Neurofibromatosis Type 1 (NF1) is one of the most common neurogenetic diseases that occurs and affects over 80,000 persons, of all ages, in the United States. NF1 may result in damage or dysfunction of multiple organs and one of the most common and severe complications is the development of growing tumors arising from the coverings of multiple nerves, called plexiform neurofibromas (PNs). Plexiform neurofibromas can grow to large size, and cause cosmetic disfigurement and organ dysfunction, including severe neurologic impairment. Other than surgery, there is no known effective treatment for progressive PNs and because of the size of the tumors and their infiltrating nature, these tumors often are not amenable to total surgical resection. Recently, there have been breakthroughs in the understanding of the development of PNs. Recent work has demonstrated the elevation of certain growth factors in PNs in patients with NF1. There is a novel agent, Pirfenidone, which is effective in treating a variety of fibrosing conditions and this agent targets the same growth factors that have been found to be elevated in PNs. In preliminary studies, this drug is well tolerated and can be given orally. There are presently no studies demonstrating the safety or effectiveness of the drug in children.

The primary hypotheses of the study are: (1) that Pirfenidone will be tolerated in children with NF1 and PNs; and (2) that the agent will increase time to progression in children with PNs. The specific aims of this study are to complete two sequential studies within a 4-year period. The first will be a Phase I study demonstrating the safety of Pirfenidone in children with NF1 and PNs. The second will be a Phase II study determining if Pirfenidone will increase time to progression for patients with PNs and NF1. In addition, the study will evaluate the utility of the use of innovative neuroimaging techniques and innovative means of evaluation, including a pediatric quality-of-life scale, in the management of children with this problem. The tumors biopsied during the study will be carefully analyzed and will become part of a centralized tissue bank for PNs.

The study design will utilize a standard means of evaluating the safety of Pirfenidone in children between 3 and 21 years of age, called a Phase I study. After the dose of Pirfenidone utilized in adult studies is found safe in children and the drug levels obtained are found to be equivalent to those obtained in adults, a second study will immediately be started. This will be a Phase II study evaluating the efficacy of Pirfenidone, designed to determine if Pirfenidone increases time to progression for patients with progressive PNs.

Children with NF1 and PNs often have tumors that are not amenable to surgery and will cause progressive morbidity and even mortality. There are no effective treatments, other than surgery, for these lesions and if Pirfenidone is found to be effective it will be of great benefit to patients with NF1 and PNs.