Phase 2 N=36 Treatment

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

Neurofibromatosis 1 · Neurofibroma, Plexiform

Bottom Line

View on ClinicalTrials.gov: NCT00076102 ↗

Enrolled (actual)

Serious AEs

8.3%

Results posted

Jul 2012

Primary outcome: Primary: Median Time to Disease Progression — 13.2 Months

Study Design & Population

Study type: Interventional
Phase: Phase 2
Interventions: Pirfenidone (Drug)
Age: Pediatric, Adult · 3+ yrs
Sex: All
Sponsor: National Cancer Institute (NCI)
Primary completion: Apr 2010

Outcome Measures

Outcome	Result	p-value
PRIMARY Median Time to Disease Progression	13.2	—
PRIMARY Number of Participants With Adverse Events	36	—
PRIMARY Percentage of Participants Who Had an Objective Response Rate	0; 0	—
SECONDARY Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline	72.7; 69.1; 72.1; 76.7; 72.4; 63.7	0.0301 sig
SECONDARY Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale	71.1; 71.8; 67.9; 69.8; 71.7; 70.6	0.6263
SECONDARY Number of Participants With A Response Evaluation Determined by the Comparison of One-Dimensional (1D) Magnetic Resonance Imaging	—	—
SECONDARY Number of Participants With A Response Evaluation Determined by the Comparison of Two-Dimensional (2D) Magnetic Resonance Imaging	—	—
SECONDARY Number of Participants With A Response Evaluation Determined by the Comparison of Three-Dimensional (3D) Magnetic Resonance Imaging	31; 0; 0; 0; 0	—
SECONDARY Number of Participants Who Contributed to the Tissue Bank	—	—

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)

Eligibility Criteria

INCLUSION CRITERIA:
Age: greater than or equal to 3 years and Less than or equal to 21 years of age. Required body surface area (BSA): greater than or equal to 0.31 m^2.
Diagnosis: Patients with NF1 and progressive plexiform neurofibromas that have the potential to cause significant morbidity, such as (but not limited to) head and neck lesions that could compromise the airway or great vessels, brachial or lumbar plexus lesions that could cause nerve compression and loss of function, lesions that could result in major deformity (e.g., orbital lesions) or significant cosmetic problems, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. Histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings, but should be considered if malignant degeneration of a plexiform neurofibroma is clinically suspected. In addition to plexiform neurofibroma(s), all study subjects must have at least one other diagnostic criteria for NF1 listed below (National Institutes of Health (NIH) Consensus Conference):
Six or more cafe-au-lait spots (greater than or equal to 0.5 cm in prepubertal subjects or greater than or equal to 1.5 cm in postpubertal subjects)
Freckling in the axilla or groin
Optic glioma
Two or more Lisch nodules
A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex)
A first-degree relative with NF1

In this study a plexiform neurofibroma is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches. A spinal plexiform neurofibroma involves two or more levels with connection between the levels or extending laterally along the nerve.

Measurable disease: Patients must have measurable plexiform neurofibroma(s). For the purpose of this study a measurable lesion will be defined as a lesion of at least 3 cm measured in one dimension. There must be evidence of recurrent or progressive disease as documented by an increase in size or the presence of new plexiform neurofibromas on MRI. Progression at the time of study entry is defined as:

A. A measurable increase of the plexiform neurofibroma (greater than or equal to 20% increase in the volume, or a greater than or equal to 13% increase in the product of the two longest perpendicular diameters, or a greater than or equal to 6% increase in the longest diameter) over the last two consecutive scans (magnetic resonance imaging (MRI) or computed tomography (CT), or over the time period of approximately one year prior to evaluation for this study.

B. Patients who underwent surgery for a progressive plexiform neurofibroma will be eligible to enter the study after the surgery, provided the plexiform neurofibroma was incompletely resected and is measurable.

Prior therapy: Patients with NFI are eligible at the time of recurrence or progression of an inoperable plexiform neurofibroma. Patients will only be eligible if complete tumor resection is not feasible, or if a patient with a surgical option refuses surgery.

Since there is no standard effective chemotherapy for patients with NF1 and progressive plexiform neurofibromas, patients may be treated on this trial without having received prior medical therapy.

Patients who received prior medical treatment for their plexiform neurofibroma(s) must have recovered from the toxic effects of all prior therapy before entering this study. The Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE-3) Version 3.0 will be used for toxicity assessment. A copy of the CTCAE version 3.0 can be downloaded from the CTEP home page (http:// ctep.cancer.gov). Recovery is defined as a toxicity grade less than 2, unless otherwise specified in the Inclusion and Exclusion Criteria.

Patients must have had their last dose of radiation therapy at least six weeks prior to study entry, and their last dose of chemo

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Data sourced from ClinicalTrials.gov (NCT00076102). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.