Know Cancer

forgot password

Phase II Trial of Pirfenidone in Children, Adolescents, and Young Adults With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas

Phase 2
3 Years
21 Years
Not Enrolling
Neurofibromatosis 1, Neurofibroma, Plexiform

Thank you

Trial Information

Phase II Trial of Pirfenidone in Children, Adolescents, and Young Adults With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas


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.


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

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

To describe and define the toxicities of pirfenidone.


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.


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.

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

1. 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)

2. Freckling in the axilla or groin

3. Optic glioma

4. Two or more Lisch nodules

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

6. 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.

3. 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.

4. 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

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:// Recovery is defined as a
toxicity grade less than 2, unless otherwise specified in the Inclusion and Exclusion

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.

5. 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

6. 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

7. 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

8. 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

9. 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.

10. 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.

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

12. 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.

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


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

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Median Time to Disease Progression

Outcome Description:

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

Outcome Time Frame:

5 years

Safety Issue:


Principal Investigator

Brigitte C Widemann, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health


United States: Federal Government

Study ID:




Start Date:

January 2004

Completion Date:

April 2010

Related Keywords:

  • Neurofibromatosis 1
  • Neurofibroma, Plexiform
  • Side Effect
  • Oral Administration
  • Nerve Sheath Tumor
  • Antifibrotic Agent
  • Volumetric Tumor Measurement
  • Plexiform Neurofibroma
  • Neurofibromatosis Type 1
  • Volumetric MRI Analysis
  • Time to Progression
  • NF1
  • Neurofibroma
  • Neurofibromatoses
  • Neurofibromatosis 1
  • Osteitis Fibrosa Cystica
  • Neurofibroma, Plexiform



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892
Childrens National Medical Center Washington, District of Columbia  
University of Alabama Birmingham, Alabama  
Johns Hopkins Oncology Center Baltimore, Maryland  21287
Beth Israel Medical Center New York, New York  10003
St. Louis Children's Hospital Saint Louis, Missouri  63110
SUNY Upstate Medical University Syracuse, New York  13210
Oregon Health Sciences University Portland, Oregon  
Childrens Hospital, Philadelphia Philadelphia, Pennsylvania  19104
Cleveland Clinic Cleveland, Ohio  44195
Texas Children's Hospital Houston, Texas  
Childrens Memorial Hospital, Chicago Chicago, Illinois  60614
Childrens Hospital, Dana-Farber Cancer Institute Boston, Massachusetts  02115
Mayo Clinic, Rochester Rochester, Minnesota  55905
Childrens Hospital, Pittsburgh Pittsburgh, Pennsylvania  15213