changes were dose
limiting. A phase II trial of Pegintron will be performed to define the activity of
Pegintron for inoperable PN in NF1.
To determine the radiographic and clinical response rate and/or progression free survival of
unresectable progressive, or symptomatic (i.e. interfering with performance status), or life
threatening NF1 associated PN to Pegintron given weekly SC.
To describe and define the toxicities of Pegintron given weekly SC for prolonged time
periods in this patient population.
To compare volumetric analysis of PN using three-dimensional MRI (3-D MRI) to conventional
two-dimensional MRI (2-D MRI) and one-dimensional MRI (1-D MRI) data analysis.
To evaluate the effects of Pegintron on serum cytokines and on induction of genes and
cytokines in peripheral blood mononuclear cells.
Individuals (greater than or equal to 6 months to 21 years of age) with NF1 and an
inoperable plexiform neurofibroma that has the potential to cause significant morbidity.
Patients will be enrolled on one of three strata depending on disease status.
Stratum 1: Radiographic progression at trial entry cannot be documented. Patient has no
clinical symptoms from the PN. Radiographic response (PN volume decrease greater than or
equal to 20 percent) will be the primary endpoint.
Stratum 2: Radiographic progression at trial entry cannot be documented. Patient has
clinical symptoms from the PN, such as pain, or decrease in function. Radiographic response
(PN volume decrease greater than or equal to 20 percent), and clinical response rate will be
the primary endpoint.
Stratum 3: Patient has a progressive PN. Time to progression (TTP) (PN volume increase
greater than or equal to 20 percent) will be the primary endpoint, and activity will be
defined by comparing TTP on Pegintron to TTP on the placebo arm of the R115777 phase II
trial for NF1 PN (01-C-0222) performed at the NCI, POB.
Stratum 4: Age between 6 and 18 months of age and must have a symptomatic and/or life
threatening plexiform neurofibroma(s).
Pegintron will be administered SC at a dose of 1.0 mcg/kg/week until disease progression, or
development of unacceptable toxicity. In addition, treatment for patients on stratum 1 and 2
will be limited to a maximum of 1 year unless they respond to treatment with Pegintron
(partial or complete response), in which case they can continue treatment for a maximum of
Tumor evaluation for volumetric MRI analysis will be performed pre treatment, and prior to
months 4, 8, 12, and then after every six months on treatment with Pegintron. Response
analysis will be performed centrally at the NCI, POB.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Radiographic response (stratum 1)
Brigitte C Widemann, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|Childrens Hospital, Pittsburgh||Pittsburgh, Pennsylvania 15213|