Pirfenidone in Children and Young Adults With Neurofibromatosis Type I and Progressive Plexiform Neurofibromas
Condition: Neurofibromatosis 1; Neurofibroma, Plexiform
MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurofibroma, Plexiform
Study type: Interventional
Phase: Phase 2

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 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.

      Funding source - Food and Drug Administration (FDA) Office of Orphan Products Development
      (OOPD)
    

Detailed 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 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.
    

Intervention name(s): Pirfenidone
Intervention type(s): Drug
Intervention description(s): Pirfenidone orally as capsules three times a day approximately every 8 hours for cycles of 28 days with no rest period between cycles (28 day treatment cycles); 500 mg/m^2 every 8 hours (1500 mg/m2/day).
Other intervention name(s): Esbriet; Deskar
Intervention MeSH terms: Pirfenidone
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Side Effect; Oral Administration; Nerve Sheath Tumor; Antifibrotic Agent; Volumetric Tumor Measurement; Plexiform Neurofibroma; Neurofibromatosis Type 1; Volumetric MRI Analysis; Time to Progression; NF1