Phase II Trial of Pirfenidone in Children, Adolescents, and Young Adults With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas
Neurofibromatosis Type 1 (NF1) is an autosomal dominant, progressive genetic disorder
characterized by diverse clinical manifestations. Patients with NF1 have an increased risk
of developing tumors of the central and peripheral nervous system including plexiform
neurofibromas, which are benign nerve sheath tumors that may cause severe morbidity and
possible mortality. The histopathology of these tumors suggests that events connected with
formation of fibroblasts might constitute a point of molecular vulnerability. Gene profile
analysis demonstrates overexpression of fibroblast growth factor, epidermal growth factor,
and platelet-derived growth factor in plexiform neurofibromas in patients with NF1.
Pirfenidone is a novel antifibrotic agent that inhibits these and other growth factors.
Clinical experience in adults has demonstrated that pirfenidone is effective in a variety of
fibrosing conditions and pirfenidone is presently under study in a phase II trial for adults
with progressive plexiform neurofibromas. A phase I trial of pirfenidone in children and
young adults with NF1 and plexiform neurofibromas was completed, and has established the
phase II dose (the dose resulting in a mean drug exposure [AUC] not more than 1 standard
deviation below the mean drug exposure [AUC] in adults who received pirfenidone at the dose
level demonstrating activity in fibrosing conditions). Pirfenidone has been well tolerated.
To determine whether pirfenidone increases the time to disease progression based on
volumetric measurements in children and young adults with NF1 and growing plexiform
To define the objective response rate to pirfenidone in NF1-related plexiform neurofibromas.
To describe and define the toxicities of pirfenidone.
Individuals (greater than or equal to 3 years to less than or equal to 21 years of age) with
a clinical diagnosis of NF1 and inoperable, measurable, and progressive plexiform
neurofibromas that have the potential to cause substantial morbidity.
The phase II dose will be used in a single stage, single arm phase II trial The natural
history of the growth of plexiform neurofibromas is unknown. For this reason, time to
disease progression on the placebo arm of an ongoing National Cancer Institute (NCI)
Pediatric Oncology Branch (POB) placebo-controlled, double-blind, cross-over phase II trial
of the farnesyltransferase inhibitor R115777 for children and young adults with NF1 and
progressive plexiform neurofibromas will be used as historical control to determine if
pirfenidone increases time to disease progression. Eligibility criteria and method of tumor
measurements are identical for both trials.
Pirfenidone will be administered orally as capsules at a dose of 500 mg/m^2 three times a
day (q8h) for cycles of 28 days with no rest period between cycles based on the results of
our pediatric phase I trial.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Median Time to Disease Progression
Time to progression is defined as greater than or equal to 20% increase in plexiform neurofibromas (PN) volume on magnetic resonance imaging (MRI).
Brigitte C Widemann, M.D.
National Cancer Institute, National Institutes of Health
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|Childrens National Medical Center||Washington, District of Columbia|
|University of Alabama||Birmingham, Alabama|
|Johns Hopkins Oncology Center||Baltimore, Maryland 21287|
|Beth Israel Medical Center||New York, New York 10003|
|St. Louis Children's Hospital||Saint Louis, Missouri 63110|
|SUNY Upstate Medical University||Syracuse, New York 13210|
|Oregon Health Sciences University||Portland, Oregon|
|Childrens Hospital, Philadelphia||Philadelphia, Pennsylvania 19104|
|Cleveland Clinic||Cleveland, Ohio 44195|
|Texas Children's Hospital||Houston, Texas|
|Childrens Memorial Hospital, Chicago||Chicago, Illinois 60614|
|Childrens Hospital, Dana-Farber Cancer Institute||Boston, Massachusetts 02115|
|Mayo Clinic, Rochester||Rochester, Minnesota 55905|
|Childrens Hospital, Pittsburgh||Pittsburgh, Pennsylvania 15213|