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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00076102
• Collaborator: (none)
• Enrollment: 36
• Locations: 15
• Arm: 1
• Actual Duration (Months): 68.3
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief 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)

Condition or Disease	Intervention/Treatment	Phase
Neurofibromatosis 1; Neurofibroma, Plexiform	Drug: Pirfenidone	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Pirfenidone in Children, Adolescents, and Young Adults With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas
• Actual Study Start Date: Jul 21, 2004
• Actual Primary Completion Date: Apr 1, 2010
• Actual Study Completion Date: Apr 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pirfenidone 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).	Drug: Pirfenidone; 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 Names: Esbriet Deskar

Outcome Measures

Primary Outcome Measures

1. Median Time to Disease Progression [5 years]

   Time to progression is defined as greater than or equal to 20% increase in plexiform neurofibromas (PN) volume on magnetic resonance imaging (MRI).

2. Number of Participants With Adverse Events [5 years]

   Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

3. Percentage of Participants Who Had an Objective Response Rate [≥4 weeks]

   Objective response rate is defined as a complete response (CR) or partial response (PR). Complete response is a complete resolution of all measurable or palpable soft tissue tumors for ≥4 weeks and no appearance of new lesions. Partial response is a ≥50% reduction in the sum of the volume of all index lesions for ≥4 weeks.

Secondary Outcome Measures

1. Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline [Baseline]

   Quality of life was assessed by the Impact of Pediatric Illness scale for children 6-18 years of age. The child's primary caregiver completed the proxy Parent Form and children answered either the self-report Child or Adolescent (11-18 years) Form. The parallel IPI Scale forms assess four domains: adaptive behavior, emotional functioning, medical/physical status, and cognitive functioning. Responses to the 43 items are made on a 3-or5-point Likert scale (1 to 5 for Parent and Adolescent Form and 1, 3, 5 for the Child Form) ranging from "not at all" to "a lot". Item scores are transformed to a scale of 0-100, and then mean scores are calculated for the four domains and total scale with higher scores indicating better QOL. Baseline comparisons between child and parent total and domain scores were performed.

2. Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale [prior to cycles 1, 4, 7 and 10.]

   Quality of life was assessed by the Impact of Pediatric Illness scale for children 6-18 years of age. The child's primary caregiver completed the proxy Parent Form and children answered either the self-report Child or Adolescent (11-18 years) Form prior to cycles 1, 4, 7 and 10. The parallel IPI Scale forms assess four domains: adaptive behavior, emotional functioning, medical/physical status, and cognitive functioning. Responses to the 43 items are made on a 3-or5-point Likert scale (1 to 5 for Parent and Adolescent Form and 1, 3, 5 for the Child Form) ranging from "not at all" to "a lot". Item scores are transformed to a scale of 0-100, and then mean scores are calculated for the four domains and total scale with higher scores indicating better QOL.

3. Number of Participants With A Response Evaluation Determined by the Comparison of One-Dimensional (1D) Magnetic Resonance Imaging [Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter until progression]

   Index lesions will be followed for progression by 1D magnetic resonance imaging. Progression is defined as a ≥20% increase in the volume of at least one of the index plexiform neurofibromas compared to the pretreatment volume measured prior to the start of treatment.

4. Number of Participants With A Response Evaluation Determined by the Comparison of Two-Dimensional (2D) Magnetic Resonance Imaging [Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter until progression]

   Index lesions will be followed for progression by 2D magnetic resonance imaging. Progression is defined as a ≥20% increase in the volume of at least one of the index plexiform neurofibromas compared to the pretreatment volume measured prior to the start of treatment.

5. Number of Participants With A Response Evaluation Determined by the Comparison of Three-Dimensional (3D) Magnetic Resonance Imaging [Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter, approximately 5 years]

   Index lesions will be followed for progression by 3D magnetic resonance imaging. Compete response is a complete resolution of all measurable or palpable soft tissue tumors for ≥4 weeks and no appearance of new lesions. Partial response is a ≥50% reduction in the sum of the volume of all index lesions for ≥4 weeks. Progression is defined as a ≥20% increase in the volume of at least one of the index plexiform neurofibromas compared to the pretreatment volume measured prior to the start of treatment. Stable disease is a <20% increase, and <25% decrease in the sum of the volume of all index lesions for ≥4 weeks. Minor response is a ≥25% but <50% reduction in the sum of the volume of all index lesions for ≥4 weeks.

6. Number of Participants Who Contributed to the Tissue Bank [5 years]

   Tumor specimens from patients who undergo tumor surgery or biopsies for clinical reasons.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

1. 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.

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):

3. 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)

4. Freckling in the axilla or groin

5. Optic glioma

6. Two or more Lisch nodules

7. A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex)

8. 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.

1. 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:

1. 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.

2. 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.

1. 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 chemotherapy at least four weeks prior to study entry. Patients who received G-CSF after the prior cycle of chemotherapy must be off G-CSF for at least one week prior to entering this study.

1. Performance Status: Performance Status: Patients should have a life expectancy of at least 12 months. Patients greater than 10 years must have a Karnofsky performance level greater than or equal to 50, and children less than or equal to 10 years must have a Lansky performance level greater than or equal to 50. Patients who are wheelchair bound because of paralysis should be considered ambulatory when they are up in their wheel chair.

2. Hematologic Function: Patients must have an absolute granulocyte count greater than or equal to 1,500/uL, a hemoglobin greater than or equal to 9.0 gm/dl, and a platelet count greater than or equal to 150,000/microliter at study entry (all transfusion independent).

3. Hepatic Function: Patients must have a bilirubin within normal limits and serum glutamic pyruvic transaminase (SGPT) less then or equal to 2x upper limit of normal. Patients with Gilbert syndrome are excluded from the requirement of a normal bilirubin. (Gilbert syndrome is found in 3-10% of the general population, and is characterized by mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis).

4. Renal Function: Patients must have an age-adjusted normal serum creatinine (see table below) OR a creatinine clearance greater than or equal to 70 mL/min/1.73 m^2.

Age Maximum Serum Creatinine

(years) (mg/dl)

less than or equal to 5 0.8

5 less than age less than or equal to 10 1.0

10 less than age less than or equal to 15 1.2

greater than 15 1.5

1. Informed Consent: All patients or their legal guardians (if the patients is less than 18 years old) must sign an Institutional Review Board (IRB) approved document of informed consent (screening protocol) prior to performing studies to determine patient eligibility. After confirmation of patient eligibility all patients or their legal guardians must sign the protocol specific informed consent to document their understanding of the investigational nature and the risks of this study before any protocol related studies are performed (other than the studies which were performed to determine patient eligibility). When appropriate, pediatric patients will be included in all discussions. Age appropriate assent forms for children from 7 through 12 years, and for children from 13 through 17 years have been developed and will be signed by the pediatric patients, when appropriate, in order to obtain written assent.

2. Durable Power of Attorney (DPA): All patients greater than or equal to 18 years of age will be offered the opportunity to assign DPA so that another person can make decisions about their medical care if they become incapacitated or cognitively impaired.

3. Patients must be able to take pirfenidone by mouth. Capsules can be opened and content mixed with food for easier consumption in small children.

4. Patients (both male and female) must be willing to practice birth control (including abstinence) during and for two months after treatment, if of a child-bearing age. For purposes of the protocol, all patients greater than 9 years of age or those showing pubertal development will be considered of childbearing age.

5. Ability to undergo magnetic resonance imaging (MRI) and no contraindication for MRI examinations following the MRI protocol outlined.

EXCLUSION CRITERIA:

1. Pregnant or breast feeding females are excluded, because the toxic effects and pharmacology of pirfenidone in the fetus and newborn are unknown.

2. Clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), which in the judgment of the Principal or Associate Investigator would compromise the patient's ability to tolerate pirfenidone or are likely to interfere with the study procedures or results.

3. An investigational agent within the past 30 days.

4. Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor, immunotherapy, or biologic therapy (for example interferon).

5. Inability to return for follow-up visits or obtain follow-up studies required to assess toxicity and response to therapy.

6. Prior treatment with pirfenidone.

7. Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35233
2	Childrens National Medical Center	Washington	District of Columbia	United States	20010
3	Childrens Memorial Hospital, Chicago	Chicago	Illinois	United States	60614
4	Johns Hopkins Oncology Center	Baltimore	Maryland	United States	21287
5	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892
6	Childrens Hospital, Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
7	Mayo Clinic, Rochester	Rochester	Minnesota	United States	55905
8	St. Louis Children's Hospital	Saint Louis	Missouri	United States	63110
9	Beth Israel Medical Center	New York	New York	United States	10003
10	SUNY Upstate Medical University	Syracuse	New York	United States	13210
11	Cleveland Clinic	Cleveland	Ohio	United States	44195
12	Oregon Health Sciences University	Portland	Oregon	United States	97201-3098
13	Childrens Hospital, Philadelphia	Philadelphia	Pennsylvania	United States	19104
14	Childrens Hospital, Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
15	Texas Children's Hospital	Houston	Texas	United States	77030

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Brigitte C Widemann, M.D., National Cancer Institute, National Institutes of Health

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Apr 17, 2008

More Information

Publications

• Cain WC, Stuart RW, Lefkowitz DL, Starnes JD, Margolin S, Lefkowitz SS. Inhibition of tumor necrosis factor and subsequent endotoxin shock by pirfenidone. Int J Immunopharmacol. 1998 Dec;20(12):685-95.
• DeClue JE, Heffelfinger S, Benvenuto G, Ling B, Li S, Rui W, Vass WC, Viskochil D, Ratner N. Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models. J Clin Invest. 2000 May;105(9):1233-41.
• Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002 May;39(5):311-4.

• Responsible Party: Brigitte Widemann, M.D., Dr. Brigitte Widemann, M.D., National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00076102
• Other Study ID Numbers: 040080; 04-C-0080; FD-R-0002128; NCT00078936
• First Posted: Jan 14, 2004
• Last Update Posted: Apr 23, 2018
• Last Verified: Apr 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Brigitte Widemann, M.D., Dr. Brigitte Widemann, M.D., National Cancer Institute (NCI): Side Effect; Oral Administration; Nerve Sheath Tumor; Antifibrotic Agent; Volumetric Tumor Measurement; Plexiform Neurofibroma; Neurofibromatosis Type 1; Volumetric MRI Analysis; Time to Progression; NF1
• Additional relevant MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurofibroma, Plexiform; Pirfenidone

Study Results

Participant Flow

Recruitment Details	36 participants were enrolled in this study

Arm/Group Title	Pirfenidone
Arm/Group Description	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).
Period Title: Overall Study
STARTED	36
COMPLETED	31
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Pirfenidone
Arm/Group Description	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).
Overall Participants	36
Age (Count of Participants)
<=18 years	34 94.4%
Between 18 and 65 years	2 5.6%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.81 (4.52)
Sex: Female, Male (Count of Participants)
Female	10 27.8%
Male	26 72.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 16.7%
Not Hispanic or Latino	29 80.6%
Unknown or Not Reported	1 2.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 13.9%
White	29 80.6%
More than one race	0 0%
Unknown or Not Reported	2 5.6%
Region of Enrollment (participants) [Number]
United States	36 100%

Outcome Measures

1. Primary Outcome

Title	Median Time to Disease Progression
Description	Time to progression is defined as greater than or equal to 20% increase in plexiform neurofibromas (PN) volume on magnetic resonance imaging (MRI).
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pirfenidone
Arm/Group Description	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).
Measure Participants	36
Median (95% Confidence Interval) [Months]	13.2

2. Primary Outcome

Title	Number of Participants With Adverse Events
Description	Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pirfenidine
Arm/Group Description	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).
Measure Participants	36
Count of Participants [Participants]	36 100%

3. Primary Outcome

Title	Percentage of Participants Who Had an Objective Response Rate
Description	Objective response rate is defined as a complete response (CR) or partial response (PR). Complete response is a complete resolution of all measurable or palpable soft tissue tumors for ≥4 weeks and no appearance of new lesions. Partial response is a ≥50% reduction in the sum of the volume of all index lesions for ≥4 weeks.
Time Frame	≥4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pirfenidine
Arm/Group Description	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).
Measure Participants	31
Complete Response	0 0%
Partial Response	0 0%

4. Secondary Outcome

Title	Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline
Description	Quality of life was assessed by the Impact of Pediatric Illness scale for children 6-18 years of age. The child's primary caregiver completed the proxy Parent Form and children answered either the self-report Child or Adolescent (11-18 years) Form. The parallel IPI Scale forms assess four domains: adaptive behavior, emotional functioning, medical/physical status, and cognitive functioning. Responses to the 43 items are made on a 3-or5-point Likert scale (1 to 5 for Parent and Adolescent Form and 1, 3, 5 for the Child Form) ranging from "not at all" to "a lot". Item scores are transformed to a scale of 0-100, and then mean scores are calculated for the four domains and total scale with higher scores indicating better QOL. Baseline comparisons between child and parent total and domain scores were performed.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Of the 36 patients enrolled, 28 were within the age range of the IPI Scale at baseline. Two patients did not have any QOL forms completed; one did not have a baseline evaluation, and six patients had missing follow-up evaluations. Thus, QOL data is presented for 19 subjects.

Arm/Group Title	Pirfenidine
Arm/Group Description	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).
Measure Participants	19
Total score parent	72.7 (10.7)
Total score child	69.1 (12.0)
Parent proxy-adaptive behavior	72.1 (10.2)
Child Self-Report-adaptive behavior	76.7 (11.8)
Parent proxy - emotional functioning	72.4 (13.4)
Child Self-Report-emotional functioning	63.7 (14.7)
Parent proxy - medical/physical status	77.6 (15.1)
Child Self-Report - medical/physical status	67.1 (16.2)
Parent proxy - cognitive functioning	62.9 (19.6)
Child Self-Report- cognitive functioning	69.4 (18.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone
	Comments	F=5.45 under the null hypothesis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0301
	Comments	The reported F statistic and p-value are representative of the difference in the Parent proxy Form and the Child Self-Report Form response for Adaptive Behavior.
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone
	Comments	F = 6.56 under the null hypothesis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0186
	Comments	The reported p-value is representative of the difference in the Parent proxy Form and the Child Self-Report Form response for Emotional Functioning.
	Method	ANOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone
	Comments	F=11.23 under the null hypothesis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0032
	Comments	The reported p-value is representative of the difference in the Parent proxy Form and the Child Self-Report Form response for Medical/Physical Status.
	Method	ANOVA
	Comments

5. Secondary Outcome

Title	Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale
Description	Quality of life was assessed by the Impact of Pediatric Illness scale for children 6-18 years of age. The child's primary caregiver completed the proxy Parent Form and children answered either the self-report Child or Adolescent (11-18 years) Form prior to cycles 1, 4, 7 and 10. The parallel IPI Scale forms assess four domains: adaptive behavior, emotional functioning, medical/physical status, and cognitive functioning. Responses to the 43 items are made on a 3-or5-point Likert scale (1 to 5 for Parent and Adolescent Form and 1, 3, 5 for the Child Form) ranging from "not at all" to "a lot". Item scores are transformed to a scale of 0-100, and then mean scores are calculated for the four domains and total scale with higher scores indicating better QOL.
Time Frame	prior to cycles 1, 4, 7 and 10.

Outcome Measure Data

Analysis Population Description

Of the 36 pts enrolled, 28 were within the age range of the IPI Scale at baseline. 2 pts did not have any QOL forms completed; 1 did not have a baseline & 6 pts had missing f/u evals. QOL data is presented for 19 pts. Due to pts not completing forms at random f/u evals, some time points have fewer than 19 pts included in the longitudinal analysis.

Arm/Group Title	Pirfenidine
Arm/Group Description	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).
Measure Participants	19
Parent Baseline (to Cycle 4)	71.1 (13.1)
Parent Pre Cycle 4	71.8 (10.7)
Child Baseline (to Cycle 4)	67.9 (12.9)
Child Pre Cycle 4	69.8 (10.8)
Parent Baseline (to Cycle 7)	71.7 (11.5)
Parent Pre Cycle 7	70.6 (9.0)
Child Baseline (to Cycle 7)	69.5 (12.8)
Child Pre Cycle 7	71.4 (12.3)
Parent Baseline (to Pre Cycle 10)	71.56 (12.6)
Parent Pre Cycle 10	72.1 (7.8)
Child Baseline (to Pre Cycle 10)	67.5 (13.0)
Child Pre Cycle 10	68.3 (14.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone
	Comments	F=0.25 under the null hypothesis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6263
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone
	Comments	F= 0.87 under the null hypothesis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3625
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone
	Comments	F=0.31 under the null hypothesis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5877
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone
	Comments	F=1.27 under the null hypothesis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2767
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone
	Comments	F=0.04 under the null hypothesis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8466
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone
	Comments	F=0.18 under the null hypothesis
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6774
	Comments
	Method	ANOVA
	Comments

6. Secondary Outcome

Title	Number of Participants With A Response Evaluation Determined by the Comparison of One-Dimensional (1D) Magnetic Resonance Imaging
Description	Index lesions will be followed for progression by 1D magnetic resonance imaging. Progression is defined as a ≥20% increase in the volume of at least one of the index plexiform neurofibromas compared to the pretreatment volume measured prior to the start of treatment.
Time Frame	Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter until progression

Outcome Measure Data

Analysis Population Description

This outcome measure was not done because only 3D imaging was performed. Due to a detailed comparison of 1D-2D and 3D imaging for another study (Tipifarnib R115777) the investigator determined that a detailed comparison of 1D-2D and 3D analysis would really add no new knowledge. Therefore only 3D analysis was performed for this trial.

Arm/Group Title	Pirfenidone
Arm/Group Description	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).
Measure Participants	0

7. Secondary Outcome

Title	Number of Participants With A Response Evaluation Determined by the Comparison of Two-Dimensional (2D) Magnetic Resonance Imaging
Description	Index lesions will be followed for progression by 2D magnetic resonance imaging. Progression is defined as a ≥20% increase in the volume of at least one of the index plexiform neurofibromas compared to the pretreatment volume measured prior to the start of treatment.
Time Frame	Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter until progression

Outcome Measure Data

Analysis Population Description

This outcome measure was not done because only 3D imaging was performed. Due to a detailed comparison of 1D-2D and 3D imaging for another study (Tipifarnib R115777) the investigator determined that a detailed comparison of 1D-2D and 3D analysis would really add no new knowledge. Therefore only 3D analysis was performed for this trial.

Arm/Group Title	Pirfenidone
Arm/Group Description	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).
Measure Participants	0

8. Secondary Outcome

Title	Number of Participants With A Response Evaluation Determined by the Comparison of Three-Dimensional (3D) Magnetic Resonance Imaging
Description	Index lesions will be followed for progression by 3D magnetic resonance imaging. Compete response is a complete resolution of all measurable or palpable soft tissue tumors for ≥4 weeks and no appearance of new lesions. Partial response is a ≥50% reduction in the sum of the volume of all index lesions for ≥4 weeks. Progression is defined as a ≥20% increase in the volume of at least one of the index plexiform neurofibromas compared to the pretreatment volume measured prior to the start of treatment. Stable disease is a <20% increase, and <25% decrease in the sum of the volume of all index lesions for ≥4 weeks. Minor response is a ≥25% but <50% reduction in the sum of the volume of all index lesions for ≥4 weeks.
Time Frame	Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter, approximately 5 years

Outcome Measure Data

Analysis Population Description

Five patients were not analyzed due to clinical progression (n=1), plexiform neurofibroma surgery (n=1), progression in a pre-existing brain tumor (n=1), and refusal of further therapy (n=2).

Arm/Group Title	Pirfenidone
Arm/Group Description	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/m^2/day).
Measure Participants	31
Progressive disease	31 86.1%
Complete response	0 0%
Partial response	0 0%
Stable disease	0 0%
MInor response	0 0%

9. Secondary Outcome

Title	Number of Participants Who Contributed to the Tissue Bank
Description	Tumor specimens from patients who undergo tumor surgery or biopsies for clinical reasons.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Participants declined to contribute specimens for the tissue bank.

Arm/Group Title	Pirfenidine
Arm/Group Description	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).
Measure Participants	0

Adverse Events

Time Frame	5 years
Arm/Group Title	Pirfenidone
Arm/Group Description	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).
All Cause Mortality
	Pirfenidone
	Affected / at Risk (%)	# Events
Total	0/36 (0%)
Serious Adverse Events
	Pirfenidone
	Affected / at Risk (%)	# Events
Total	3/36 (8.3%)
Blood and lymphatic system disorders
Hemorrhage, CNS	1/36 (2.8%)	1
Respiratory, thoracic and mediastinal disorders
Adult Respiratory Distress Syndrome (ARDS)	1/36 (2.8%)	1
Atelectasis	1/36 (2.8%)	1
Bronchospasm, wheezing	1/36 (2.8%)	1
Cough	1/36 (2.8%)	1
Dyspnea (shortness of breath)	1/36 (2.8%)	1
Hypoxia	1/36 (2.8%)	1
Pneumothorax	1/36 (2.8%)	1
Other (Not Including Serious) Adverse Events
	Pirfenidone
	Affected / at Risk (%)	# Events
Total	36/36 (100%)
Blood and lymphatic system disorders
Hemoglobin	5/36 (13.9%)	10
Lymphatics-Other (Specify-bilateral lymphadenopathy)	4/36 (11.1%)	4
Lymphopenia	6/36 (16.7%)	8
Cardiac disorders
Cardiac arrhythmia-Other, specify- sinus tachycardia	1/36 (2.8%)	1
Cardiac general, Other-(specify-fluid retention)	1/36 (2.8%)	1
Supraventricular and nodal arrhythmia: sinus tachycardia	1/36 (2.8%)	1
Ear and labyrinth disorders
Hearing: patients without baseline audiogram and not enrolled in a monitoring program	1/36 (2.8%)	1
Otitis, middle ear (non-infectious)	3/36 (8.3%)	6
Pain: middle ear	1/36 (2.8%)	1
Pain-Other (Specify-left ear pain)	4/36 (11.1%)	6
Eye disorders
Dry eye syndrome	1/36 (2.8%)	1
Ocular/Visual-Other (Specify-blurred vision intermittent)	2/36 (5.6%)	2
Vision-photophobia	1/36 (2.8%)	1
Gastrointestinal disorders
Anorexia	9/36 (25%)	22
Constipation	6/36 (16.7%)	6
Dehydration	3/36 (8.3%)	3
Dental: teeth	1/36 (2.8%)	1
Diarrhea	21/36 (58.3%)	63
Gastrointestinal-Other (Specify- 1 episode of incontinence of bowel)	2/36 (5.6%)	2
Heartburn/dyspepsia	2/36 (5.6%)	2
Mucositis/stomatitis (clinical exam): oral cavity	2/36 (5.6%)	3
Nausea	29/36 (80.6%)	157
Pain: dental/teeth/peridontal	2/36 (5.6%)	3
Pain: esophagus	1/36 (2.8%)	1
Pain: stomach	2/36 (5.6%)	2
Pain: throat/pharynx/larynx	4/36 (11.1%)	5
Taste alteration (dysgeusia)	1/36 (2.8%)	1
Vomiting	25/36 (69.4%)	119
General disorders
Constitutional symptoms (Other, specify-cold symptoms)	3/36 (8.3%)	4
Edema: head and neck	1/36 (2.8%)	1
Edema: limb	1/36 (2.8%)	1
Fatigue (asthenia, lethargy, malaise)	11/36 (30.6%)	21
Fever (in the absence of neutropenia, where neutropenia is defined as ANC < 1.0 x 10e9/L)	10/36 (27.8%)	20
Flu-like syndrome	6/36 (16.7%)	7
Immune system disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	7/36 (19.4%)	8
Infections and infestations
Infection (documented clinically or microbiologically) with grade 3 or 4 neutrophils (ANC < 1.0 x 10	1/36 (2.8%)	1
Infection-Other (specify-infection)	6/36 (16.7%)	7
Infection with normal ANC or Grade 1 or 2 neutrophils : bronchus	2/36 (5.6%)	2
Infection with normal ANC or Grade 1 or 2 neutrophils : catheter-related	1/36 (2.8%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils : conjunctiva	2/36 (5.6%)	2
Infection with normal ANC or Grade 1 or 2 neutrophils : foreign body (e.g. graft, implant, prosthesi	1/36 (2.8%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils : lung (pneumonia)	1/36 (2.8%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils : middle ear (otitis media)	2/36 (5.6%)	2
Infection with normal ANC or Grade 1 or 2 neutrophils : penis	1/36 (2.8%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils : pharynx	1/36 (2.8%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils : sinus	2/36 (5.6%)	2
Infection with normal ANC or Grade 1 or 2 neutrophils : skin (cellulitis)	2/36 (5.6%)	3
Infection with normal ANC or Grade 1 or 2 neutrophils : upper aerodigestive NOS	1/36 (2.8%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils : upper airway NOS	5/36 (13.9%)	7
Infection with unknown ANC : external ear (otitis externa)	2/36 (5.6%)	3
Infection with unknown ANC : lung (pneumonia)	1/36 (2.8%)	1
Infection with unknown ANC : sinus	2/36 (5.6%)	2
Infection with unknown ANC : trachea	1/36 (2.8%)	1
Infection with unknown ANC : upper airway NOS	2/36 (5.6%)	3
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase)	2/36 (5.6%)	2
Bicarbonate, serum low	4/36 (11.1%)	7
Leukocytes (total WBC)	8/36 (22.2%)	22
Neutrophils/granulocytes (ANC/AGC)	7/36 (19.4%)	24
PTT (partial thromboplastin time)	1/36 (2.8%)	1
Platelets	3/36 (8.3%)	5
AST, SGOT (serum oxaloacetic transaminase)	2/36 (5.6%)	3
Alkaline phosphatase	3/36 (8.3%)	3
Metabolism and nutrition disorders
Albumin, serum low (hypoalbuminemia)	5/36 (13.9%)	7
Calcium, serum-high (hypercalcemia)	4/36 (11.1%)	5
Calcium, hypocalcemia	9/36 (25%)	13
Glucose, serum-high (hyperglycemia)	4/36 (11.1%)	4
Glucose, serum low (hypoglycemia)	1/36 (2.8%)	1
Magnesium, serum high (hype	8/36 (22.2%)	9
Magnesium, serum low (hypomagnesemia)	3/36 (8.3%)	3
Phosphate, serum low (hypophosphatemia)	2/36 (5.6%)	3
Potassium, serum high (hyperkalemia)	1/36 (2.8%)	1
Potassium, serum low (hypokalemia)	4/36 (11.1%)	6
Sodium, serum-high (hypernatremia)	3/36 (8.3%)	3
Sodium, serum-low (hyponatremia)	2/36 (5.6%)	2
Musculoskeletal and connective tissue disorders
Lumbar spine-range of motion	1/36 (2.8%)	3
Muscle weaknesses, generalized or specific area (not due to neuropathy): extreme-lower	2/36 (5.6%)	2
Pain: back	5/36 (13.9%)	6
Pain: bone	1/36 (2.8%)	2
Pain: buttock	1/36 (2.8%)	1
Pain: chest wall	1/36 (2.8%)	2
Pain: chest/thorax NOS	4/36 (11.1%)	4
Pain: extremity-limb	7/36 (19.4%)	13
Pain: joint	2/36 (5.6%)	3
Pain: muscle	4/36 (11.1%)	7
Pain: neck	5/36 (13.9%)	15
Nervous system disorders
Dizziness	4/36 (11.1%)	5
Mood alteration: agitation	2/36 (5.6%)	2
Mood alteration: depression	2/36 (5.6%)	3
Neurology-Other (specify-tic, constant clearing of throat)	1/36 (2.8%)	1
Neuropathy: motor	3/36 (8.3%)	3
Neuropathy: sensory	2/36 (5.6%)	2
Pain: head/headache	21/36 (58.3%)	52
Pain: pain NOS	4/36 (11.1%)	4
Tremor	1/36 (2.8%)	1
Psychiatric disorders
Personality/behavioral	5/36 (13.9%)	7
Renal and urinary disorders
Hemorrhage, GU: urinary NOA	1/36 (2.8%)	2
Incontinence, urinary	2/36 (5.6%)	2
Pain: bladder	1/36 (2.8%)	3
Reproductive system and breast disorders
Hemorrhage, GU: Ovary	1/36 (2.8%)	1
Pain: abdomen NOS	5/36 (13.9%)	8
Pain: pelvis	1/36 (2.8%)	1
Pain: penis	1/36 (2.8%)	1
Respiratory, thoracic and mediastinal disorders
Bronchospasm, wheezing	1/36 (2.8%)	2
Hemorrhage, pulmonary/upper respiratory: nose	2/36 (5.6%)	3
Obstruction/stenosis of airway: bronchus	1/36 (2.8%)	1
Obstruction/stenosis of airway: larynx	1/36 (2.8%)	1
Pneumonitis/pulmonary infiltrates	1/36 (2.8%)	1
Pulmonary/upper respiratory-Other (Specify-bloody nose)	3/36 (8.3%)	5
Cough	10/36 (27.8%)	11
Skin and subcutaneous tissue disorders
Atrophy, skin	1/36 (2.8%)	1
Dermatology/Skin-Other (Specify-multiple bug bites)	4/36 (11.1%)	6
Pain: skin	1/36 (2.8%)	1
Pruritis/itching	5/36 (13.9%)	7
Rash/desquamation	2/36 (5.6%)	4
Rash: acne/acneiform	1/36 (2.8%)	1
Rash: hand-foot skin reaction	2/36 (5.6%)	3
Ulceration	1/36 (2.8%)	1
Vascular disorders
Hypertension	3/36 (8.3%)	3
Vascular-Other (Specify-vascular other specify, coolness LL)	1/36 (2.8%)	1
Flushing	1/36 (2.8%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.