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Pirfenidone in Children and Young Adults With Neurofibromatosis Type I and Progressive Plexiform Neurofibromas

2014-08-27 03:54:39 | BioPortfolio

Summary

Background:

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.

Objectives:

To determine whether pirfenidone increases the time to disease progression based on volumetric measurements in children and young adults with NF1 and growing plexiform neurofibromas.

To define the objective response rate to pirfenidone in NF1-related plexiform neurofibromas.

To describe and define the toxicities of pirfenidone.

Eligibility:

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.

Design:

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 NCI 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 w...

Description

Background:

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.

Objectives:

To determine whether pirfenidone increases the time to disease progression based on volumetric measurements in children and young adults with NF1 and growing plexiform neurofibromas.

To define the objective response rate to pirfenidone in NF1-related plexiform neurofibromas.

To describe and define the toxicities of pirfenidone.

Eligibility:

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.

Design:

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 NCI 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.

Study Design

Masking: Open Label, Primary Purpose: Treatment

Conditions

Neurofibromatosis 1

Intervention

Pirfenidone

Location

University of Alabama
Birmingham
Alabama
United States
35233

Status

Completed

Source

National Institutes of Health Clinical Center (CC)

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:54:39-0400

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Medical and Biotech [MESH] Definitions

A group of disorders characterized by an autosomal dominant pattern of inheritance with high rates of spontaneous mutation and multiple neurofibromas or neurilemmomas. NEUROFIBROMATOSIS 1 (generalized neurofibromatosis) accounts for approximately 95% of cases, although multiple additional subtypes (e.g., NEUROFIBROMATOSIS 2, neurofibromatosis 3, etc.) have been described. (From Neurochirurgie 1998 Nov;44(4):267-72)

Tumor suppressor genes located on the long arm of human chromosome 22. Mutation or loss of these genes causes NEUROFIBROMATOSIS 2.

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A protein found most abundantly in the nervous system. Defects or deficiencies in this protein are associated with NEUROFIBROMATOSIS 1, Watson syndrome, and LEOPARD syndrome. Mutations in the gene (GENE, NEUROFIBROMATOSIS 1) affect two known functions: regulation of ras-GTPase and tumor suppression.

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