Conditions: Neurofibromatosis 1 Neurofibroma, Plexiform
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
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 36
Healthy volunteers: no

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)

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.

Arms:
arm 1: 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).

Interventions: intervention 1: Pirfenidone
Intervention descriptions: intervention 1: 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).

Protocol document:
Prot_SAP_ICF_000.pdf: 
PROTOCOL NO.
04c0080-c
PROTOCOL SUBMISSION FORM
Amendment Form
PRINCIPAL INVESTIGATOR (NlH Employee Name, InsUBr, Telephone and e-mail):
Brigitte Widemann NCI 
POB 
301.496 .4256 
widemanb@mait.nih.1
PROTOCOL TITLE: "Phase ll Trial of Pirfenidone in Children, Adolescents, and Young Aclults with Neurofibromatosis 
Type 1 and progressive
Plexiform Neurofi bromas',
ABBREVIATED 
TITLE: 04C0090
Reference Number: 301345
Amendment Version Date: 04/0612008
Amendment Letter: D
The Following revisions were incorporated into this protocol and approved by:
f,| frpedited Review (risk/ benefit ratio not changed)
f] 
fult Board Review (meeting date)
Amendment includes changes required by:
[run
fl rucr 
rne
I crcn
ffi otner Sponsor
I ron
I otner
lf Other, Iist:
Amendment requires PRMC review (entail
Ives 
A No
ADM I N ISTRATIVE 
CHANGES
I 
Protocol Title/ Abbreviated 
Title
[ 
ruew Principal Investigator
[ 
rulH Personnel 
Change
f] Non-NlH Personnel 
Change
fl Converting 
to multi-institutional 
triat
DEC clearance 
required? [ 
Ves E
Date submitted 
to lC DEC: N/A
PROTOCOL 
CONTENT 
CHANGES
ffi erecis
I 
Stuoy Objectives
" 
E Background 
and Rationale
I 
etigibility 
Assessment 
and Enroilment
[J trnplementation 
of Study Design
f] 
Srpportive Care
I 
nccrual Ceiling 
Changed to: N/A
Does the amendment impact the risk/benefit assessment?
Ives 
trNo
INFORMED 
CONSENT 
DOCUMENTATION
ffi fext Revisions 
to Consent(s)
ffi lnvestigator 
Contact Information 
on Consent(s)
[J ttto Changes to Consent Form
substantive change to the objectives, design, or statistical section; or converted to multi-institutional 
study)?
No
Date cleared by lC DEC: N/A
I 
Oata Collection/Evaluation
ffi Human Subject Protections
f, 
Oata Reporting
tr IND/IDE Information
f, 
enarmaceutical 
Information
E nppendices
SIGNATURE
APPROVALS
Briqitte Widemann 
- applied siqnature 
on 0410712008 
6:42 PM EDT
New and Old Principal Investigators - electronic signature and date
Crvstal Mackall - applied siqnature on 04/0812008 8:22 AM EDT
Branch Chief - electronic signature and date
Mark Udev - applied siqnature on 041111200810:06 AM EDT
Clinical Director- electronic signature and date
Wanda Salzer - applied sionature on 0411712008 8:56 AM EDT
Chair, IRB Review - electronic signature and date
-frurAfu
IRB Meeting Date:
Page # 1
o f 3
4,k,otr M \
Protocol 
Submission 
Form - Amendment 
Form
(v 1.1 3/1/2008)


CC Protocol No: 
04-C-0080 
Amendment: 
D 
Revised: 
 4/6/2008 
IRB Approval Date: 
 
 
 
 
Phase II Trial of Pirfenidone in Children, Adolescents, and Young Adults with 
Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas 
Coordinating Center: Pediatric Oncology Branch, NCI 
NCI Principal Investigator: Brigitte C. Widemann, M.D., NCI∗ 
Cooperative Study Group PI: 
Coop. Study Group Co-PI: 
Roger J. Packer, MD (CNMC) 
Dusica Babovic-Vuksanovic (Mayo Clinic) 
 
 
Trial Sponsor (IND Holder): Dusica Babovic-Vuksanovic (Mayo Clinic) 
Drug Supplier: InterMune, Inc. ∗∗ 
Medical Monitor: Tracy Glauser, M.D. (Cincinnati Children’s Hospital) 
Associate Investigators: Frank Balis, M.D. (NCI, POB) 
 Elizabeth Fox, M.D. (NCI, POB) 
 Eva Dombi, M.D. 
 Anne Goodwin, R.N. (NCI, POB) 
 Wendy Goodspeed, R.N. (NCI, POB) 
 Andy Gillespie, R.N. (NCI, POB) 
 Kathy Warren, M.D. (NCI, NOB) 
 Seth Steinberg, Ph.D. (NCI) 
 Nicholas Patronas, M.D. (NCI, CC) 
 Staci Martin, Ph.D. (NCI, MICC) 
 Pamela Wolters, Ph.D. NCI, MICC) 
 Brian P. O’Neil, M.D. (Mayo Clinic) 
 Tobey MacDonald, M.D. (CNMC) 
 David Gutmann, M.D., Ph.D. (St. Louis Children’s 
Hospital) 
 Jeffrey Solomon, (NCI and Sensor Systems, Inc.) 
 Participating Institution: 
Responsible Investigator: 
 
 
 
 
IRB Contact: 
 
 
 
 
Pharmacy Contact: 
Children’s National Medical Ctr., Washington DC 
(M1316) 
Roger Packer, M.D. 
Department of Neurology 
111 Michigan Avenue NW, Washington DC 20010 
Phone: 202-884-2120; Fax: 202-884-5226 
E-mail: rpacker@cnmc.org 
John L. Sever, M.D., Chairperson 
Children’s National Medical Center, IRB 
111 Michigan Ave, NW 
Washington, DC 20010-2970 
Phone: 202-884-4132, E-mail: jserver@cnmc.org 
Cynthia Giles, R.Ph. 
Children’s National Medical Center 
Pharmacy Department, 4th floor 
111 Michigan Ave, NW 
Washington, DC 20020-2970 
Phone: 202-884-3576, E-mail: cjiles@cnmc.org 


 4/6/2008 
 
 
 
 
 
 
 
 
 
2
 
Participating Institution: 
Responsible Investigator: 
 
 
 
 
 
 
 
IRB Contact: 
 
 
 
 
 
 
Pharmacy Contact: 
 
 
St. Louis Children’s Hospital, St. Louis, MO 
(M1123)  
Allison King, M.D. 
Washington University School of Medicine 
660 S. Euclid Avenue 
Campus Box 8116 
St. Louis, MO 63110 
Phone: 314-286-1170, Fax: 314-454-2780 
E-mail: king_a@kids.wustl.edu 
Kirsten Cady 
Washington University School of Medicine 
660 S. Euclid Ave 
Campus Box 8056 
St. Louis, MO 63110 
Phone:  314-362-7773, Fax:  314-747-0232 
E-mail:  kcady@im.wustl.edu 
Melissa Heigham, RPh 
Investigational Pharmacist 
St. Louis Children’s Hospital 
One Children’s Place 8W25 
St. Louis, MO 63110 
Phone: 314-454-2361, fax: 314-454-2441 
E-mail: mheigham@bjc. 
 
 
Participating Institution: 
Responsible Investigator: 
 
 
 
 
 
 
 
IRB Contact: 
 
 
 
Pharmacy Contact: 
Johns Hopkins Oncology Center (M1011) 
Kenneth Cohen, MD 
The Sidney Kimmel Comprehensive Cancer Center 
Johns Hopkins 
CMSC-800 
600 N. Wolfe St. 
Baltimore, MD 21287 
Phone: (410) 614-5055, Fax: (410) 955-0028 
E-mail: kcohen@jhmi.edu 
Monica Carlton 
550 N. Broadway, Room 1121 
Baltimore, MD 21287 
Phone: (410) 955-0350, Fax: (410) 614-1328 
Pauline Newman 
600 N. Wolfe Street 
Baltimore, MD  21205 
CMSC 209 Pediatric Pharmacy 
Phone: (410) 955-5926, Fax: (410) 955-0283 
E-mail: pnewman@JHH.Pharmacy 
 
 
Participating Institution: 
Responsible Investigator: 
 
The Children’s Hospital of Philadelphia (M1257) 
Jean Belasco, MD 
34th and Civic Center Boulevard 


 4/6/2008 
 
 
 
 
 
 
 
 
 
3
 
 
 
IRB Contact: 
 
 
 
 
 
Pharmacy Contact: 
Room 4326 Wood Building 
Philadelphia, PA  19104 
Phone: (215) 590-2848, Fax: (215) 590-4183 
E-mail: belasco@email.chop.edu 
Carol Sazama 
1st Floor, Abramson Building 
3517 Civic Center Boulevard 
Philadelphia, PA  19104-4399 
Phone:  (215) 590-2830 
E-mail: bickert@email.chop.edu 
Betsy Bickert, Pharm D. 
4th Floor Pharmacy, 4th Floor Main Building 
34th and Civic Center Boulevard 
Philadelphia, PA  19104 
Phone:  (215) 590-3833 
E-mail:  bickert@email.chop.edu 
 
 
Participating Institution: 
Responsible Investigator: 
 
 
 
 
 
IRB Contact: 
 
 
 
 
 
Pharmacy Contact: 
Children’s Hospital of Pittsburgh, PA (M1230) 
Regina Jakacki, M.D. 
Children’s Hospital of Pittsburgh 
3520 Fifth Ave., Suite 205 
Pittsburgh, PA 15213 
Phone: (412)-692-5055, Fax: (412)-692-7693 
E-mail: jakackr@chplink.chp.edu 
Dr. Ev Vogeley 
Children’s Hospital of Pittsburgh 
Research Administration 
3705 Fifth Avenue 
Pittsburgh, PA 15213 
Phone: 412-692-5247, Fax: 412-692-5723 
Becky Hursen 
Children’s Hospital of Pittsburgh 
3520 Fifth Ave., Suite 100 
Pittsburgh, PA 15213 
Phone: 412-692-8047, Fax: 412-692-6675 
 
 
Participating Institution: 
Responsible Investigator: 
 
 
 
 
 
IRB Contact: 
 
 
 
 
 
Children’s Memorial Hospital, Chicago, IL (M1484) 
Stewart Goldman, M.D. 
Children’s Memorial Hospital 
2300 Children’s Plaza, Box # 30 
Chicago, IL 60614 
 
Phone: (773)-880-3270, Fax: (773)-880-3053 
E-mail: sgoldman@childrensmemorial.org 
April Baker, IRB Manager 
Ellen Brooks, Ph.D., IRB Chair 
Children’s Memorial Research Center 
Institutional Review Board 
2300 Children’s Plaza, Box # 205 
Chicago, IL 60614 


 4/6/2008 
 
 
 
 
 
 
 
 
 
4
 
 
Pharmacy Contact: 
Phone: 773-880-8116 
Susan Berg, R.Ph. (Hem/Onc Pharmacy) 
Peter Anley, PharmD., Manager, Clinical Pharmacy 
Services 
Children’s Memorial Hospital  
2300 Children’s Plaza, Box 74 
Chicago, IL 60614 
Phone: 773-880-4471 
 
 
Participating Institution: 
Responsible Investigator: 
 
 
 
 
 
IRB Contact: 
 
 
 
 
 
 
Pharmacy Contact: 
 
Dana-Farber Cancer Institute, Boston, MA (M1034) 
Mark W. Kieran, MD, PhD 
Director, Pediatric Medical Neuro-Oncology 
Dana-Farber Cancer Institute 
44 Binney Street, Boston, MA, 02115 
Phone: (617) 632-4907; Fax: (617) 632-4248 
E-mail: mark_kieran@dfci.harvard.edu 
Cheryl Harris, Protocol Administrator 
Office for the Protection of Research Subjects 
Dana-Farber Cancer Institute 
20 Overland Street 
Boston, MA 02115 
Phone: 617-632-5706, Fax: 617-632-2686 
E-mail : charris8@partners.org 
Peter Blanding 
Clinical Pharmacist-Pediatric  Clinic 
Department of Pharmacy L-2 
Dana-Farber Cancer Institute 
44 Binney Street 
Boston, MA 02115 
Phone 617-632-3785, Fax: 617-632-4410 
E-mail: peter_blanding@dfci.harvard.edu 
 
 
Participating Institution: 
Responsible Investigator: 
 
 
 
 
 
IRB Contact: 
 
 
 
 
Pharmacy Contact: 
Beth Israel Medical Center (FWA00003885) 
Jeffrey Allen, MD 
Singer Division 
170 E. End Ave., New York, NY 10570 
Phone: 212-870-9407, Fax: (212) 870-9424 
E-mail: jallen@bethisraelny.org 
Keith King 
Committee on Scientific Activities 
Beth Israel Medical Center 
First Ave at 16th Street, New York, NY  10003 
Phone: (212-387-3870, x5700 
Sylvia Thomas, MS, RPh 
Beth Israel Medical Center – Singer Division 
170 East End Ave, 13th Floor 
New York, NY  10128 
Phone: (212) 870-9503 
 
 
Participating Institution: University of Alabama at Birmingham (M1149) 


 4/6/2008 
 
 
 
 
 
 
 
 
 
5
Responsible Investigator: 
 
 
 
 
 
IRB Contact: 
 
 
 
 
 
 
Pharmacy Contact: 
Alyssa Reddy, MD 
1600 7th Ave. South 
ACC 512 
Birmingham, AL  35233 
Phone:  (205) 939-9285, Fax: (205) 975-6377 
E-mail: areddy@peds.uab.edu 
Sheila Moore 
Director, UAB Institutional Review Board 
Administration Building, Room 470 
701 20th Street, South 
Birmingham, AL  35294 
Phone: (205) 934-3789 
E-mail: smoore@provost.uab.edu 
Kathleen (Keen) Blair 
Investigational Study Pharmacist 
1600 7th Ave., South 
Birmingham, AL  35233 
Phone: (205) 939-5918, Fax: (205) 939-9934 
E-mail: keen.blair@chsys.org 
 
 
Participating Institution: 
Responsible Investigator: 
 
 
 
 
IRB Contact: 
 
 
 
 
 
 
Pharmacy Contact: 
Cleveland Clinic (FWA00005367) 
Bruce Cohen, MD 
9500 Euclid Avenue, Cleveland, OH  44195 
Phone: (216) 444-9182, Fax: (216) 445-9139 
E-mail:  cohenb2@ccf.org 
Daniel Beyer 
Director, IRB, Cleveland Clinic 
9500 Euclid Avenue – Wb2 
Cleveland, OH  44195 
Phone: 
E-mail:  beyerd@ccf.org 
To be advised 
Cleveland Clinic 
9500 Euclid Avenue 
Cleveland, OH  44195 
Phone: 
 
 
Participating Institution: 
Responsible Investigator: 
 
 
 
 
 
IRB Contact: 
 
 
 
 
Oregon Health Sciences University (FWA00000161) 
Stacey Nicholson, MD 
3181 SW Sam Jackson Park Road 
Mailcode CDRC-P, Portland, OR  97201-3098 
Phone: 503-494-1543, Fax: 503-494-0714 
E-mail: nicholss@ohsu.edu 
Gordana B. Dragosavac 
Oregon Health Sciences University 
3181 SW Sam Jackson Park Road 
mail Code: CDRC-P 
Portland, OR 97201-3098 
Phone: 503-494-1628, Fax: 503-494-0714 


 4/6/2008 
 
 
 
 
 
 
 
 
 
6
 
 
Pharmacy Contact: 
 
 
 
 
E-mail: drafosv@ohsu.edu 
Karen Schoenbrun 
Investigational Drug Pharmacist 
Oregon Health Sciences University 
Pharmacy Department 
3181 SW Sam Jackson Park Road 
Mail Code: CR94, Portland, OR 97201-3098 
Phone: 503-494-6865, Fax: 503-494-1096 
E-mail: schoenbk@ohsu,edu 
 
 
Participating Institution: 
Responsible Investigator: 
 
 
 
 
 
IRB Contact: 
 
 
 
 
 
Pharmacy Contact: 
 
Mayo Clinic (FWA00005001) 
Dusica Babovic-Vuksanovic, MD 
Mayo Clinic E-7, 200 First Street SW 
Rochester, MN 55905 
Phone: 507-284-3215, Fax: 507-284-1067 
E-mail: dbabovic@mayo.edu 
Cindy Boyer 
Mayo IRB, Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
Phone: 507-226-2808, Fax: 507-538-0051 
E-mail: boyer.cindy@mayo.edu 
Bradley J. Christensen 
Mayo E-12 
Medical Oncology, 200 First Street SW 
Rochester, MN  55905 
Phone: (507) 284-2511 
 
 
Participating Institution: 
Responsible Investigator: 
 
 
 
 
 
IRB Contact: 
SUNY Upstate Medical University, NY (M1303) 
Ronald Dubowy, MD 
Department of Pediatrics – 5C 
750 E. Adams Street, Syracuse, NY  13210 
Phone: (315) 464-5294, Fax: (315) 464-7238 
E-mail: dubowyr@upstate.edu 
Karen Bilynsky, RN, CCRA 
Suny Upstate Medical University, NY 
Department of Pediatrics 
5C – 750 E. Adams St, Syracuse, NY  13210 
Phone: (315-464-7601, Fax: 315-464-7515) 
Andrea Allen 
SUNY Upstate Medical University, NY 
Department of Pharmacy  5C 750 E Adams Street, 
Syracuse, NY 13210 
Phone: 315-464-4210, Fax: 315-464-4314 
E-mail: allena@upstate.edu 
Participating Institution: 
Responsible Investigator: 
 
 
Texas Children's Hospital, Houston, TX (M1060) 
Susan, M. Blaney, M.D. 
Division of Hematology/Oncology, 6621 Fannin 
Street, Texas Children's Hospital, CC 1410.00, 


 4/6/2008 
 
 
 
 
 
 
 
 
 
7
 
 
IRB contact: 
 
 
 
 
 
Pharmacy contact: 
Houston, TX 77030 
Phone: 832-822-1482; Fax: 832-825-4299 
E-mail: sblaney@bcm.tmc.edu 
Stacey Berg M.D., Kay Motil, M.D. 
Baylor College of Medicine 
One Baylor Plaza S108 
Houston, TX 77030 
Phone: 713-798-6970 
E-mail: sberg@txccc.org, kmotil@bcm.tmc.edu 
Renee A. Robinson RPh 
Texas Children’s Hospital 
Pharmacy department MC 2-2510  
6621 Fannin Street 
Houston, TX 77030 
Phone: 713-770-3899 
E-mail rarobins@txccc.org 
*Pharmacology & Experimental Therapeutics Section 
Pediatric Oncology Branch, NCI, CCR 
10 Center Drive, 10-CRC, Rm 1-5750, MSC 1101 
Bethesda, MD 20892-1920 
Phone: (301) 496-7387/Fax: (301) 480-8871 
E-mail: widemanb@mail.nih.gov 
** Starting no later than May 19, 2008, any 
pirfenidone shipped to sites for this study 
will be supplied by InterMune, Inc., 
instead of Solanan, Inc. and/or Marnac, 
Inc. 
Solanan, Inc. 
6723 Desco Drive 
Dallas, TX 75225 
Phone: 214-692-8544 
Fax: 214-692-8510 
 
 
InterMune, Inc. 
Medical Affairs Department 
3280 Bayshore Blvd. 
Brisbane, CA 94005 
Phone: 415-466-4416 or 415-466-2200 
Fax: 415-466-4516 or 415-466-2300 


 4/6/2008 
 
 
 
 
 
 
 
 
 
8
PRECIS 
 
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 anti-
fibrotic 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 (≥3 years 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/m2 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.   


 4/6/2008 
 
 
 
 
 
 
 
 
 
9
TABLE OF CONTENTS 
PRECIS ................................................................................................................................................................................ 8 
1.0 
INTRODUCTION ..................................................................................................................................................11 
1.1 
OBJECTIVES ..........................................................................................................................................................11 
1.2 
BACKGROUND AND RATIONALE..........................................................................................................................11 
1.2.1 
Neurofibromatosis type I and plexiform neurofibromas...........................................................................11 
1.2.2 
Imaging and measurement of plexiform neurofibromas...........................................................................13 
1.2.3 
Molecular vulnerability of neurofibromas.................................................................................................14 
1.2.4 
Gene profile analysis of plexiform neurofibromas....................................................................................14 
1.2.5 
Pirfenidone...................................................................................................................................................15 
1.2.6 
Preclinical studies Pirfenidone ..................................................................................................................15 
1.2.7 
Human studies pirfenidone .........................................................................................................................18 
1.2.8 
Clinical Pharmacokinetics of pirfenidone .................................................................................................21 
1.2.9 
Proposed Pediatric Phase II Trial of Pirfenidone ....................................................................................22 
1.2.10 
Update Of The Pediatric Phase II Trial of Pirfenidone .........................................................................23 
2.0 
ENROLLMENT PROCEDURES........................................................................................................................24 
2.1 
ELIGIBILITY CRITERIA (ELIGIBILITY CHECKLIST APPENDIX 1) ..........................................................................24 
2.1.1 
Inclusion Criteria ........................................................................................................................................24 
2.1.2 
Exclusion Criteria .......................................................................................................................................26 
2.2 
PRE-TREATMENT EVALUATION (SEE APPENDIX 3)............................................................................................27 
2.3 
PATIENT REGISTRATION ......................................................................................................................................28 
3.0 
IMPLEMENTATION OF STUDY......................................................................................................................28 
3.1 
STUDY DESIGN .....................................................................................................................................................28 
3.1.1 
Overall trial Design ....................................................................................................................................28 
3.1.2 
Monitoring Time to Progression and Response ........................................................................................29 
3.1.3 
Definition of Tumor Progression................................................................................................................29 
3.2 
DRUG ADMINISTRATION......................................................................................................................................30 
3.2.1 
Supply of pirfenidone from Solanan, Inc./Marnac, Inc.............................................................................30 
3.2.2 
Supply of pirfenidone from InterMune, Inc. ..............................................................................................30 
3.3 
TREATMENT MODIFICATIONS..............................................................................................................................32 
3.3.1 
For Pirfenidone from Solanan, Inc. (200-mg and 400-mg Capsules) .....................................................32 
3.3.2 
For Pirfenidone from InterMune, Inc. (267-mg Capsules) ......................................................................33 
3.4 
ON STUDY EVALUATION (APPENDIX 3)..............................................................................................................33 
3.5 
CONCURRENT THERAPIES....................................................................................................................................34 
3.6 
OFF STUDY CRITERIA ..........................................................................................................................................35 
3.6.1  
Administrative: ...........................................................................................................................................35 
3.6.2  
Toxicity........................................................................................................................................................35 
3.6.3 
Tumor Progression......................................................................................................................................35 
3.7 
POST THERAPY EVALUATION ..............................................................................................................................35 
4.0 
SUPPORTIVE CARE............................................................................................................................................36 
5.0 
DATA COLLECTION AND EVALUATION...................................................................................................36 
5.1 
DATA COLLECTION ..............................................................................................................................................36 
5.1.1 
Case Report Forms......................................................................................................................................36 
5.2 
RESPONSE CRITERIA ............................................................................................................................................37 
5.3 
TOXICITY CRITERIA .............................................................................................................................................38 
5.4 
STATISTICAL CONSIDERATIONS ..........................................................................................................................38 
5.4.1 
Subject Accrual............................................................................................................................................38 
5.4.2 
Statistics and Feasibility.............................................................................................................................38 
5.5 
MULTI-INSTITUTIONAL GUIDELINES...................................................................................................................40 


 4/6/2008 
 
 
 
 
 
 
 
 
 
10
5.5.1 
IRB Approvals..............................................................................................................................................40 
5.5.2 
Amendments and Consents .........................................................................................................................41 
5.5.3 
Patient Registration.....................................................................................................................................41 
5.5.4 
Data Collection and Toxicity Reporting ....................................................................................................41 
5.5.5 
Data and Center Audits...............................................................................................................................42 
6.0 
HUMAN SUBJECTS PROTECTIONS..............................................................................................................42 
6.1 
RATIONALE FOR SUBJECT SELECTION.................................................................................................................42 
6.2 
PARTICIPATION OF CHILDREN .............................................................................................................................42 
6.3 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS........................................................................................43 
6.4 
RISK/BENEFIT ANALYSIS.......................................................................................................................................43 
6.5 
CONSENT AND ASSENT PROCESS AND DOCUMENTATION ....................................................................................43 
6.6 
HANDLING OF RESEARCH SAMPLES.....................................................................................................................44 
7.0 
DATA REPORTING .............................................................................................................................................44 
7.1 
PATIENT REGISTRATION ......................................................................................................................................44 
7.2 
CASE REPORT FORMS...........................................................................................................................................44 
7.3 
SAFETY REPORTING .............................................................................................................................................44 
7.3.1 
Adverse Events.............................................................................................................................................44 
7.3.2 
Adverse Event Reporting.............................................................................................................................45 
7.3.3 
Adverse Event Reporting To US Army.......................................................................................................47 
7.4 
MEDICAL MONITOR AND DATA SAFETY MONITORING BOARD (DSMB) .........................................................47 
8.0 
PHARMACEUTICAL INFORMATION PIRFENIDONE ............................................................................48 
8.1 
PIRFENIDONE........................................................................................................................................................48 
8.2 
DRUG ORDERS ......................................................................................................................................................50 
8.2.1 
Pirfenidone supplied by Solanan, Inc./Marnac Inc...................................................................................50 
8.2.2 
Pirfenidone supplied by InterMune, Inc. ...................................................................................................50 
10.0 
REFERENCES .....................................................................................................................................................51 
11.0 
APPENDICES.......................................................................................................................................................55 
APPENDIX 1:  ELIGIBILITY CHECKLIST FOR PIRFENIDONE PHASE II PROTOCOL.........................................................55 
APPENDIX 2: PERFORMANCE STATUS SCALES/SCORES ...............................................................................................56 
APPENDIX 3: REQUIRED STUDY EVALUATIONS PRIOR TO STARTING TREATMENT, DURING, AND POST TREATMENT 
WITH PIRFENIDONE........................................................................................................................................................57 
APPENDIX 4:  PROTOCOL FOR REQUIRED PRE STUDY AND ON STUDY MRI STUDIES ...............................................58 
APPENDIX 5: PATHOLOGY ANALYSIS OF PLEXIFORM NEUROFIBROMAS......................................................................63 
APPENDIX 5A: INSTRUCTIONS FOR TISSUE ACQUISITION OF DISCRETE AND PLEXIFORM NEUROFIBROMAS ..............65 
APPENDIX 6: PATIENT DIARY FOR PIRFENIDONE PHASE II ..........................................................................................67 
 


 4/6/2008 
 
 
 
 
 
 
 
 
 
11
1.0 
INTRODUCTION 
1.1 
OBJECTIVES 
PRIMARY STUDY OBJECTIVES: 
1.1.1 To determine whether pirfenidone, administered on a chronic oral 
schedule (28 day cycles with no rest period between cycles), increases the 
time to disease progression based on volumetric measurements in 
children and young adults with neurofibromatosis type 1 (NF1) and 
growing plexiform neurofibromas.  
1.1.2 To define the objective response rate to pirfenidone in NF1-related 
plexiform neurofibromas.  
1.1.3 To describe and define the toxicities of pirfenidone, administered on a 
chronic oral schedule (28 day cycles with no rest period between cycles), 
in children and young adults with NF1.  
SECONDARY STUDY OBJECTIVES 
1.1.4 To assess the quality of life of patients treated with pirfenidone using the 
National Institutes of Health (NIH) Impact of Pediatric Illness (IPI) Scale, 
which assesses the impact of disease and treatment on children’s behavior, 
and to evaluate the ability of this new assessment tool to measure changes 
in a child’s quality of life. 
1.1.5 To assess the value of three-dimensional MRI (3-D MRI) in the evaluation 
of plexiform neurofibromas, and to compare 3-D MRI to conventional 
two-dimensional MRI (2-D MRI) and one-dimensional MRI (1-D MRI) 
data analysis.  
1.1.6 To contribute tumor specimens from patients who undergo tumor surgery 
or biopsies for clinical reasons to an already-existing tissue bank at 
Washington University, St. Louis, MO.  Tumor specimens of plexiform 
neurofibromas will undergo central pathology review, including detailed 
morphological, ultrastructural immunohistochemical, and mRNA gene 
expression profile analysis 
1.1.7 To make tumor specimens that are obtained on this trial available to the 
scientific community, after obtaining IRB approval, in order to collect 
more information on the pathology, genetics, and cell biology of plexiform 
neurofibromas. 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 NEUROFIBROMATOSIS TYPE I AND PLEXIFORM NEUROFIBROMAS 
Neurofibromatosis type 1 (NF1) is a common autosomal dominant, progressive 
disorder with an incidence of 1:3000 (>80,000 persons affected in the United States). NF1 
is characterized by diverse, progressive cutaneous, neurological, skeletal and neoplastic 
manifestations with no standard drug treatment options available. Patients with NF1 
have an increased risk of developing tumors of the central and peripheral nervous 
system 
including 
plexiform 
neurofibromas 
(27%), 
optic 
gliomas 
(15-20%), 


 4/6/2008 
 
 
 
 
 
 
 
 
 
12
pheochromocytomas (1%), malignant peripheral nerve sheath tumors, (5%), and 
neurofibrosarcomas (6%) (Korf, 1999; Korf, 2000). 
The two main peripheral nerve tumors in patients with NF1 are neurofibroma, a benign 
tumor, and malignant peripheral nerve sheath tumor (MPNST).  These tumors are 
related in that most MPNST arise by malignant transformation of neurofibroma.  Such 
an event occurs in about 5% of NF1 patients (Korf, 2000).  However, based on a recent 
study, the life time risk of MPNST in NF1 is much higher with 8-13% (Evans, 2002). 
There are multiple types of neurofibromas including localized cutaneous neurofibroma, 
localized intraneuronal neurofibroma, diffuse neurofibroma, massive soft tissue 
neurofibroma and plexiform neurofibroma. Plexiform neurofibromas are benign nerve 
sheath tumors that grow along the length of nerves and involve multiple branches of a 
nerve.  These tumors are usually diagnosed early in life, may be multiple and might 
develop throughout life. Early childhood, puberty and childbearing age in females are 
considered to be the periods of greatest risk for disease progression (Needle et al., 1997).  
Approximately 20-44% of individuals with NF1 develop plexiform neurofibromas 
(Huson et al, 1988).  These tumors may cause significant disfigurement, as well as 
compression of vital structures.  As examples, plexiform neurofibromas may infiltrate 
the orbit and displace the globe and compromise vision; paraspinal tumors (also 
referred to as dumbbell lesions) can compress the spinal cord and cause paralysis; 
tumors in mediastinum may compress the trachea or great vessels; and tumors of the 
extremities can cause local nerve infiltration, progressive neurologic deficit and often 
unremitting pain (Needle et al., 1997).   
Plexiform neurofibromas and paraspinal neurofibromas cause major morbidity and 
mortality in NF1 (Rasmussen et al., 2001; Korf, 1999).  There is no currently accepted 
effective drug therapy for plexiform neurofibromas.  The rate of growth of this 
histologically benign neoplasm is commonly unpredictable and often episodic (Korf, 
2000).  Plexiform neurofibromas rarely regress spontaneously, and in many patients 
their growth is relentless.  The management of plexiform neurofibromas is especially 
difficult due to the infiltrating nature of tumors. 
Management of plexiform neurofibromas is generally surgical.  However, up to 44% of 
tumors progress after the first surgery, most commonly in patients younger than ten 
years of age with head and neck tumors that could not be completely resected. (Needle 
et al., 1997). There is no other standard treatment modality for patients with progressive 
plexiform neurofibromas.  
The unknown natural history of plexiform neurofibromas in NF1 and difficulties in 
measuring changes in size of these complex, large, and slow growing lesions have made 
it difficult to define the benefit of medical treatments for plexiform neurofibromas. 
However, a number of medical treatments including thalidomide (Gupta et al., 2003), 
cis retinoic acid, interferon alfa 2b, methotrexate and vinblastine, PEG interferon alfa-
2b, and the farnesyltransferase inhibitor R115777 have been evaluated or are 
undergoing evaluation in early clinical trials for patients with NF1 and plexiform 
neurofibromas with the goal to reduce the growth rate or shrink these tumors. 
Published results are available only for the phase I thalidomide trial. In this trial 
thalidomide was administered to 20 patients with NF1 and plexiform neurofibromas at 
doses up to 200 mg/day. Response was assessed by clinical measurements and 2-D 
radiographic measurements. Of 12 patients who completed 1 year of treatment, four 


 4/6/2008 
 
 
 
 
 
 
 
 
 
13
showed a <25% reduction in tumor size, and seven showed symptomatic improvement 
with predominantly a decrease in pain. To date no medical treatment has demonstrated 
clear benefit for patients with NF1 and plexiform neurofibromas. 
 
1.2.2 IMAGING AND MEASUREMENT OF PLEXIFORM NEUROFIBROMAS 
Tumor response criteria that are used for cancers are based on one-dimensional (1-D) 
and two-dimensional (2-D) tumor measurements (Therasse et al., 2000; Estey et al, 
1986). These methods have limited value in the assessment of treatment outcome for 
plexiform neurofibromas, which are frequently large, have a complex (non-spherical) 
shape, and have a slow, erratic growth pattern. In order to reproducibly quantify the 
size of these complex lesions and detect small changes in the size over time, we used 
MR imaging characteristics of plexiform neurofibromas to develop an automated 
method of lesion detection and volume measurement. Short T1-Inversion Recovery 
(STIR) MR images, on which plexiform neurofibromas are bright lesions compared with 
normal surrounding tissue, were used to develop a program for automated image 
analysis within MEDx (v3.41) software (Sensor Systems, Inc. Sterling, VA). 
Reproducibility and inter-observer variability of this automated method were 
determined by 2 observers who 
quantified volumes for plexiform 
neurofibromas of the orbit (n=2), 
face/neck (n=3), abdomen (n=1), 
and pelvis (n=3) on three different 
days. For each MR image (Figure 
1A), the tumor is roughly outlined 
manually including a rim of low 
signal 
intensity 
normal 
tissue 
(Figure 1B). The program then 
performs a histogram analysis of 
signal intensity pixel by pixel and a 
threshold that distinguishes high 
signal intensity tumor from normal 
tissue is defined (Figure 1C). Tumor 
contours are then determined using 
a gradient image, connected component analysis and automatic edge following 
operation (Figure 1D). There is an option for re-analysis of MR images using an average 
or selected threshold. Tumor volume is calculated by summing the results from all 
images based on the resulting 2-D contours and slice thickness; and a report is 
generated. 
 
For comparison, plexiform neurofibroma volume was also determined by manually 
tracing the tumor borders on each MR image. The results of application of the 
automated method are shown in the table below. 
 
Observer 1 
Observer 2 
Mean tumor volume ml, median (range) 
291 (80.9-1581) 
290 (75.7-1603) 
Inter-day CV %, median (range) 
3.6 (0.7-6.0) 
1.6 (0.6-5.6) 
Median (range) % difference in volume between 
observers 
6.4 (1.4 – 11.9) 
Correlation automated vs. manual method, R 
0.999 
0.999 
Figure 1: Axial MRI of pelvic plexiform 
neurofibroma. Steps of automated volumetric 
analysis A-D. 
A
B
D
C


 4/6/2008 
 
 
 
 
 
 
 
 
 
14
This automated volumetric MRI analysis is applicable to most plexiform neurofibromas, 
has excellent intra- and inter-observer reproducibility and agrees with volumes 
determined by manual tumor tracing. This method is used in the currently ongoing 
phase II trial of the farnesyltransferase inhibitor R115777 and in the phase I trial of 
pirfenidone for children with NF1 and plexiform neurofibromas to assess changes in 
tumor size, and in both clinical trials tumor progression is defined as an increase in 
tumor volume by ≥20%.  
This volume increase corresponds to much smaller changes in 1-D, or 2-D 
measurements as outlined in the table below.  
Phase II R117555 
Response Criteria 
RECIST 
Diameter, 2r 
WHO 
Product, (2r)2 
Volume, 4/3Πr3 
Disease progression (Increase) 
20 
44 
73 
12 
25 
40 
 
6 
13 
20 
Shaded areas show current criteria used to define disease progression by RECIST, WHO, and the ongoing 
R115777 NF1 phase II trial 
1.2.3 MOLECULAR VULNERABILITY OF NEUROFIBROMAS 
The histopathology of cutaneous neurofibromas is characterized by slender spindle 
cells with abundant extracellular matrix of dense, wavy collagen fibers and extracellular 
mucoid material. Up to 70% of the tumor dry weight of a neurofibroma is collagen 
[Peltonen et al., 1985; Uitto et al., 1986]. Type I collagen is most abundant, and collagens 
type III and V are represented in lesser amount [Uitto et al., 1986; Konomi et al., 1989]. 
In comparison with normal skin fibroblasts, early passage fibroblasts from 
neurofibromas synthesize and secrete higher amounts of collagen [Peltonen et al., 1985; 
Uitto et al., 1986].  Several studies imply that fibroblasts might have an important role in 
the pathogenesis of these tumors [Kadano et al., 1994; Sasaki et al., 1992]. The role of 
growth-promoting cytokines, such as transforming-growth factor-beta 1 (TGF-beta1), 
fibroblast growth factor (FGF), epidermal growth factor (EGF) and platelet-derived 
growth factor (PDGF) in proliferation of fibroblasts, is well established [Kaneko et al., 
1998]. There is evidence that neurofibroma-derived fibroblasts are stimulated by basic 
fibroblast growth factor (bFGF), EGF, TGF-beta1 and PDGF in lower concentration than 
control fibroblasts [Kitano et al., 1992; Atit et al. 1999] In addition, Nf1+/- mouse skin 
wounds have abnormal granulation tissue, composed mostly of collagen. They also 
showed increase in collagen deposited by Nf1-/- fibroblasts, which are activated by a 
RAS-independent pathway. More recently, De Clue et al. [2000] demonstrated 
epidermal growth factor receptor (EGF-R) expression in Schwann cell-derived tumors 
similar to NF1, and suggested that EGF-R expression plays a significant role in NF1 
tumorigenesis and Schwann cell transformation.  De Clue et al. also showed that 
growth of NF1 MPNST lines and the transformed NF1–/– mouse embryo Schwann cells 
was greatly stimulated by EGF in vitro and could be blocked by agents that antagonize 
EGF-R function.  These findings suggest that events connected with fibrogenesis might 
constitute a point of molecular vulnerability of NF1-related tumors. 
1.2.4 GENE PROFILE ANALYSIS OF PLEXIFORM NEUROFIBROMAS 
Gene expression profiling was performed on 5 individual snap frozen plexiform 
neurofibromas using the Affymetrix G110 microarray (1,992 human transcripts) at the 


 4/6/2008 
 
 
 
 
 
 
 
 
 
15
Children’s National Medical Center.  Genes that are potential targets of the novel anti-
fibrotic agent, pirfenidone, were specifically analyzed for their level of mRNA 
expression.  These include FGF, FGFR1, PDGF, PDGFR, EGF, EGFR, and fibronectin. 
The following preliminary data were obtained: 
 
Gene 
%NF-1 
Tumors 
Positive 
% Transcripts 
Positive 
NF-1 Mean 
Expression 
Level 
Medulloblastoma 
Mean Expression 
Level 
FGF 
100%  (5/5) 
100%  (15/15) 
706 
196 
FGFR1 
100%  (5/5) 
100%  (10/10) 
532 
125 
PDGF 
20%    (1/5) 
20%    (1/5) 
885 
303 
PDGFR 
100%  (5/5) 
100%  (5/5) 
586 
392 
EGF 
20%    (1/5) 
20%    (1/5) 
223 
156 
EGFR 
60%   (3/5) 
60%    (3/5) 
566 
179 
Fibronectin 
60%   (3/5) 
60%    (3/5) 
2,461 
936 
These preliminary data confirm that most gene targets (except for PDGF and EGF) for 
pirfenidone are overexpressed by neurofibromas at relatively high levels (compared to 
a cohort of 30 medulloblastomas profiled at this institution).  These data provide 
justification for the study of novel agents targeting these molecules in this group of 
tumors. 
1.2.5 PIRFENIDONE 
Pirfenidone, 5-methyl-1-phenyl-2-(1H)-pyridone, is a novel anti-fibrotic drug that has 
been shown to inhibit fibroblast growth and collagen synthesis. It modulates the action 
of cytokines, including platelet derived growth factor (PDGF), fibroblast growth factor 
(FGF), epidermal growth factor (EGF), intercellular adhesion molecule-1 (ICAM-1) 
(Kaneko et al., 1998), and TGF-alpha-1-induced fibronectin synthesis (Zhang et al., 
1998).  These effects result in inhibition of proliferation and collagen matrix synthesis by 
human fibroblasts. Antifibrotic effects are well-documented in vitro, in vivo and animal 
experiments, indicating therapeutic potential in many fibrosing conditions (Shimizu et 
al., 1997, 1998; Iyer et al., 1998; Al-Took et al., 1998; Dosanjh et al., 1998; Suga et al., 
1995).  Although the understanding of molecular events that lead to the development of 
neurofibromas in NF1 is still primitive, comparison of the effects of pirfenidone with 
the observed alterations in NF1 lead to a hypothesis that pirfenidone may exert a 
therapeutic effect in NF, perhaps leading to shrinkage or decreased growth rate of 
existing neurofibromas, or prevention of new lesions. 
1.2.6 PRECLINICAL STUDIES PIRFENIDONE 
In vitro studies: In vitro cell culture studies demonstrated a dose dependent inhibition 
of human (WI38) lung fibroblasts and collagen formation by pirfenidone.  Effects are 
present at concentration 10 to 20 times lower than those impairing cell viability (1200 
mcg/ml).  (Lefkoviwitz and Margolin 1993).  Pirfenidone blocked the proliferation of 
W138 fibroblasts after exposure to TGF-β-1, PDGF, FGF and EGF.  Collagen output by 
these cells was also inhibited by pirfenidone.  Similar effects were observed in serum-


 4/6/2008 
 
 
 
 
 
 
 
 
 
16
stimulated myometrial and leiomyoma cells (Lee et al., 1998).  Pirfenidone efficiently 
decreased cellular proliferation in both myometrial and leiomyoma cells.  Densitometric 
analysis of Northern blot showed decreased expression of collagen type I and type III 
mRNA.  Pirfenidone moderates fibronectin synthesis by cultured human retinal 
pigment epithelial cells when stimulated with TGF-β-1, but does not have an effect on 
fibronectin synthesis in non-stimulated cells. It has been shown that the excessive cell 
proliferation induced by cytokine growth factors such as TGF-β-1, can be completely 
arrested by pirfenidone in the culture media at concentrations that are 1/10 to 1/20 of 
the toxic dose.  Transfer of such pirfenidone-exposed cells to culture media, which 
contain no pirfenidone, results in recovery of normal proliferation capacity (Margolin 
2001).  Therefore, the anti-fibrotic effect of pirfenidone may be partly mediated through 
inhibition of TGF-β-1-induced fibronectin synthesis (Zhang et al, 1998).   
Kaneko et al (1998) investigated the effect of pirfenidone on the expression of 
intercellular cell adhesion molecules (ICAM-1).  The synovial fibroblasts were treated 
with interleukin 1-α in the presence and absence of Pirfenidone, and assayed for the 
expression of cell adhesion molecules.  pirfenidone significantly down-regulated the 
expression of ICAM-1 on cultured synovial fibroblasts in a dose-dependent manner.  In 
contrast, expression of endothelial-leukocyte adhesion molecule-1 was not affected.  
Pirfenidone also significantly suppressed cellular binding between cultured 
lymphocytes and IL-1-α-stimulated synovial fibroblasts.  Therefore, down-regulation of 
ICAM-1 might be another mechanism of action of pirfenidone. The results from another 
study suggest that pirfenidone may have antitumor effects on malignant gliomas, 
whose biological properties resemble those of NF-1-derived tumors, and that these 
effects may be mediated, in part, through EGFR phosphorylation inhibition (Krishnan 
et al, 2007). 
In vivo studies: The effects of pirfenidone on survival and growth of neurofibroma 
xenografts were evaluated (Babovic-Vuksanovic et al., 2000; 2004).  Sixteen SCID mice 
with implanted tumors (7 schwannoma and 9 neurofibroma) were treated with oral 
pirfenidone (in a dose of 500 mg/kg per day, equivalent to 1500 mg/m2/day)).  Sixteen 
untreated mice with implants from the same tumors were used as controls.  Tumor 
implants were monitored over a period of six weeks.  Tumor survival and progression 
were evaluated at autopsy examination.  The survival of subcutaneously implanted 
tumors was slightly higher than the survival of tumors implanted into the epineurium 
of the sciatic nerve (p>0.5).  Survival of implanted schwannomas and neurofibromas in 
animals that received pirfenidone was significantly lower than in control animals (see 
table below). 
Effect of treatment with pirfenidone on survival rate of human xenotransplants in SCID 
mice   
 
Pirfenidone therapy 
 
Survival of human 
xenotransplant 
Treated 
Not treated 
p 
Neurofibroma 
21/32 (65.6%) 
31/32 (96.8%) 
<0.001 
Schwannoma 
17/21 (80.9%) 
20/21 (95.2%) 
<0.01 


 4/6/2008 
 
 
 
 
 
 
 
 
 
17
No mortality or signs of drug toxicity were noted in animals treated with pirfenidone.  
The data suggest that pirfenidone interferes with neural tumor survival and that this 
agent might be a good candidate for clinical trials in patients with neurofibromatosis. 
Experiments on hamsters showed that pirfenidone abolishes the fibrosing effects of 
bleomycin on the lung (Schelegle et al., 1997), blocking polyhydroxylase activity and the 
rise of hydroxyproline level.  Histopathologic studies of these animals revealed that 
there were fewer lesions of alveolar consolidation and fibrosis in the lungs of the 
hamsters that received bleomycin and pirfenidone (Iyer 1995, 1998).  Similar effects 
against cyclophosphamide-induced pulmonary fibrosis in rats were reported (Kehrer 
and Margolin, 1997).  Further experiments provided evidence that the antifibrotic effect 
of pirfenidone was partly due to suppression of the bleomycin-induced inflammation 
and partly due to down-regulation of bleomycin-induced over-expression of lung 
procollagen I and III genes (Iyer et al., 1998).  Gurujealakshmi (1999) postulated that the 
protective effect of pirfenidone against bleomycin-induced lung fibrosis might be 
mediated by a reduced PDGF isoforms production by lung macrophages. 
In other studies oral pirfenidone given to nude mice caused degradation and absorption 
of human keloid xenografts (Shetlar et al, 1995; 1998) and benign prostate hypertrophy 
tissues transplanted into such mice (Shetlar et al., 1992).  Shimizu et al. (1998 and 1997) 
reported favorable effects of pirfenidone on the experimentally induced renal disease in 
rats, demonstrating that it can attenuate both renal fibrosis and renal damage in the 
animal model.  The authors suggested that this drug might be useful for preventing 
progressive, irreversible renal failure. 
In vivo laboratory data also show that pirfenidone is effective against experimentally 
induced glomerulosclerosis in rats (Shimizu et al., 1996) and liver cirrhosis in rats 
(Teraokas et al., 1996). Pirfenidone showed protective effects against gastric ulcers and 
mucosal irritation in rats exposed to large doses of phenylbutazone or aspirin. 
Preclinical toxicity: The laboratory animal studies performed on several species 
evaluated acute, subacute and subchronic effects of pirfenidone. For the several species 
exposed to very high or fatal systemic dosages of pirfenidone, CNS side effects (ataxia, 
loss of skeletal tone, loss of righting reflex, reduction in respiratory rate and amplitude) 
were observed. Death was precipitated by acute respiratory failure. No significant 
gastrointestinal erosion was observed in animals treated with high doses of oral 
pirfenidone.  
Acute oral toxicity of pirfenidone 
Species 
LD50 mg/kg body weight 
Rodents (mice, rats, hamsters, guinea pigs) 
600-900 
Dogs 
300 
Cats 
500 
Similarly, topical preparation containing 2.0% pirfenidone in aqueous solution, failed to 
produce significant eye irritation in albino rabbits. Subacute (two week, one month and 
two months) and subchronic (three months) administration of oral pirfenidone to rats 
showed that the maximum tolerated dose of pirfenidone was in excess of 300 
mg/kg/day. Pirfenidone caused no deaths at dosages as high as 1,000 mg/kg/day. No 


 4/6/2008 
 
 
 
 
 
 
 
 
 
18
significant changes that could be attributed to pirfenidone treatment were observed in 
the general condition or appearance of treated animals, on ophthalmologic evaluation, 
on hematologic determinations and on gross and microscopic examinations at autopsy. 
Reproduction and teratogenicity studies in rodents showed no difference in the 
incidence of pregnancies, or the size of the litters, or adverse effects on embryo/fetal 
development in comparisons of the control and the pirfenidone-treated groups. In the 
standard and in vitro Ames test for mutagenicity and carcinogenicity, a wide range of 
concentrations of Pirfenidone in the culture media failed to show any mutagenic or 
carcinogenic potential.  Carcinogenicity studies in rats and mice exposed to pirfenidone 
for 104 weeks found an increase in the incidence of uterine adenocarcinomas (in rats but 
not mice), hepatocellular adenomas (in rats and mice), and hepatocarcinomas and 
hepatoblastomas (in mice but not rats). These doses are equivalent to 2250-9000 mg/m2 
BSA /day in humans. The relevance to humans is unknown at this time (InterMune 
2007) 
1.2.7 HUMAN STUDIES PIRFENIDONE 
Pirfenidone was well tolerated in 10 healthy adult men after a single dose of 400 mg.  
Subacute tolerance of pirfenidone administered orally was evaluated in twenty normal 
adults (18 men, 2 women). Pirfenidone was administered for 22 days at increasingly 
higher daily doses, starting with 300 mg/day (divided in three daily doses) for three 
days and reaching a maximum of 2400 mg daily for three days. The drug was well 
tolerated even at the maximal oral dose. Three of the subjects reported mild side effects 
including tiredness and transient mild gastric disturbance, photosensitivity rash and 
palpitations. At entry and at the end of the study, physical examination, 
electrocardiogram, blood chemistries and urinalyses were performed and no clinically 
significant changes were found compared to premedication baseline and normal clinical 
values (Margolin, 2001).  
Open and Controlled Trials: 
To investigate for the clinical usefulness of pirfenidone, a prospective, phase II clinical 
trial in 54 patients with “end stage” pulmonary fibrosis of different etiologies was 
undertaken. The mean age of patients was 62.  Pirfenidone was given in dose 2400 
mg/day for 3 to 36 months. Approximately 75% of the ill patients had clinical signs of 
improvement within six months after beginning this treatment. The patients reported 
reduction of incidence of coughs, reduction in supplemental oxygen requirement at 
rest, reduced dyspnea during conversation or ambulation, resumption of normal daily 
tasks, weight gain, and decreased incidence of hospital admissions and prolongation of 
survival. There was a clear improvement in pulmonary function gauged by chest X-ray, 
spirometry and CO diffusion. The improvement continued while the patients were 
maintained on the daily oral dosages of pirfenidone for 12 to 24 more months. The 
incidence of adverse effects was low and relatively mild, consisting of occasional 
drowsiness improved by caffeinated beverages, gastric discomfort remedied by 
antacids or food, or dermal photosensitivity (Raghu et al., 1999). 
Pirfenidone has been used in several open studies: in three patients with peritoneal 
sclerosis for 6 to 18 months, in four patients with benign prostatic hypertrophy for three 
months, one patient with systemic lupus erythematosus for 14 months, 9 patients with 
scleroderma, 11 patients with rheumatoid arthritis, 10 patients with acute trauma and 3 


 4/6/2008 
 
 
 
 
 
 
 
 
 
19
patients with ophthalmic inflammation. In all a positive response was noted with 
minimal side effects. In two patients with psoriasis, the treatment with oral and local 
Pirfenidone did not have any positive effects. Pirfenidone also showed promising 
effects in treatment of multiple sclerosis in one patient, prompting involvement of 
another 20 individuals with progressive multiple sclerosis in an open-label clinical trial 
(Margolin, 2001; Bowen et al. , 2003). The effects are thought to be mediated by an anti-
TNF-alpha (tumor necrosis factor-alpha) activity of pirfenidone, well supported by in 
vitro study (Cain et al., 1998). A pilot study evaluating oral pirfenidone in the treatment 
of desmoid tumors in familial adenomatous polyposis syndrome has been recently 
completed.  No drug toxicity was observed in the 14 patients entered. Of seven of 
patients who received drug for at least 18 months, two experienced a reduction in the 
size of all desmoid tumors, two experienced symptomatic improvement, and three 
experienced no change in symptoms or tumor size (Lindor et al., 2003). In three patients 
with keloidal scars 0.7% pirfenidone ointment was applied and the surgical wound 
healed effectively with no recurrence of keloid over a 12-month follow-up interval 
(Okada Y, 1993).  
Other double-blinded controlled studies evaluating pirfenidone’s cytoprotective and 
anti-inflammatory activities have been completed. These studies have been done in 
patients with resistant perennial allergic rhinitis and sinusitis compared with placebo, 
in patients with rheumatoid arthritis compared with oxyphenbutazone and in patients 
with neurodermatitis compared with betamethasone. Pirfenidone was better than 
placebo in the first trial and at least as effective as the active drug in the last two studies.  
Pirfenidone was well tolerated in daily dose of 2400 mg, and no major toxicity has been 
encountered with its use. 
Two double-blind controlled clinical protocol of pirfenidone for adult patients with 
idiopathic pulmonary fibrosis are currently underway, sponsored by InterMune, Inc. 
Based on these preliminary results for pirfenidone in other conditions, and the scientific 
rationale for pirfenidone’s use in plexiform neurofibromas, a Phase II study has been 
undertaken in adults with NF1 and progressive plexiform neurofibromas, coordinated 
by Mayo Clinic.  This study, headed by Dr. Dusica Babovic-Vuksanovic, who is a co-
principal cooperative group investigator on the present study, has entered 24 patients to 
date.  Pirfenidone (2400 mg/day divided in three doses) was well tolerated in all 
enrolled patients except for three individuals who experienced toxicity (significant 
nausea or upset stomach) and in whom therapy was discontinued, and one other 
patient whose dose was reduced due to persistent nausea. On this trial pirfenidone was 
administered at reduced dose for the initial treatment days, and subsequently escalated 
to full dose to prevent nausea, which was observed when patients were started at the 
full dose of pirfenidone. At the end of treatment, 11 of the 17 patients (65%) who 
completed 24 months of treatment had stable disease, three had minor response, and 
three had tumor progression. The seven patients who did not complete 24 months of 
therapy were stable at their last evaluation, with the exception of 1 patient who had a 
partial response to therapy after 12 months. Ten patients reported improvement in 
neurologic symptoms (Babovic-Vuksanovic et al., 2006). 
 
In summary, clinical investigations (phase I and phase II) in open clinical trials in adults 
have shown that pirfenidone exerts noteworthy anti-fibrotic actions. A maximum 


 4/6/2008 
 
 
 
 
 
 
 
 
 
20
tolerated dose of pirfenidone has not been determined in ongoing clinical trials in 
adults, but at the dose used in clinical trials (daily dosing with no rest period: 2400 
mg/day divided in three daily doses) pirfenidone appears to be well tolerated even 
after prolonged administration.  
Based on the results of the adult trials with pirfenidone, a phase I trial of pirfenidone in 
children with NF1 and plexiform neurofibromas was initiated and completed. Four 
patients were entered on the starting dose level of 750 mg/m2/day (250 mg/m2/q8h), 
and twelve patients were entered at the second dose level of 1500 mg/m2/day (500 
mg/m2 q8h). The formulation of pirfenidone as 200 mg and 400 mg capsules only, did 
not allow for smaller dose increments in this trial. The median age of the patients 
entered was 10.5 years (range 3 years to 19 years). Overall, pirfenidone was well 
tolerated. No dose-limiting toxicities were observed at the first level. Non dose-limiting 
toxicities at least possibly related to pirfenidone included diarrhea (n=1), fatigue (n=1), 
and gastritis (n=1). All 12 patients entered at the second dose level were evaluable for 
toxicity. Two patients developed dose-limiting toxicity during the first treatment cycle, 
which is used to define the maximum tolerated dose or the dose of pirfenidone, which 
achieves comparable drug exposure (AUC) to adults. One patient developed dose-
limiting persistent (> 7 days) grade 2 diarrhea, which subsided after treatment with 
pirfenidone was held, and thus appeared to be related to pirfenidone treatment. 
Pirfenidone was restarted at reduced dose for this patient and tolerated well. One 
additional patient developed dose-limiting persistent grade 2 nausea associated with 
vomiting, which subsided after pirfenidone was held. Pirfenidone was restarted at a 
reduced dose for this patient. Non dose-limiting toxicities observed during the first 
treatment cycle included nausea (n=4), vomiting (n=7), diarrhea (n=1), fatigue (n=3), 
abdominal pain (n=2), pruritus (n=1), palpitations (n=1), and dyspepsia (n=1). In three 
patients nausea and vomiting developed after the initial doses of pirfenidone, which 
resolved quickly after drug was held. Pirfenidone was well tolerated in all three 
patients when restarted at initially reduced dose and subsequently full dose. These 
toxicities were thus not considered dose-limiting. Two patients developed grade 3 
toxicities after the first treatment cycle of pirfenidone: One patient developed grade 3 
hypokalemia (potassium 2.8 mmol/L) on the third treatment cycle of pirfenidone. The 
potassium level was low normal (3.4 mmol/L, lower limit of normal 3.3 mmol/L) at the 
time of trial entry, and hypokalemia may thus be related to pirfenidone treatment. 
Pirfenidone was held, the patient was started on potassium supplementation, and after 
documentation of normal serum potassium, pirfenidone was restarted at reduced dose. 
The patient has tolerated the reduced pirfenidone dose well, and the potassium level 
has remained normal initially with and subsequently without supplementation of 
potassium. One additional patient with stable preexisting optic and thalamic glioma 
developed a grand mal seizure on the fifth treatment cycle with pirfenidone. This 
patient had no prior seizure history. Pirfenidone treatment was held, anti-seizure 
medication was initiated, and no seizure has been observed since. A MRI of the brain 
was performed and demonstrated no disease progression based on outside and NCI 
review. The patient restarted pirfenidone at full dose and has not developed further 
seizures. This toxicity is possibly related to pirfenidone. One patient with a history of 
syncopes prior to the start of treatment with pirfenidone experienced more frequent 
episodes of fainting beginning during cycle # 19. No decrease in the frequency of 
syncopes was noted while pirfenidone was held for a 2-week period, and treatment 
with pirfenidone was re-initiated (Babovic-Vuksanovic et al., 2007).   


 4/6/2008 
 
 
 
 
 
 
 
 
 
21
Thus, of 12 evaluable patients entered at the second dose level in the phase I trial, two 
patients experienced dose-limiting toxicity felt to be related to pirfenidone. The second 
dose (1500 mg/m2/day) will thus be the phase II dose for this proposed trial. Due to the 
initial nausea and emesis in 3 of 12 patients entered on the second dose level, and 
experience of the Mayo Clinic with initial nausea following administration of 
pirfenidone, which could be overcome by administration of pirfenidone at reduced 
dose for the initial days of treatment, pirfenidone will be administered at reduced dose 
for the first week of treatment in the proposed phase II trial (Section 3.2).  
Analysis of plasma pharmacokinetics has been completed for all 16 patients entered on 
the phase I trial, and defined the comparable dose of pirfenidone as 1500 mg/m2/day 
(500 mg/m2 q8h) (see table below in Section 1.2.8 Clinical PK of pirfenidone).  
1.2.8 CLINICAL PHARMACOKINETICS OF PIRFENIDONE  
Acute oral tolerance of pirfenidone in humans has been evaluated in 10 healthy adult 
men. Following the single dose of 400 mg, a significant amount of pirfenidone was 
found in the serum at 15 minutes after ingestion (average 4.0 mcg/ml). At one, four and 
six hours, the average serum level was 5.6 mcg/ml, 2.3 mcg/ml and 1.6 mcg/ml, 
respectively. These data indicate that the highest serum levels of pirfenidone occurred 
between one and three hours. The serum half-life was 2.9 hours. Pulse rate, respiratory 
rate and blood pressures were monitored at 15 minutes, one hour and four hours after 
the pirfenidone dose. Laboratory parameters including hematology, biochemistry and 
urinalyses were measured and none of these values differed significantly from the 
pretreatment determination or from the normal value range (Margolin, 1999).  
After oral administration, pirfenidone is readily absorbed from the gastrointestinal 
tract, distributed into many tissues and metabolized by the liver and dermis layer of the 
skin.  The primary metabolite of pirfenidone is the derivative with a hydroxy 
substitution in the para position of the phenyl group.  Since pirfenidone is quite rapidly 
metabolized and eliminated from the body’s circulation and tissues, it does not 
accumulate in the body, even when given repeatedly for many months (Margolin 2001). 
In the phase I study of pirfenidone for children with NF1 and plexiform neurofibromas, 
the primary objectives were to define the toxicities and the dose of pirfenidone that 
produces comparable drug exposure (AUC) to adults. The comparable dose of 
pirfenidone was defined as the dose level at which the mean AUC in children is within 
one standard deviation of the mean AUC in adults who were treated with 800 mg 
pirfenidone three times daily, the dose that demonstrated activity in adults with 
conditions other than NF1.  
A comparison of the drug exposure to pirfenidone measured as AUC for healthy adults, 
adults with renal dysfunction due to focal segmental glomerulosclerosis, and children 
entered on the phase I trial of pirfenidone for NF1 and plexiform neurofibromas is 
shown below.  


 4/6/2008 
 
 
 
 
 
 
 
 
 
22
Comparison of pirfenidone drug exposure (AUC) in adults and children: 
Pirfenidone dose 
Fixed Dose (mg)       mg/m2 Dose 
        Adult                     Pediatric  
Patients 
N 
AUC (µg•h/ml) 
Mean± SD 
400 
267 
Adult healthy 
10 
21 ± 10 
400 
267 
Adult renal 
dysfunction 
12 
16 ± 10 
375 
250 
Children NF1 
4 
12 ± 3 
800 
533 
Adult renal 
dysfunction 
8 
36 ± 21 
750 
500 
Children NF1 
12 
56 ± 43 
 
The results demonstrate that drug exposure in children with NF1 at the starting dose 
level of 250 mg/m2/dose is within one standard deviation of drug exposure in healthy 
adults and adults with segmental glomerulosclerosis treated at 400 mg three times 
daily. At the 1500 mg/m2/day (500 mg/m2/dose) dose level drug exposure in children 
is also within one SD above the mean AUC in 8 adults treated with a similar dose. The 
500 mg/m2/dose (1500 mg/m2/day) dose level is considered the comparable dose to 
the dose active in adults for the pediatric phase I trial, and will be the dose for the 
proposed pediatric phase II study, provided it will be well tolerated in the expanded 
patient cohort (see below).   
1.2.9 PROPOSED PEDIATRIC PHASE II TRIAL OF PIRFENIDONE 
This study will be conducted as a single stage, single arm phase II trial with time to 
progression as the primary endpoint.  The natural history of the growth of plexiform 
neurofibromas is unknown. For this reason, a double-blinded, placebo-controlled, cross-
over trial design is used to determine the activity of the farnesyltransferase inhibitor 
R115777 in an ongoing phase II trial for children with NF1 and progressive plexiform 
neurofibromas (CC protocol number 01-C-0222). The proposed phase II pirfenidone 
trial will use the initial placebo arm from this trial, containing 30 patients, as a historical 
control to determine the effect of pirfenidone on time to disease progression (see Section 
5.4.2 Statistics and Feasibility). 
Pirfenidone will be administered at a dose of 1500 mg/m2/day (500 mg/m2/dose) 
which was determined in the pediatric phase I trial of pirfenidone for patients with NF1 
and plexiform neurofibromas. Pirfenidone will be administered three times daily (q8h) 
for 28 days with no rest period between cycles (28 day cycles). The dose of pirfenidone 
will be 500 mg/m2/dose every 8 hours (1500 mg/m2/day), which appears to produce 
an AUC in children that is higher than the AUC in adults treated with 800 mg 
pirfenidone three times daily, the dose that showed activity in adults with conditions 
associated 
with 
excessive 
fibrosis 
(pulmonary 
fibrosis, 
peritoneal 
sclerosis, 
scleroderma). During the first week of the first treatment cycle only pirfenidone will be 


 4/6/2008 
 
 
 
 
 
 
 
 
 
23
administered at reduced dose to prevent nausea and vomiting observed in few patients 
with initial doses of pirfenidone in the pediatric phase I and adult phase II trial for NF1. 
Volumetric MRI data analysis of MRI studies from all participating institutions will be 
performed at the NCI POB using MEDx software to determine changes in tumor 
volume, and disease progression will be defined as a ≥ 20% increase in tumor volume 
(see Section 1.2.2).  Volume measurements will be compared to conventional 2-D MRI 
analysis and 1-D MRI analysis to assess its reproducibility and sensitivity in 
determining disease status of plexiform neurofibromas. The protocol described in 
Appendix 4 will be used to image plexiform neurofibromas.  
Patients will be able to continue on study for as long as no disease progression or 
intolerable toxicity is documented, or other off study criteria are met (Section 3.7).  
The quality of life of patients treated with pirfenidone on this study will be assessed 
using the National Institutes of Health (NIH) Impact of Pediatric Illness (IPI) Scale. This 
questionnaire was developed to assess the effects of chronic illness and treatment on the 
everyday behavior of children. It assesses adaptive behavior, emotional functioning, 
physical status and central nervous system symptoms. This questionnaire has not been 
completely validated, and means and standard deviations for different subgroups of 
patients on the scale and subscales are not available yet. Without normative data on this 
scale for patients with NF1, and having a relatively small sample size in the protocol, it 
may be difficult to analyze the data as an outcome measure for this particular study. 
However, the data will be useful for evaluating the ability of this new tool to measure 
changes in quality of life over time in children with NF1. The IPI scale should be 
administered to all patients ≥ 6 years and ≤ 18 years of age and their primary caregiver 
prior to the start of therapy. This questionnaire will not be administered to patients > 18 
years. This assessment consists of an age-appropriate questionnaire and generally takes 
less than 30 minutes to complete.  Patients between the ages of 6 and 10 years of age 
should be administered the IPI-Young Child form; patients between 11 and 18 years of 
age should be administered the IPI-Older Child/Adolescent form; the patient’s primary 
caregiver should receive the IPI-Parent Form. Quality of life will not be evaluated in 
children younger than 6 years or older than 18 years. 
Tumor biopsies will only be obtained on this trial if clinically indicated.  Attempts will 
be made to contribute tumor specimens obtained on this trial to an already-existing 
tissue bank.  Tumor specimens of plexiform neurofibromas will undergo central 
pathology 
review, 
including 
detailed 
morphological, 
ultrastructural 
immunohistochemical, and mRNA gene expression profile analysis. Tumor samples 
will be made accessible to the scientific community after obtaining IRB approval in 
order to collect more information on the pathology, genetics, and cell biology of 
plexiform neurofibromas (Appendix 5). 
1.2.10 UPDATE OF THE PEDIATRIC PHASE II TRIAL OF PIRFENIDONE  
Protocol 04-C-0080 enrolled 36 patients from July 21, 2004 to July 11, 2007, and 
enrollment on this trial is thus complete. Pirfenidone has been well tolerated. Only 2 
patients required dose reductions for dose-limiting toxicities: nausea (n=1) and grade 3 
neutropenia (n=1). As of March 2008, the median number of completed treatment cycles 
for all patients enrolled is 10 (range 3-42 cycles). Currently nine patients remain on 
study: NCI POB (n=3), Children’s National Medical Center, Washington, DC (n=2), 
Children’s Memorial Hospital, Chicago, IL (n=2), Dana-Farber Cancer Institute, Boston, 


 4/6/2008 
 
 
 
 
 
 
 
 
 
24
MA (n=1), and Cleveland Clinic, Cleveland, OH (n=1). The median number of 
completed treatment cycles for these patients is 17 (9-37 cycles). The body surface are of 
these patients ranges from 0.66 to 1.88 m2. 
Initially, pirfenidone was supplied by Solanan Inc. as 200 and 400 mg capsules, and 
dosing for this trial was devised for identical doses three times daily on a continuous 
doing schedule. The biopharmaceutical company InterMune has taken over the 
development of pirfenidone and will provide pirfenidone, and starting no later than 
May 19th, 2008, as pirfenidone shipments are requested by active sites, they will be 
provided by InterMune, Inc. until the trial is complete. The date for sites to begin 
dispensing InterMune drug supply may vary by site, depending on each site’s 
availability of existing Solanan/Marnac supply, their procurement of IRB approval, and 
timing of patient re-consent.  Drug supply from Intermune will be in form of 267 mg 
capsules. The protocol is therefore being revised in March 2008 to provide new dosing 
guidelines. 
 
2.0 ENROLLMENT PROCEDURES 
2.1 
ELIGIBILITY CRITERIA (ELIGIBILITY CHECKLIST APPENDIX 1) 
2.1.1 INCLUSION CRITERIA 
2.1.1.1  Age:  ≥3 years and ≤21 years of age. Required body surface area (BSA) : ≥ 
0.31 m2.  
2.1.1.2  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 (NIH Consensus Conference): 
1. Six or more café-au-lait spots (≥0.5 cm in prepubertal subjects or ≥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. 


 4/6/2008 
 
 
 
 
 
 
 
 
 
25
2.1.1.3 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 measurable increase of the plexiform neurofibroma (≥ 20% increase in the 
volume, or a ≥ 13% increase in the product of the two longest perpendicular 
diameters, or a ≥ 6% increase in the longest diameter) over the last two 
consecutive scans (MRI or CT), or over the time period of approximately one 
year prior to evaluation for this study. 
• 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.  
2.1.1.4  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 
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 (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 <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. 
2.1.1.5  Performance Status: Performance Status: Patients should have a life 
expectancy of at least 12 months. Patients > 10 years must have a Karnofsky 
performance level ≥ 50, and children ≤ 10 years must have a Lansky performance level ≥ 
50. (See Appendix 2). Patients who are wheelchair bound because of paralysis should be 
considered “ambulatory” when they are up in their wheel chair.  
2.1.1.6  Hematologic Function:  Patients must have an absolute granulocyte count  
≥1,500/µL , a hemoglobin ≥ 9.0 gm/dl, and a platelet count ≥150,000/µL at study entry 
(all transfusion independent). 
2.1.1.7  Hepatic Function:  Patients must have a bilirubin within normal limits 
and SGPT ≤ 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). 


 4/6/2008 
 
 
 
 
 
 
 
 
 
26
2.1.1.8  Renal Function:  Patients must have an age-adjusted normal serum 
creatinine (see table below) OR a creatinine clearance ≥ 70 mL/min/1.73 m2. 
Age 
(Years) 
Maximum Serum Creatinine 
(mg/dl) 
≤ 5 
0.8 
5 < age ≤ 10 
1.0 
10 < age ≤ 15 
1.2 
> 15 
1.5 
2.1.1.9  Informed Consent: All patients or their legal guardians (if the patients is 
<18 years old) must sign an 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.  
2.1.1.10 Durable Power of Attorney (DPA):  All patients ≥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. 
2.1.1.11 Patients must be able to take pirfenidone by mouth. Capsules can be 
opened and content mixed with food for easier consumption in small children. 
2.1.1.12 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. 
2.1.1.13 Ability and to undergo MRI and no contraindication for MRI 
examinations following the MRI protocol outlined in Appendix 4. 
 
2.1.2 EXCLUSION CRITERIA 
2.1.2.1  Pregnant or breast feeding females are excluded, because the toxic effects 
and pharmacology of pirfenidone in the fetus and newborn are unknown. 
2.1.2.2 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. 
2.1.2.3  An investigational agent within the past 30 days. 
2.1.2.4  Ongoing radiation therapy, chemotherapy, hormonal therapy directed at 
the tumor, immunotherapy, or biologic therapy (for example interferon).  


 4/6/2008 
 
 
 
 
 
 
 
 
 
27
2.1.2.5  Inability to return for follow-up visits or obtain follow-up studies 
required to assess toxicity and response to therapy. 
2.1.2.6  Prior treatment with pirfenidone. 
2.1.2.7  Evidence of an optic glioma, malignant glioma, malignant peripheral 
nerve sheath tumor, or other cancer requiring treatment with chemotherapy or 
radiation therapy.  
2.2 
PRE-TREATMENT EVALUATION (SEE APPENDIX 3) 
Pre-treatment blood tests should be performed within 2 weeks prior to enrollment 
on the trial unless otherwise stated. The evaluation required prior to starting treatment 
is listed in table form in Appendix 3. 
2.2.1  HISTORY AND PHYSICAL EXAMINATION: Complete history (including prior and 
concurrent therapy), physical examination including documentation of measurable 
disease, performance status, and signs and symptoms. Height, weight and body surface 
area must be recorded.  
The BSA should be calculated using the formula used at the participating 
institution from the average of 3 repeated measurements of weight and height on the 
same day. 
2.2.2  HEMATOLOGY:  Complete blood counts, differential, platelet count. 
2.2.3 CHEMISTRIES: Electrolytes (including sodium, potassium, chloride, CO2, 
calcium, phosphorus and magnesium), creatinine, BUN, glucose, SGOT, alkaline 
phosphatase, SGPT, and bilirubin.  
2.2.4 URINE OR SERUM PREGNANCY TEST: For all females of child-bearing potential 
(females greater than 9 years of age or those showing pubertal development).  This test 
is to be performed within 72 hours prior to enrollment on the trial. 
2.2.5 RADIOGRAPHIC EVALUATION (APPENDIX 4):  MRI scan of the progressing 
plexiform neurofibroma(s) within 2 weeks of enrollment on study.  In addition, if 
possible, MRI scan of all known additional, measurable plexiform neurofibroma(s) 
within 2 weeks of enrollment on study.  The progressing plexiform neurofibroma(s) will 
be identified as index lesion(s), and will be studied by 3-D MRI. Should there be more 
than 3 progressing plexiform neurofibromas, the three most clinically relevant 
plexiform neurofibromas will be followed by 3-D MRI analysis. The imaging protocol 
outlined in Appendix 4 will be used each time MRI examinations are performed to 
assess the effect to pirfenidone. 
2.2.6 TISSUE PROCUREMENT: Biopsy of plexiform neurofibroma, only if clinically 
indicated.  (Tissue sent as in appendix 5). 
2.2.7  QUALITY OF LIFE (QOL) ASSESSMENT:  The National Institutes of Health (NIH) 
Impact of Pediatric Illness (IPI) Scale, which assesses the impact of disease and 
treatment on children’s behavior, should be administered to all patients ≥ 6 and ≤ 18 
years of age and their primary caregiver prior to the start of therapy.  This assessment 
consists of an age-appropriate questionnaire and generally takes less than 30 minutes to 
complete.  Patients between the ages of 6 and 10 years of age should be administered 
the IPI-Young Child form; patients between 11 and 18 years of age should be 
administered the IPI-Older Child/Adolescent form; the patient’s primary caregiver 


 4/6/2008 
 
 
 
 
 
 
 
 
 
28
should receive the IPI-Parent Form. To allow for more meaningful analysis of the QOL 
questionnaires, a “backgound information sheet” will be completed by the parent one 
time, preferably at trial entry. This sheet includes information about education, current 
educational services, behavioral/psychiatric medications, visibility of NF1 tumors, and 
severity of NF1 symptoms. Quality of life will not be evaluated in children younger 
than 6 years or older than 18 years.    
 
2.3 
PATIENT REGISTRATION 
Patients must be registered by contacting Ms. Anne Goodwin or Ms. Wendy 
Goodspeed at the Pediatric Oncology Branch (POB) (phone number, 301-594-4762, e-
mail: goodwina@mail.nih.gov or goodspew@mail.nih.gov). When registering a patient, 
information about all entry criteria (e.g., laboratory results) must be available to allow 
for verification of eligibility. Dr. Brigitte Widemann (phone number: 301-496-7387, e-
mail: bw42y@nih.gov) or Dr. Frank Balis (phone number 301-496-0085, e-mail 
balisf@nih.gov) must also be contacted to discuss the patient prior to entry on study. 
The POB will ship a module with the necessary materials to administer the quality of 
life assessment to each participating institution at the time of receipt of IRB approval of 
each site. 
The completed Eligibility Checklist (Appendix 1) must be faxed to the POB c/o Ms. 
Anne Goodwin or Ms. Wendy Goodspeed (Fax: 301-480-8871). All patients (from all 
institutions) will be registered with Harris Technical Services (phone: 301-402-1732, fax: 
301-480-0757) by the POB research nurse, and an identification number will be assigned 
to each patient by the POB research nurse. The POB research nurse will notify the trial 
sponsor Dr. Babovic-Vuksanovic about registration of each patient entered on the trial 
by faxing eligibility checklist and trial entry document.  
The POB research nurse must be notified when a participating patient is removed from 
the protocol.  The POB research nurse will notify the trial sponsor Dr. Babovic-
Vuksanovic when a patient is removed from the protocol. 
3.0 IMPLEMENTATION OF STUDY 
 3.1 STUDY DESIGN 
3.1.1 OVERALL TRIAL DESIGN 
This is an open label phase II trial of oral pirfenidone in pediatric and young adult 
patients with NF1 and inoperable, progressive plexiform neurofibromas that have the 
potential to cause significant morbidity.  Patients will receive pirfenidone orally as 
capsules three times a day (“approximately” q8hours) for cycles of 28 days with no rest 
period between cycles (28 day treatment cycles). The investigational agent to be used in 
this study (pirfenidone) is not approved by the Food and Drug Administration (FDA) 
for commercial use; however, the FDA has permitted its use in this research study.  The 
trial will be conducted in compliance with the GCP and applicable regulating 
requirements. Based upon the data from the pirfenidone phase I study in children, the 
dose of pirfenidone will be 500 mg/m2 q8 hours (1500 mg/m2/day). Patients will 
remain on trial for as long as there is no disease progression and no other off study 
criteria have been met (Section 3.7). 


 4/6/2008 
 
 
 
 
 
 
 
 
 
29
This study is designed to determine the time to disease progression while on a chronic 
oral dose of pirfenidone (28 day cycles with no rest periods between cycles). In order to 
determine if pirfenidone benefits patients with NF1 and progressive plexiform 
neurofibromas time to disease progression on pirfenidone will be compared to time to 
disease progression on the placebo arm of the ongoing phase II trial of the 
farnesyltransferase inhibitor R115777 for children with progressive plexiform 
neurofibromas (Section 5.4.2). 
In addition, this trial will evaluate the toxicity profile of pirfenidone in children and 
young adults with NF1 and progressive plexiform neurofibroma(s).   
3.1.2 MONITORING TIME TO PROGRESSION AND RESPONSE  
This phase II trial is designed to determine the time to tumor progression and 
response rate with pirfenidone in patients with NF1 and progressive plexiform 
neurofibromas.  The primary endpoint will be time to progression.  At the time of study 
entry the progressing plexiform neurofibroma(s) will be identified as index lesion(s), 
and followed for progression by 3-D MRI.  Results obtained with 3-D MRI analysis will 
be compared to conventional 2-D MRI and 1-D MRI analysis for their ease of use, 
sensitivity, and reproducibility. In addition, if possible, all known additional, 
measurable plexiform neurofibroma(s) will be followed for progression by 3-D MRI.  
Results obtained with 3-D MRI analysis will be compared to conventional 2-D MRI and 
1-D MRI analysis for their ease of use, sensitivity, and reproducibility.  The imaging 
protocol outlined in Appendix 4 will be used each time MRI scans are performed to 
assess response to pirfenidone. MRI scans are performed prior to cycles 1, 4, 7, 10, and 
then after every 6 cycles while on study.  All MRI studies required per protocol will be 
submitted to the NCI POB for assessment of response by volume measurement within 2 
weeks of study acquisition. The NCI POB will notify the participating site of the 
volumetric measurement and response assessment. Until response assessment at the 
NCI POB is completed, patients will remain on treatment with pirfenidone. If a patient 
is removed from study because of clinical evidence of disease progression, the MRI 
scans should be repeated if they had not been performed within the past 6 weeks. 
3.1.3 DEFINITION OF TUMOR PROGRESSION 
• A ≥ 20% increase in the volume (by 3D-MRI) of at least one of the index plexiform 
neurofibroma(s) compared to the pretreatment volume measured prior to the start 
of treatment. 
• Appearance of new discrete dermal neurofibroma(s) does not qualify for disease 
progression. 
• Worsening of existing symptoms or the appearance of new symptoms that persist 
for more than 7 days and that are felt to be definitely related to plexiform 
neurofibroma should be evaluated by repeating the MRI.  Patients should not be 
classified as having progressive disease solely on the basis of new or increased 
symptoms without discussing the case with the protocol Principal Investigator (NCI, 
POB). 
• Patients with other evidence of disease progression than outlined above should also 
be discussed with the Principal Investigator. 
 


 4/6/2008 
 
 
 
 
 
 
 
 
 
30
3.2 
DRUG ADMINISTRATION  
3.2.1 SUPPLY OF PIRFENIDONE FROM SOLANAN, INC./MARNAC, INC. 
Pirfenidone will be supplied in 200 mg and 400 mg capsules by Solanan, Inc./Marnac 
Inc. under the IND # 60,584 held by Dr. Dusica Babovic-Vuksanovic.  Pirfenidone will 
be administered orally with food three times daily (approximately every 8 hours) for 28-
day cycles with no rest period between cycles (28-day treatment cycle). The pirfenidone 
dose will be 500 mg/m2 q8 hours (1500 mg/m2/day). BSA will be calculated using the 
formula used at the treating institution.  
Each patient’s dose will be rounded to the nearest 200 mg using the pirfenidone dose 
nomogram below based on the body surface area. Each treatment of the three daily 
doses will be identical. 
 
Dosing nomogram for pirfenidone 
BSA* 
0.31-0.6 
0.61-1.0 
1.01-1.4 
≥1.41 
Dose† 
200 
400 
600 
800 
*  BSA, body surface area in m2. 
†  Actual dose in mg (capsules sizes 200 and 400 mg) administered every 8 hours 
During the first week of the first treatment cycle only, pirfenidone will be administered 
at a reduced dose to prevent nausea and vomiting, which was observed in few patients 
with the initial doses of pirfenidone in the pediatric phase I and adult phase II trial for 
NF1. The reduced dosing for the first week will be as follows: 
Pirfenidone full dose 
Pirfenidone reduced dose week 1, cycle 1 
200 mg TID 
200 mg BID 
400 mg TID 
200 mg TID 
600 mg TID 
400 mg TID 
800 mg TID 
400 mg TID 
 
The formulation of pirfenidone as 200 and 400 mg capsules only does not allow for a 
more consistent dose reduction. Following the first week of treatment at reduced dose, 
pirfenidone will be administered at full dose.  
 
3.2.2 SUPPLY OF PIRFENIDONE FROM INTERMUNE, INC.  
Starting no later than May 19th, 2008, when pirfenidone shipments are requested by 
study sites they will be supplied as 267 mg capsules by InterMune Inc. Since this dosage 
form and all related information supportive of its use has been submitted under 
InterMune’s IND #67,284, InterMune is authorizing the cross reference of this trial’s 
IND #60,584 to InterMune’s IND #67,284. Pirfenidone will be administered orally with 
food three times daily (approximately every 8 hours) for 28-day cycles with no rest 


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31
period between cycles (28-day treatment cycle). The pirfenidone dose will be 500 
mg/m2 q8 hours (1500 mg/m2/day). BSA will be calculated using the formula used at 
the treating institution.  
Each patient’s dose will be rounded to the nearest 267 mg using the pirfenidone dose 
nomogram below based on the body surface area (BSA). In order to allow for precise 
dosing with the new formulation (267 mg/capsule) dosing cannot always be 
maintained with three identical doses. Pirfenidone will therefore be administered three 
times daily as outlined in the nomogram below. 


 4/6/2008 
 
 
 
 
 
 
 
 
 
32
 
Pirfenidone dosing nomogram 
BSA (m2) 
≤0.61 
0.62-0.79 
0.8-097 
0.98-1.15 1.16-1.32 
1.33-1.5 
≥1.51 
Dose (mg/day) 
801 
1068 
1335 
1602 
1869 
2136 
2403 
Dose 
(Capsules/day) 
3 
4 
5 
6 
7 
8 
9 
Dose† 
(Capsules/dose) 
1-1-1 
1-1-2 
1-2-2 
2-2-2 
2-2-3 
2-3-3 
3-3-3 
†Capsules/dose to be administered approximately every 8 hours 
At follow-up evaluations, pirfenidone doses will be adjusted for changes in body 
surface area according to the dosing nomogram for pirfenidone.  
Dose modifications for patients who experience toxicities are outlined in Section 3.3. 
Pirfenidone capsules may be opened and the content mixed with food for easier 
consumption in young children.  
Pirfenidone should be re-taken if vomiting occurs within 15 minutes of taking the dose, 
but not if vomiting occurs more than 15 minutes after taking pirfenidone.  
Patients or their guardians will keep a diary to document the intake of each dose of 
pirfenidone and potential side effects. The patient diary should be reviewed with the 
patient's family at each required clinical study evaluation. In addition, leftover study 
medication should be collected at each on study evaluation, and drug should be 
accounted for at this time (Appendix 6).  These diaries will be forwarded to Ms. Anne 
Goodwin or Ms. Wendy Goodspeed (Pediatric Oncology Branch, NCI, Fax: 301-480-
8871, Phone: 301-594-4762) after every 3 treatment cycles. 
3.3 
TREATMENT MODIFICATIONS 
3.3.1 FOR PIRFENIDONE FROM SOLANAN, INC. (200-MG AND 400-MG CAPSULES) 
Patients who experience grade 2 toxicity (CTCAE -3) related to pirfenidone should have 
pirfenidone withheld until the toxicity resolves (grade ≤1) and then restarted at the 
same dose level.  If the grade 2 toxicity recurs, the pirfenidone dose should be withheld 
again until the toxicity resolves (grade ≤1) and then reduced as follows: For patients 
receiving 200 mg TID, 400 mg TID, 600 mg TID, or 800 mg TID, the dose will be 
administered BID, which is an equivalent to a 33% dose reduction. Each treatment cycle 
should be no longer than 28 days.  Doses withheld while recovering from toxicity 
should not be made up.  If the grade 2 toxicity recurs after a dose reduction the patient 
should be taken off protocol.   
Patients who experience grade 3 toxicity related to pirfenidone should have their 
dose withheld.  If the toxicity returns to grade ≤1 within 14 days, patients may resume 
pirfenidone at a dose reduced as follows: For patients receiving 200 mg TID, 400 mg 
TID, 600 mg TID, or 800 mg TID, the dose will be administered BID, which is an 


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33
equivalent to a 33% dose reduction. Each treatment cycle should be no longer than 28 
days. Doses withheld while recovering from toxicity should not be made up. If the 
toxicity persists at grade ≥2 for >14 days without administration of pirfenidone or the 
grade 3 or 4 toxicity recurs at the lower dose level, the patient should be removed from 
the study (see Section 3.7). 
Patients who experience grade 4 toxicity related to pirfenidone will be removed 
from the study.   
3.3.2 FOR PIRFENIDONE FROM INTERMUNE, INC. (267-MG CAPSULES) 
Patients who experience grade 2 toxicity (CTCAE -3) related to pirfenidone should have 
pirfenidone withheld until the toxicity resolves (grade ≤1) and then restarted at the 
same dose level.  If the grade 2 toxicity recurs, the pirfenidone dose should be withheld 
again until the toxicity resolves (grade ≤1) and then reduced as outlined for patients 
with grade 3 toxicity in the table below. Each treatment cycle should be no longer than 
28 days.  Doses withheld while recovering from toxicity should not be made up.  If the 
grade 2 toxicity recurs after a dose reduction the patient should be taken off protocol.   
Patients who experience grade 3 toxicity related to pirfenidone should have their 
dose withheld.  If the toxicity returns to grade ≤1 within 14 days, patients may resume 
pirfenidone at a dose reduced as outlined in the table below: 
 
Full Dose 
Reduced Dose 
Capsules/day 
Capsules/dose† 
Capsules/day 
Capsules/dose† 
% Dose 
reduction 
3 
1-1-1 
2 
1-0-1 
33.3 
4 
1-1-2 
3 
1-1-1 
25 
5 
1-2-2 
3 
1-1-1 
40 
6 
2-2-2 
4 
1-1-2 
33.3 
7 
2-2-3 
5 
1-2-2 
28.6 
8 
2-3-3 
6 
2-2-2 
25 
9 
3-3-3 
6 
2-2-2 
33.3 
†Capsules/dose to be administered approximately every 8 hours 
Each treatment cycle should be no longer than 28 days. Doses withheld while 
recovering from toxicity should not be made up. If the toxicity persists at grade ≥2 for 
>14 days without administration of pirfenidone or the grade 3 or 4 toxicity recurs at the 
lower dose level, the patient should be removed from the study (see Section 3.7). 
Patients who experience grade 4 toxicity related to pirfenidone will be removed 
from the study. 
3.4 
ON STUDY EVALUATION (APPENDIX 3) 
3.4.1  HISTORY 
AND 
PHYSICAL 
EXAMINATION: History and full physical 
examination, with evaluation of signs of toxicity from pirfenidone, will be repeated 
prior to cycles 1, 2, 3, 4, and subsequently after every 3 treatment cycles as long as the 
patient remains on study. Height, weight, body surface area and performance status (if 


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34
changed from baseline) must be recorded. Visible plexiform neurofibromas should be 
directly measured (tape measure), if possible. 
3.4.2  HEMATOLOGY: Complete blood counts, differential, platelet prior to cycles 
1, 2, 3, 4, 7, 10, and subsequently after every 6 treatment cycles long as the patient 
remains on study.  
3.4.3  CHEMISTRIES: Electrolytes (including sodium, potassium, chloride, CO2, 
calcium, phosphorus and magnesium), creatinine, BUN, glucose, SGOT, alkaline 
phosphatase, SGPT, gamma-GTP, and bilirubin prior to cycles 1, 2, 3, 4, 7, 10, and 
subsequently after every 6 treatment cycles long as the patient remains on study. 
3.4.4  RADIOGRAPHIC EVALUATION (APPENDIX 4):  Evaluate the index lesions by 
MRI prior to cycle 1, 4, 7, 10 and then every 6 cycles thereafter while on study.  The 
imaging protocol outlined in Appendix 4 will be used each time MRI examinations are 
performed to assess progression or response to pirfenidone. In patients with clinical 
suspicion of disease progression, MRI analysis should be performed earlier using the 
protocol outlined in Appendix 4. 
3.4.5 QUALITY OF LIFE (QOL) ASSESSMENT: The National Institutes of Health 
(NIH) Impact of Pediatric Illness (IPI) Scale, which assesses the impact of disease and 
treatment on children’s behavior, should be administered to all patients ≥6 years to 18 
years of age and their primary caregiver prior to the start of therapy, prior to cycles 4, 7, 
and then after every 6 cycles. This assessment consists of an age-appropriate 
questionnaire and generally takes less than 30 minutes to complete.  Patients between 
the ages of 6 and 10 years of age should be administered the IPI-Young Child form; 
patients between 11 and 18 years of age should be administered the IPI-Older 
Child/Adolescent form; the patient’s primary caregiver should receive the IPI-Parent 
Form. To allow for more meaningful analysis of the QOL questionnaires, a 
“background information sheet” will be completed by the parent one time, preferably at 
trial entry.  This sheet includes information about education, current educational 
services, behavioral/psychiatric medications, visibility of NF1 tumors, and severity of 
NF1 symptoms. The QOL questionnaire will not be administered to patients > 18 years. 
The “background information sheet”, and patient and parent response forms should be 
photocopied after completion and copies sent to Dr. Pamela Wolters, Ph.D., Building 82, 
Room 109, 9030 Old Georgetown Road, Bethesda, MD 20892-8200, ideally within 48 
hours and no later than 2 weeks after completion of the questionnaire.  Any questions 
regarding the administration of the IPI Scale should be addressed to Dr. Pam Wolters, 
Ph.D. at phone: 301-496-0561, fax; 301-402-1734, e-mail: woltersp@mail.nih.gov. 
3.5 
CONCURRENT THERAPIES 
Other cancer chemotherapy, radiation therapy, immunotherapy, biologic therapy, 
hematopoietic growth factors or investigational agents cannot be administered to 
patients receiving pirfenidone.  
Use of corticosteroids for control of symptoms related to the underlying NF1 or for 
other reasons will be allowed, as no effect on the growth of plexiform neurofibromas is 
expected. 


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35
Alternative Therapy: Oral vitamin or nutritional supplements may be used if approved 
by the patient’s primary physician, and should be recorded in the patient’s history and 
diary. 
3.6 
OFF STUDY CRITERIA 
3.6.1  ADMINISTRATIVE:   
A patient may be taken off the study for the following non-medical or administrative 
reasons: 
• Patient refusal of further treatments (reasons must be noted on the patient's 
CRF). 
• It is deemed in the best interest of the patient (for example, availability of new 
surgical treatment option for a patient).  In this instance the Principal 
Investigator should be notified and the reasons for withdrawal should be noted 
in the CRF.  
• Serious protocol violation as determined by the principal investigator. 
3.6.2  TOXICITY  
Recurrent grade 2, 3 or 4 toxicity after dose reduction or persistent toxicity grade ≥2 for 
>14 days without administration of drug that is considered primarily related to study 
drug.  Persistent (>14 days) grade 2 toxicity should be discussed with the PI prior to 
removing the patient from the study. 
The protocol Principal Investigator should be notified immediately in the event of 
severe or life-threatening toxicity (Dr. Brigitte Widemann, 301-496-7387, 301-496-1211 
page operator). The POB will then contact Dr. Babovic-Vuksanovic at (507) 284-3215 
and Dr. Roger J. Packer at (202) 884-2120. The Medical Monitor will be formally 
contacted by Dr. Babovic-Vuksanovic. 
3.6.3 TUMOR PROGRESSION 
Any patient with clinical or radiographic evidence of progressive disease (see Section 
3.1.3) on treatment, as documented by a ≥ 20% increase in tumor volume on 3-D MRI, 
following any treatment cycle will be removed from the study (see Sections 3.1.3 and 
5.2).  The POB research nurses, Ms. Anne Goodwin or Ms. Wendy Goodspeed, must be 
notified when a patient has tumor progression and goes off-study at 301-594-4762.   
3.7 
POST THERAPY EVALUATION 
The following tests and procedures should be performed, if possible, at the time a 
patient comes off study regardless of the reason for coming off study, unless the test or 
procedure has been performed in the last 6 weeks (2 weeks for physical examination 
and laboratory assessment). 
• History and physical examination, performance status, and measurement of 
visible or palpable tumor lesions). 
• Laboratory Assessment:  Complete blood count, differential and platelet count, 
electrolytes, creatinine, calcium, magnesium, phosphorus, SGPT, bilirubin, and 
urinalysis. 


 4/6/2008 
 
 
 
 
 
 
 
 
 
36
• MRI Scan of the plexiform neurofibroma(s) and any other progressing lesions 
using the protocol outlined in Appendix 4. 
• Quality-of-Life Scale, see Instruments. 
• Case report form and patient diaries. 
4.0 SUPPORTIVE CARE 
GENERAL: Appropriate antibiotics, blood product support, and general supportive care 
will be used as indicated. Antiemetics and drugs to manage diarrhea (for example 
loperamide) may be used intermittently, but for no more than 7 consecutive days in a 
treatment cycle. Hematopoietic growth factors cannot be administered to patients 
receiving pirfenidone. 
5.0 DATA COLLECTION AND EVALUATION 
Dr. Roger Packer, who has received a Clinical Trial Award by the U.S. Department of 
Defense to fund aspects of this trial, will be the Cooperative Study Group Principal 
Investigator. Dr. Babovic-Vuksanovic is the IND holder for this study (IND #60,584). 
She will sponsor this trial, and will serve as Cooperative Study Group Co-Principal 
Investigator. The trial will be coordinated by the Pediatric Oncology Branch of the NCI 
with Dr. Brigitte Widemann as Principal Investigator. Dr. Tracy Glauser, M.D., 
Associate Professor for neurology at the Cincinnati Children’s Hospital, will serve as 
Medical Monitor for this trial. In Spring 2008, the supplier of drug for this study will 
transition from Solanan, Inc./Marnac, Inc. to InterMune, Inc. InterMune is authorizing 
the cross-reference of this study’s IND to InterMune’s IND #67,284 for pirfenidone. 
5.1 DATA COLLECTION 
The POB, NCI will coordinate the clinical trial and data collection, and supply the data 
to the trial sponsor Dr. Dusica Babovic-Vuksanovic via case report forms. Data will be 
entered into the NCI, Center for Cancer Research (CCR) C3D database.  Documentation 
and date of IRB approval must be provided to the POB, NCI prior to initial patient entry 
from each institution. The completed Eligibility Checklist (Appendix 1) must be faxed to 
Ms. Anne Goodwin or Ms. Wendy Goodspeed at (301) 480-8871 prior to patient entry 
onto the trial.  
5.1.1 CASE REPORT FORMS   
All case report forms and patient diaries will be identified by a study number, not 
names or initials.  This will be done to protect patient confidentiality.  
Unless otherwise stated, all forms should be submitted to:  
Pediatric Oncology Branch, NCI 
c/o Ms. Anne Goodwin or Ms. Wendy Goodspeed 
Bldg. 10 CRC, Room 1-5742 
10 Center Drive, MSC 1101 
Bethesda, MD 20892- 
Phone: 301-594-4762 
FAX: (301) 480-8871 
Case Report Forms:  Case Report Forms have been developed by Dr. Babovic-
Vuksanovic in collaboration with the POB. CRFs will be completed at the treating 


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37
institution after each patient evaluation and submitted within 2 weeks of each required 
evaluation to Ms. Anne Goodwin or Ms. Wendy Goodspeed, NCI, POB. Participating 
sites will be contacted to provide source documents or additional information if 
necessary. Data will be entered into the NCI, CCR C3D database.     
Eligibility Checklist (Appendix 1):  To be completed at study entry and forwarded to 
Ms. Anne Goodwin or Ms. Wendy Goodspeed (301) 480-8871 (phone 301 402 1848). 
Patient Diaries (Appendix 6): Patients or their guardians will keep a diary to document 
the intake of each dose of pirfenidone and potential side effects. These diaries will be 
forwarded to Ms. Anne Goodwin or Ms. Wendy Goodspeed after each required 
evaluation. 
QOL Assessment (NIH IPI Scale) Forms:  The “background information sheet”, and 
patient and parent response forms should be photocopied after completion and copies 
sent to Ms. Dr. Pamela Wolters, Ph.D., FAX: (301)-402-1734, Building 82, Room 109, 9030 
Old Georgetown Road, Bethesda, MD 20892-8200, ideally within 48 hours and no later 
than 2 weeks after completion of the questionnaire. Any questions regarding the 
administration of the IPI Scale should be addressed to Dr. Pam Wolters, Ph.D. at phone: 
301-301-496-0561, e-mail: woltersp@mail.nih.gov. 
MRI studies and protocols (Appendix 4): All MRI studies requested per protocol will be 
submitted to the NCI POB within 2 weeks of acquisition for volume analysis. At the 
same time, a copy of the MRI protocol used to obtain the MRI study will be sent to the 
NCI POB, or faxed to Ms. Anne Goodwin or Ms. Wendy Goodspeed. The goal is to 
electronically submit imaging studies via InSite One (Appendix 4), but transfer via CD 
or optical disk will be acceptable.  
Protocol Violations: Any protocol violation should be directly reported to Dr. Brigitte 
Widemann (phone: 301-496-7387, fax: 301-480-8871, e-mail: bw42y@nih.gov). 
 
5.2 RESPONSE CRITERIA 
Response is assessed at the time that follow-up 3D-MRI scans are performed (prior to 
cycle 4, 7, 10, and then after completion of every 6 cycles thereafter). For the purpose of 
determining the level of response (complete, partial, minor, etc.) measurements from 
the follow-up scans are compared to the tumor size in the pretreatment MRI scan using 
3D data analysis. Response determined using 3D-MRI volumetric analysis will be 
compared with 2D- and 1D-MRI measurements.   
COMPLETE RESPONSE (CR): A complete resolution of all measurable or palpable soft 
tissue tumors for ≥ 4 weeks and no appearance of new lesions. 
PARTIAL RESPONSE  (PR): A ≥50% reduction in the sum of the volume of all index 
lesions for ≥4 weeks.  
MINOR RESPONSE (MR): A ≥25% but <50% reduction in the sum of the volume of all 
index lesions for ≥4 weeks.  
STABLE DISEASE (SD): A <20% increase, and < 25% decrease in the sum of the 
volume of all index lesions for ≥4 weeks.  
PROGRESSIVE DISEASE (PD):  


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38
• A ≥ 20% increase in the volume (by 3D-MRI) of at least one of the index plexiform 
neurofibromas compared to the pretreatment volume measured prior to the start of 
the current treatment phase. 
• The appearance of new discrete subcutaneous neurofibromas does not qualify for 
disease progression.  
• Worsening of existing symptoms or the appearance of new symptoms that persist 
for more than 7 days and that are felt to be definitely related to the plexiform 
neurofibroma should be evaluated by repeating the MRI.  Patients should not be 
classified as having progressive disease solely on the basis of new or increased 
symptoms without discussing the case with the protocol Principal Investigator. 
• Patients with other evidence of disease progression than outlined above should also 
be discussed with the Principal Investigator. 
5.3 TOXICITY CRITERIA 
Toxicity will be graded according to the CTEP Expanded Common Terminology 
Criteria for Adverse Events, Version 3.0. The Cancer Therapy Evaluation Program 
Common Terminology Criteria (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).  The CTCAE 3.0 does not have to be appended to the 
protocol, however, all appropriate treatment areas should have access to a copy of the 
CTCAE version 3.0. 
5.4 STATISTICAL CONSIDERATIONS 
5.4.1 SUBJECT ACCRUAL 
Subjects of both genders, from all racial and ethnic groups are eligible for this trial if 
they meet the criteria outlined in Section 2.1. To date, there is no information that 
suggests differences in drug metabolism or disease response among racial or ethnic 
groups or between the genders, indicating that results of the trial will be applicable to 
all groups. Most plexiform neurofibroma grow out of proportion to somatic growth for 
a period of time during childhood, but reach a plateau by the end of puberty.  Efforts 
will be made to extend the accrual to a representative population, but in a phase II 
study with limited accrual, a balance must be struck between patient safety 
considerations and limitations on the number of individuals exposed to potentially 
toxic or ineffective treatments on the one hand and the need to explore gender, racial, 
and ethnic aspects of clinical research on the other. If differences in outcome that 
correlate to gender, age, racial, or ethnic identity are noted, accrual may be expanded or 
additional studies may be performed to investigate those differences more fully.  
5.4.2 STATISTICS AND FEASIBILITY 
The primary objective of this Phase II trial is to determine whether the use of 
pirfenidone in pediatric patients with NF1 is able to increase time to disease 
progression.  This study will be conducted as a single stage, single arm phase II trial 
with time to progression as the primary endpoint.  The natural history of the growth of 
plexiform neurofibromas is unknown. For this reason, a complex trial design (double-
blinded, placebo-controlled, cross-over trial) is currently used in an ongoing phase II 
trial (01-C-0222) of the farnesyltransferase inhibitor R115777 for children with NF1 and 
progressive plexiform neurofibromas to determine the potential benefit of R115777.  


 4/6/2008 
 
 
 
 
 
 
 
 
 
39
Twenty-five patients have been enrolled to date on the ongoing phase II trial of 
R115777/placebo for patients with NF1 and progressive plexiform neurofibromas. Most 
patients have been entered at the NCI, POB. The accrual goal is 60 patients, and steps 
are currently being taken, which will likely allow more institutions to open the study 
and should result in an increased accrual to the trial. Using a volume increase of ≥ 20% 
to define progression of a plexiform neurofibroma, 7 patients developed disease 
progression on treatment phase A after a median of 9 months (range 6-26 months), and 
11 patients have stable disease on treatment phase A after a median of 9 months (range 
5-23 months). Of the patients who crossed over to treatment phase B, three developed 
progression after 4, 6, and 9 months, respectively, and were removed from the protocol. 
Another 3 patients remain stable on treatment phase B at 6, 9, and 13 months, 
respectively. One patient was removed from the study for dose-limiting grade 3 
neutropenia, and another patient was removed from the study, when the biopsy of a 
focal increasing mass within the plexiform neurofibroma was found to be a malignant 
peripheral nerve sheath tumor. Enrollment on this trial is complete s of the end of 2007.  
The proposed phase II pirfenidone trial will use the initial placebo arm from the 
R115777 trial, containing 30 patients, as a historical control.  
The method described in Dixon and Simon (J Clin Epidemiol 41: 1209-1213, 1988) will 
be used to determine the sample size required in the present study.  It will be assumed 
that the median time to progression of the placebo arm for the R115777 patients is 6 
months, and that the eligibility criteria and distribution of potential prognostic factors 
for the present trial are identical to those of the R115777 trial.  It is further assumed that 
accrual of 2.5 to 3 patients per month can be enrolled onto this trial, and that it will be of 
interest to identify a doubling of the median time to progression, from 6 to 12 months.  
A Kaplan-Meier analysis using a log-rank test is the primary method of analysis to 
compare the two arms.  Using an intended one-sided alpha=0.05, and with 50% of the 
30 patients on the previous trial having progressed, at a median of 6 months, then 
accrual of 36 patients on the present study will provide at least 80% power to detect a 
doubling against the control arm from the prior trial.  
Even though 30 patients have to be enrolled on the placebo arm of the ongoing phase II 
trial of R115777 for NF1 for a solid analysis of time to disease progression, interim 
analyses of time to progression will be performed while patients are still enrolled on the 
trial and continue on the first treatment phase. As long as the median time to disease 
progression on the placebo arm can be defined with reasonable precision using Kaplan-
Meier analysis, a new estimate of time to disease progression can be made while the 
trial is still ongoing and prior to completion of the first treatment phase in all patients. 
The protocol may then be amended to use this estimate to adjust the sample size for the 
pirfenidone phase II trial should it be longer than anticipated. 
Because this trial design uses a historical comparison, it is possible that some difference 
in patient characteristics may explain any differences identified.  However, since the 
identical institutions will be participating, the identical eligibility criteria will apply, the 
primary trial endpoint will be assessed in identical way, and the study will be initiated 
immediately after accrual is completed to the trial of R115777, it is anticipated that 
differences in patient characteristics and related factors will be minimal.  Nonetheless, 
an analysis to compare the characteristics of patients on both arms will be undertaken 
and if any important differences are identified (e.g., a difference in an important 
prognostic factor with a p-value of <0.10, two-sided), then a Cox proportional hazards 


 4/6/2008 
 
 
 
 
 
 
 
 
 
40
model analysis may be performed to determine whether pirfenidone is able to be 
associated with increased time to progression after adjusting for important prognostic 
factors. 
With accrual of 2.5 to 3 patients per month, it is expected that accrual of 36 patients can 
be completed in approximately 12-14 months, and that analysis could be performed 
approximately 12 months after the last patient was enrolled. 
As a secondary objective, 3-D MRI analysis will be performed in the evaluation of 
plexiform neurofibromas, and will be compared to conventional 1-D MRI and 2-D MRI 
data analyses.  The exact method used to perform the volumetric MRI analysis is 
described in Section 1.2.2, and Appendix 4 describes the imaging protocol. Since both a 
phase I trial and a phase II trial of pirfenidone will be undertaken, the results from both 
studies will be considered in the overall evaluation of the three MRI techniques relative 
to each other.  Since this analysis will be interpreted as exploratory, all findings will be 
considered as hypothesis generating and would require additional evaluation in 
subsequent patients in order to provide confirmation. 
 “Quality-of-life” of patients treated with pirfenidone will be explored using the NIH 
Impact of Pediatric Illness scale, which assesses the impact of disease and treatment on 
children’s behavior.  The ability of this new assessment tool to measure changes in a 
child’s quality of life will also be assessed at baseline and at fixed intervals, as outlined 
in the description of the protocol.  The assessments will be done using exploratory 
techniques, and any findings identified in either the Phase I or Phase II trial will be 
considered hypothesis generating. 
 
5.5 
MULTI-INSTITUTIONAL GUIDELINES 
5.5.1 IRB APPROVALS 
The PI from each participating institution will provide the Study Coordinator (POB, 
NCI) with a copy of the initial IRB protocol approval and the yearly IRB continuing 
reviews. The Study Coordinator will submit these to the NCI IRB and to Dr. Roger 
Packer, who will submit these documents to the US Army IRB. Registration will be 
halted at a participating institution if a current continuing approval is not on file at the 
NCI POB.  
As this trial receives funding by the US Army, approval of the protocol and of all 
protocol amendments will also be obtained from the HSRRB in addition to the 
institutional IRB prior to implementation. 
Each participating institution is required to maintain a current MPA or FWA in order to 
participate in government-sponsored Group research.  The files will be copied or made 
available for review by authorized persons as required for conduct of this trial. 
Any deviation to the protocol that may have an effect on the safety or rights of the 
subject or the integrity of the study must be reported to the USAMRMC ORP HRPO as 
soon as the deviation is identified.  
A copy of the approved continuing review report and the local IRB approval 
notification will be submitted to the USAMRMC ORP HRPO as soon as these 
documents become available.  A copy of the approved final study report and local IRB 
approval notification will be submitted to the USAMRMC ORP HRPO as soon as these 


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41
documents become available.  
The knowledge of any pending compliance inspection/visit by the FDA, OHRP, or 
other government agency concerning clinical investigation or research, the issuance of 
Inspection Reports, FDA Form 483, warning letters or actions taken by any Regulatory 
Agencies including legal or medical actions and any instances of serious or continuing 
noncompliance with the regulations or requirements will be reported immediately to 
USAMRMC ORP HRPO. 
 
5.5.2 AMENDMENTS AND CONSENTS 
The PI from each participating institution will provide the Study Coordinator (NCI, 
POB) with a copy of IRB approval of all amendments to the protocol or consent. The 
Study Coordinator will provide these institutional reviews to Dr. Roger Packer, who 
will submit these documents to the US Army IRB.  As this trial receives funding by the 
US Army, approval of all protocol amendments will be obtained from the HSRRB in 
addition to the institutional IRB prior to implementation.  
5.5.3 PATIENT REGISTRATION 
All patients entered will be registered by the POB with the CCR Central Office 
(ORKAND). The completed Eligibility Checklist (Appendix 1) must be FAXed to the 
POB prior to enrollment on the trial. 
5.5.4 DATA COLLECTION AND TOXICITY REPORTING 
The trial is being sponsored by Dr. Babovic-Vuksanovic, and drug has been supplied by 
Solanan, Inc./Marnac Inc. Starting no later than May 19, 2008, any drug shipped for this 
study will be supplied by InterMune, Inc. Case report forms developed by Dr. Babovic-
Vuksanovic and the Pediatric Oncology Branch will be used for submitting clinical data 
to the coordinating center.  Data must be submitted to the Coordinating Center within 2 
weeks of completing each required evaluation while the patient is on study. This 
information will be entered into the NCI CCR C3D system, an electronic database for 
ongoing clinical trials coordinated at the NCI. This System gives access only to persons 
directly involved in specific clinical trials (such as PI, associate investigators, research 
nurse for the trial, and data manager for the trial), and is password protected. Hard 
copies of CRF’s, informed consents, and other patient identifying materials will be kept 
in locked filing cabinets.  
Tumor samples obtained on this trial will be stored at Washington University as 
outlined in Appendix 5. MRI data will be stored at InSite One (contracted for transfer 
and storage of MRI data), and at the NCI POB. Only InSite One and the NCI POB will 
have access to the MRI data (Appendix 4). Representatives from the NCI, Solanan Inc., 
InterMune, Inc., Dr. Babovic-Vuksanovich, the FDA, and the U.S. Army Medical 
Research and Materiel Command will have access to the data and research records.  
Data will be stored for at least 2 years after the NDA is approved for marketing. If an 
NDA is not filed, or is disapproved, all data will be stored for 2 years after the 
investigation is discontinued and the FDA is notified. 
All adverse events (as defined in Section 7.3.2) from participating institutions will be 
submitted to the NCI IRB by the Study Coordinator. The NCI POB will forward adverse 


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42
event reports to Dr. Babovic-Vuksanovic and to Dr. Roger Packer. The Medical Monitor, 
Dr. Tracy Glauser, M.D., will be formally contacted by Dr. Babovic-Vuksanovic. The US 
Army IRB will be contacted by Dr. Roger Packer.  
Dr. Tracy Glauser, the medical monitor will operate as a patient advocate and is 
independent of the clinical study team.  He will oversee the progress of the protocol, 
especially issues of individual subject/patient management and safety.  The medical 
monitor is required to review all unanticipated problems involving risks to subjects or 
others, including all serious and unexpected adverse events associated with the 
protocol as defined in Section 7.3.2.  The monitor provides an unbiased written report of 
the event.  
3-D-MRI analysis will be performed centrally by the POB, NCI. 
5.5.5 DATA AND CENTER AUDITS 
The trial will be audited by the NCI CCR via contract for compliance and safety. 
Independent monitors will visit participating sites and review case report forms and 
source documentation. Missing or spurious information and protocol deviations will be 
communicated in a report to the trial coordinating center. Protocol deviations, which 
may result in compromise to safely administer study drug, or to determine study 
endpoints will be included in the annual protocol review for the NCI and US Army IRB.   
 
All unexpected and serious adverse events will be forwarded to the Medical Monitor by 
Dr. Dusica Babovic-Vuksanovic as defined in Section 7.3.2.  
Volumetric MRI analysis will be used to determine disease progression, and patients 
will not be removed from study based on 1-D or 2-D MRI measurements or based on 
clinical measurement of superficial lesions. The volumetric analysis for all 
measurements will be performed centrally at the NCI, POB with Dr. N. Patronas 
serving as the responsible neuroradiologist for this trial.   
6.0 HUMAN SUBJECTS PROTECTIONS 
6.1 RATIONALE FOR SUBJECT SELECTION 
Neurofibromatosis type 1 is a genetic disorder and the incidence of the disease in the 
various racial and ethnic groups may vary. This may impact on our ability to recruit 
sufficient numbers of patients within each group to this trial.  Subject accrual in regards 
to gender, and racial and ethnic groups is described in Section 5.4.1.  None of these 
groups are being excluded from participation in the trial.  Females who are pregnant or 
breast feeding will not be eligible for entry onto the trial because of the potential and 
unknown risks that pirfenidone could pose to the fetus or newborn.  This trial is 
designed to determine whether pirfenidone is able to increase time to disease 
progression in children and young adults with NF1 and progressive plexiform 
neurofibromas and, therefore, children will be entered onto this research trial.  
6.2 
PARTICIPATION OF CHILDREN  
This trial is designed to determine whether pirfenidone is able to increase time to 
disease progression in children and young adults with NF1 and progressive plexiform 
neurofibromas.  Therefore children who meet eligibility criteria for this trial will be 
entered in the study.  Children will be evaluated and cared for by physicians trained in 
pediatrics and pediatric oncology, and will be followed in the Pediatric Oncology, 
Pediatric Neurology, and Pediatric Genetics Clinics. 


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43
6.3 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS  
The primary objective of this trial is to determine whether pirfenidone is able to increase 
time to disease progression in children and young adults with NF1 and progressive 
plexiform neurofibromas. Pirfenidone has been well tolerated in adults at doses that 
show activity of pirfenidone in fibrosing conditions. The equivalent dose level (1500 
mg/m2/day) has been well tolerated in the ongoing pediatric phase I trial of 
pirfenidone. Pharmacokinetic analysis demonstrated that drug exposure at this dose 
level is comparable to drug exposure in adults receiving the same dose. The 1500 
mg/m2/day dose level will thus be used in the proposed phase II trial. The benefit may 
include improved physical and neurologic functions, improved physical appearance or 
even prolongation of life, for those patients with plexiform neurofibromas, which are 
life-threatening.   
6.4 RISK/BENEFIT ANALYSIS 
The primary objective of this Phase II trial is to determine whether the use of 
pirfenidone in pediatric patients with NF1 and progressive plexiform neurofibromas is 
able increase time to disease progression. Patients entered on the trial will be treated 
with therapeutic intent and response to the therapy will be closely monitored. The 
pirfenidone study has the intent to benefit patients.  Pirfenidone has been effectively 
used in adult patients with fibrosing conditions and plexiform neurofibromas are 
marked by excessive fibroblast proliferation.  In addition, in the Phase II study of 
pirfenidone in adults with progressive plexiform neurofibromas, none of the treated 
patients had further progression of lesions, as determined by a volumetric MRI analysis, 
and some patients have experienced symptomatic improvement. It is intended that 
patients responding to treatment will have an improvement in their deficits or 
dysfunctions caused by the plexiform neurofibroma.  Furthermore, by just entering the 
study, patients will be followed very carefully, in an organized coherent fashion, which 
will also benefit their overall care. 
Therefore, this protocol involves greater than minimal risk to children, but presents the 
potential for direct benefit to individual subjects.   
6.5 CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
The investigational nature and objectives of this trial, the procedures and treatments 
involved and their attendant risks and discomforts and benefits, and potential 
alternative therapies will be carefully explained to the patient or the patient’s parents or 
guardian if he/she is a child, and a signed informed consent document will be obtained. 
The investigators have received a waiver from the IRB to allow only one parent to sign 
the informed consent to enter a child on the protocol.  Because many patients must 
travel to the clinical site from long distances at substantial expense, requiring both 
parents to be present for the consent process could be a financial hardship for many 
families.  Consent will be obtained by the PI, an associate investigator, or an 
investigator assigned by the PI on the trial.  Where deemed appropriate by the clinician 
and the child’s parents or guardian, the child will also be included in all discussions 
about the trial. 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 in order to obtain written assent. This is a multi-institutional trial, and 
the NCI as coordinating center will require evidence of local IRB approval of the 
protocol prior to allowing for accrual of patients at that institution. This trial will be 


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44
conducted in compliance with the protocol, Good Clinical Practice (GCP) and the 
applicable regulatory requirements.  
6.6 
HANDLING OF RESEARCH SAMPLES 
This study is coordinated by the NCI, Pediatric Oncology Branch, and receives funding 
by the U.S. Army. No research samples are collected on this trial with the exception of 
patients who undergo surgery to their plexiform neurofibroma for clinical reasons. For 
these patients the plan is to obtain a tumor specimen not required for clinical care in 
order to perform detailed analyses as outlined in Appendix V. Handling and storage of 
these research specimens is described in detail in Appendix V. 
7.0 DATA REPORTING 
Unless otherwise stated, all forms should be submitted to:  
Ms. Anne Goodwin or Ms. Wendy Goodspeed, R.N. 
Pediatric Oncology Branch, National Cancer Institute 
Building 10 CRC, Room 1-5742 
10 Center Drive 
Bethesda, MD 20892-1101 
Phone (301) 594-4762 
FAX (301) 480-8871 
7.1 PATIENT REGISTRATION  
See Section 2.3.  The eligibility checklist is in Appendix 1. 
7.2 
CASE REPORT FORMS 
The POB will provide Case Report Forms for recording relevant clinical data for 
each patient entered on the trial (Section 5.1). Patient diaries (Appendix 6) should be 
provided to patients and their families and submitted after completion of each required 
evaluation. Data will be entered into the NCI, CCR C3D database. 
7.3 
SAFETY REPORTING 
7.3.1 ADVERSE EVENTS  
Adverse events are any unfavorable and unintended sign (including an abnormal 
laboratory finding) symptom or disease temporally associated with the use of a medical 
treatment or procedure regardless of whether it is considered related to the medical 
treatment or procedure (attribution of unrelated, unlikely, possible, probable or 
definite). 
Life-threatening adverse events are any adverse event that places the patient or 
subject, in view of the investigator at an immediate risk of death from the reaction. 
Serious adverse events are any adverse event occurring at any dose that result in 
any of the following outcomes: Death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, a congenital anomaly/birth defect, and other medically 
significant events. 
Unexpected adverse events are any adverse events, which are not listed in the 
Investigator Brochure and informed consent for this trial. Known toxicities observed to 
date are listed in Section 8.1.10. 


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45
All observed or volunteered adverse events, regardless of suspected causal relationship 
to study drug, will be recorded on the case report form. Events involving adverse drug 
reactions, illnesses with onset during the study, or exacerbation of pre-existing illnesses 
should be recorded. Objective test findings (e.g., electrocardiogram changes, abnormal 
laboratory test results) that result in a change in study drug dosage should also be 
recorded. 
Adverse events should be graded according to the NCI Common Terminology Criteria 
for Adverse Events Version 3 (CTCAE-3), which can be downloaded from 
http://ctep.cancer.gov.  Next it will be determined if the adverse event is related to the 
medical treatment (attribution). If so, it will be determined whether the adverse event is 
expected or unexpected. Using the guidelines outlined in Section 7.3.2-7.3.4. adverse 
events will then be reported to the NCI POB using a routine report (case report forms) 
or an expedited reporting mechanism using the FDA Medwatch form, available on the 
FDA website http://www.fda.gov/medwatch/safety/3500a.pdf in addition to the case 
report forms. 
The adverse event page will contain information if the reported event was expected or 
unexpected, and if the reported toxicity is included in the informed consent. A 
justification will be provided on the adverse event page if the observed toxicity in not 
included in the informed consent. For all adverse events, the investigator must pursue 
and obtain information adequate both to determine the outcome of the adverse event 
and to assess whether it meets the criteria for classification as a serious adverse event 
requiring immediate notification to the sponsor. Follow-up of the adverse event, even 
after the date of therapy discontinuation, is required if the adverse event or its sequelae 
persist. Follow-up is required until the event or its sequelae resolve or stabilize at a level 
acceptable to the investigator and sponsor.  
7.3.2 ADVERSE EVENT REPORTING 
All adverse events occurring during the study, whether or not attributed to study drug, 
observed by the investigator or reported by the subject, will be recorded on the case 
report form.  Medically significant adverse events considered related to the 
investigational product (pirfenidone) by the investigator will be followed until resolved 
or considered stable.  The following attributes must be assigned:  description; dates of 
onset and resolution; severity; assessment of relatedness to study drug, other suspect 
drug, or device; and action taken.   
The following adverse events require expedited reporting: 
• All adverse events that are both serious and unexpected  
• Adverse event that might influence the benefit-risk assessment of pirfenidone  
 
Expedited reports are to be submitted to the NCI POB using the FDA Medwatch form 
available on the FDA website http://www.fda.gov/medwatch/safety/3500a.pdf.  
 
A list of all known toxicities of pirfenidone can be found in the protocol document 
(Section 8.1.10).  
 
All adverse events requiring expedited reporting must be reported to: 


 4/6/2008 
 
 
 
 
 
 
 
 
 
46
Brigitte Widemann, M.D. 
Pediatric Oncology Branch 
Bldg. 10/Rm. 13NC103 
Phone: (301) 496-7387 
Pager: (301) 496-9310 
FAX: (301) 480-8871 
E-mail:  bw42y@nih.gov 
In addition, all adverse events, serious or not, which result in the subject’s permanent 
withdrawal from study drug or from the study should be reported to the study Dr. 
Brigitte Widemann. 
Reporting to the NCI IRB:  
The NCI PI is responsible for reporting to the NCI IRB events that occur in participants 
enrolled at all participating sites and that meet the requirements for expedited reporting 
within 7 days of notification of the adverse event.  
The protocol PI will report to the NCI-IRB: 
• All serious adverse events (SAEs)as defined in Section 7.3.1 for NCI patients that 
are not in the consent form, but are possibly, probably or definitely related to the 
research.  An SAE is defined as an untoward medical occurrence that: 
o resulted in a death; 
o was life-threatening; 
o required or prolonged hospitalization; 
o caused persistent or significant disability/incapacity; 
o resulted in congenital anomalies or birth defects; or 
o required intervention to prevent permanent impairment or death. 
• All other deaths not included in the SAE category above. Deaths that occur 
within 30 days of the last dose of pirfenidone. 
• All grade 3 and 4 (CTCAE) events that are not in the consent and that are 
possibly, probably or definitely related to the research, but not included in the 
SAE category above. 
Reports must be received by the NCI-IRB within 7 days of notification of the event. 
The study PI will forward these adverse event reports to the trial sponsor Dr. Babovic-
Vuksanovic, who will report these events to the FDA, and to the Medical Monitor, and 
to Dr. Roger Packer, who will report these events to the US Army IRB.   
The study PI (NCI, POB) will forward all reportable adverse events (as defined above) 
to the responsible investigators at participating sites. 
Additionally, any SAE reports from this study that are assessed as possibly related, 
probably related, or related to pirfenidone will be forwarded by the trial sponsor, Dr. 
Babovic-Vuksanovic, to the Drug Safety Risk Management Department at InterMune, 
Inc. (SAE@InterMune.com). 


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47
The investigator at participating institutions should notify their IRB of reportable 
serious adverse events occurring at the site and other adverse event reports received, in 
accordance with local procedures. 
7.3.3 ADVERSE EVENT REPORTING TO US ARMY  
This trial receives funding by a Grant of the U.S. Army. Per US Army request, adverse 
events will therefore also be reported by Dr. Roger Packer to the US Army as follows: 
All adverse events, which require expedited reporting (as defined in Section 7.3.2), and 
all unanticipated problems involving risk to subjects or others, serious adverse events 
related to participation in the study and subject deaths related to participation in the 
study 
should 
be 
promptly 
reported 
by 
phone 
(301-619-2165), 
by 
email 
(hsrrb@det.amedd.army.mil), or by facsimile (301-619-7803) to the USAMRMC, Office 
of Research Protections, Human Research Protection Office.  A complete written report 
will follow the initial notification.  In addition to the methods above, the complete 
report will be sent to the U.S. Army Medical Research and Materiel Command, ATTN: 
MCMR-ZB-PH, 504 Scott Street, Fort Detrick, Maryland 21702-5012.  
7.4 
MEDICAL MONITOR AND DATA SAFETY MONITORING BOARD (DSMB) 
Dr. Tracy Glauser, M.D., associate professor for pediatric neurology at the Cincinnati 
Children’s Hospital, will be medical monitor for this study. He is a qualified physician, 
other than the Principal Investigator, not associated with this particular protocol, and 
able to provide medical care to research subjects for conditions that may arise during 
the conduct of the study. He will monitor the subjects during the conduct of the study.  
He will review all adverse events, which require expedited reporting  (see Section 7.3.1) 
associated with the protocol and provide an unbiased written report of the event within 
10 calendar days of the initial report. The medical monitor is also required to review all 
unanticipated problems involving risk to subjects or others, serious adverse events and 
all subject deaths associated with the protocol and provide an unbiased written report 
of the event.  At a minimum, the medical monitor must comment on the outcomes of 
the event or problem and in case of a serious adverse event or death, comment on the 
relationship to participation in the study.  The medical monitor must also indicate 
whether he/she concurs with the details of the report provided by the principal 
investigator.  Reports for events determined by either the investigator or medical 
monitor to be possibly or definitely related to participation and reports of events 
resulting in death must be promptly forwarded to the USAMRMC ORP HRPO. 
Contact information for Dr. Tracy Glauser is as follows: 
Cincinnati Children’s Hospital 
Department of Neurology OSB-3 
3333 Burnett Avenue 
Cincinnati, OH 45229 
Phone: 513-559-4738 
Fax: 513-475-3980 
Dr. Roger Packer (cooperative group PI), Dr. Dusica Babovic-Vuksanovic (cooperative 
Group Co-PI and trial sponsor), Dr. Brigitte Widemann (trial coordinating center), Dr. 
Tracy 
Glauser 
(Medical 
Monitor), 
Dr. 
Kim 
Hunter-Schaedle 
(National 
Neurofibromatosis Foundation Clinical Trial Coordinator, and Mr. E Stern (Lawyer of 
the National Neurofibromatosis Foundation will form the DSMB. The 3 members 
directly associated with the study (Dr. Babovic-Vuksanovic, Dr. Packer, and Dr. 
Widemann) will serve as non-voting members. The members who are independent of 


 4/6/2008 
48
 
the study (Dr. Hunter-Schaedle, Dr. Glauser, Mr. Stern) will serve as voting members. 
The DSMB will review the study progress regularly. Patients entered on the trial and 
adverse events will be reviewed to ensure that the study is implemented as outlined in 
Section 3.0. A conference call will be held at least every 4 months. 
8.0 PHARMACEUTICAL INFORMATION PIRFENIDONE 
8.1 PIRFENIDONE  
8.1.1  CHEMICAL NAME: 5-methyl-1-phenyl-2-(1H)-pyridone 
8.1.2 CHEMICAL STRUCTURE: 
 
8.1.3  MOLECULAR WEIGHT:  185.2 
8.1.4  FORMULATION:  
Pirfenidone supplied by Solanan, Inc./Marnac, Inc.: 200 mg and 400 mg capsules.  
Pirfenidone supplied by InterMune, Inc.: 267 mg, size 1, white, opaque, hard 
gelatin capsules. 
8.1.5  STORAGE:  
For pirfenidone supplied by Solanan, Inc./Marnac Inc.: At room temperature. 
For pirfenidone supplied by InterMune, Inc.: Pirfenidone 267 mg capsules are 
packaged in 200 cc high-density polyethylene bottles (180 capsules per bottle) and 
sealed with a 38 mm child-resistant induction seal closure system. Drug should be 
stored at controlled room temperature between 15° and 30° C (59° to 86°F); it should 
neither be refrigerates nor frozen. 
8.1.6  STABILITY:  
For pirfenidone supplied by Solanan, Inc./Marnac Inc.: The crystalline pirfenidone 
powder, and gelatin capsules containing pirfenidone have remained stable when 
evaluated at elevated temperatures or stored for many months at room temperature. 
For pirfenidone supplied by InterMune, Inc.: 24 months at room temperature 
(27±2° C). The contents of pirfenidone 267-mg capsules is as follows: pirfenidone 267 
mg (82.15%), croscarmellose sodium 26.5 mg (8.15%), microcrystalline cellulose 24 
mg (7.38%), povidone 6 mg (1.85%), magnesium stearate 1.5 mg (0.46%). The total 
capsule weight is 325 mg. 
8.1.7  ROUTE OF ADMINISTRATION: Oral. The capsules may be opened and the 
content mixed with food if a patient is unable to swallow the intact capsule; 
however, the entire capsule content must be administered. 
8.1.8 Dose:  Pirfenidone will be administered orally as capsules with a meal three 
times daily (approximately every 8 hours). The pirfenidone dose level is 1500 


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49
mg/m2/day (500 mg/m2/dose) for 28-day cycles with no rest period between 
cycles.  
For pirfenidone supplied by Solanan, Inc./Marnac Inc., each of the three daily 
doses will be identical and rounded to the nearest 200 mg (see nomogram Section 
3.2.1). 
For pirfenidone supplied by InterMune, Inc., pirfenidone dosing will be rounded 
to the nearest 267 mg (see nomogram Section 3.2.2). 
8.1.9 DRUG INTERACTIONS: In vitro data suggest a low risk of drug interactions 
in patients, but the possibility cannot be ruled out of mild interactions with drugs 
that are extensively metabolized by CYP1A2, such as drugs including theophylline, 
caffeine, and (R)-warfarin. Care is advised when these drugs are co-administered 
with pirfenidone. 
8.1.10  KNOWN TOXICITIES:  
In laboratory animals exposed to very high or fatal doses of pirfenidone CNS 
side effects (ataxia, loss of skeletal tone, loss of righting reflex, reduction in 
respiratory rate and amplitude) were observed. Death was precipitated by acute 
respiratory failure. Carcinogenicity studies in rats and mice exposed to pirfenidone 
for 104 weeks found an increase in the incidence of uterine adenocarcinomas (in rats 
but not mice), hepatocellular adenomas (in rats and mice), and hepatocarcinomas 
and hepatoblastomas (in mice but not rats). No reports of liver or uterine tumors in 
patients participating in clinical trials with pirfenidone have been reported to date. 
In adult patients gastric disturbance, upper abdominal pain, abdominal 
distension, dyspepsia, nausea, vomiting, diarrhea, anorexia, gastroesophageal 
reflux, heartburn, elevation of gamma-GTP, photosensitivity, rash, palpitations, 
increased heart rate, dizziness, headache, fatigue, somnolence, and cold syndrome 
were observed. Lightheadedness and syncope with possible attribution to 
pirfenidone was observed in several adult patients with head and neck cancer on 
NCI protocol 01-C-0143. On this protocol patients received prifenidone concurrently 
with radiation therapy to the head and neck.  
In children with NF1 entered on the phase I trial of pirfenidone nausea, 
vomiting, diarrhea, abdominal pain, fatigue, and palpitations were observed. 
Possibly related to pirfenidone treatment, a decrease in the serum potassium level 
was observed in one patient, and a grand mal seizure was observed in another 
patient with preexisting stable optic and thalamic tumor (see Section 1.2.7 for 
detailed description of toxicities observed). One patient with a history of syncopes 
prior to initiation of treatment with pirfenidone experienced an increased frequency 
in syncopes during cycle #19 of treatment with pirfenidone. The frequency of 
syncopes did not decrease when pirfenidone was held for a 2 week period, and 
pirfenidone was restarted. It was felt to be unlikely that pirfenidone contributed to 
the frequency of syncopes.   
In 3 children entered on this ongoing phase II trial of pirfenidone for children 
with progressive plexiform neurofibromas and NF1, grade 2 behavioral changes 
including decreased attention, acting more defiant, immature, and impulsive were 
noted. These changes were felt to be unlikely related to pirfenidone, and 
discontinuation of pirfenidone for a period of 2 weeks did not result in changes in 


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50
behavior in 2 of these patients. Pirfenidone has been well tolerated as of 3/2008. The 
toxicity profile is similar to adults with nausea and vomiting as most frequent AEs. 
Other toxicities include fatigue, diarrhea, rash, dizziness. Dose limiting toxicities 
were observed in 2 patients (grade 3 nausea n=1, and grade 3 neutropenia n=1). 
8.2 DRUG ORDERS 
8.2.1 PIRFENIDONE SUPPLIED BY SOLANAN, INC./MARNAC INC. 
Questions about drug orders should be addressed to Solanan, Inc./Marnac Inc. (Ms. 
Judy Lexvold) by calling 214-692-8544 Monday through Friday between 8:30am and 
4:30pm Eastern Time. Participating sites can order an adequate starter supply of 
pirfenidone by contacting Solanan, Inc./Marnac Inc. (Ms. Judy Lexvold, phone: 214-
692-8544, fax: 214-692-8510). Solanan, Inc./Marnac Inc. will ship drug to the research 
pharmacist at the participating site. The research pharmacist/pharmacy of each 
institution will be responsible for drug labeling and dispensing to the patient, 
through the participating institution’s principal investigator or their designate.  
8.2.2 PIRFENIDONE SUPPLIED BY INTERMUNE, INC.  
Pirfenidone will be provided by InterMune Inc. Questions about drug orders should 
be addressed to InterMune, Inc. (Ms. Brenda Hamilton) by calling 415-466-4416 or e-
mailing bhamilton@intermune.com.  InterMune, Inc. will ship drug to the research 
pharmacist at the participating site. The research pharmacist/pharmacy of each 
institution will be responsible for drug labeling and dispensing to the patient, 
through the participating institution’s principal investigator or their designate.  
 


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51
10.0 REFERENCES 
 
Al-Took S, Murray C, Tulandi T.  Effects of Pirfenidone and dermoid cyst fluid on adhesion 
formation.  Fertility & Sterility 69:341-343, 1998. 
 
Atit RP, Crowe MJ, Greenhalgh DG, et al.  The Nf1 tumor suppressor regulates mouse skin 
wound healing, fibroblast proliferation, and collagen deposited by fibroblasts.  J Invest Dermatol 
112:835-842, 1999. 
 
Babovic-Vuksanovic D, Ballman K, et al. Phase II trial of pirfenidone in adults with 
neurofibromatosis type 1. Neurology 67:1860-1862, 2006. 
 
Babovic-Vuksanovic D, Knudwen BE, et al.  Effect of pirfenidone on human neurofibroma and 
schwannoma xenotransplants in scid mouse: animal model for neurofibromatosis.  The NNFF 
International Consortium for Molecular Biology of NF1 and NF2, Aspen, Colorado, June 4-7, 
2000. 
 
Babovic-Vuksanovic D, Petrovic L, et al. Survival of human neurofibroma in immunodeficient 
mice and initial results of therapy with pirfenidone. J Biomed Biotechnol 2004(2):79-85, 2004. 
 
Babovic-Vuksanovic D, Widemann B, et al. Phase I trial of pirfenidone in children with 
neurofibromatosis 1 and plexiform neurofibromas. Pediatr Neurol 36(5):293-300, 2007. 
 
Bowen JD, Maravilla K, margolin SB. Open-label study of pirfenidone in patients with 
progressive forms of multiple sclerosis. Mult Scler 9: 280-3, 2003. 
 
Cain WC, Stuart RW, Lefkowitz DL, et al.  Inhibition of tumor necrosis factor and subsequent 
endotoxin shock by pirfenidone.  International Journal of Immunopharmacology 20:685-695, 
1998. 
 
DeClue JE, Heffelfinger S, Benvenuto G, et al.  Epidermal growth factor receptor expression in 
neurofibromatosis type 1-related tumors and NF1 animal models.  J Clin Invest 105(9):1233-
1241, 2000. 
 
Dixon and Simon, J Clin Epidemiol 41:1209-1213, 1988. 
 
Donsanjh AK, Wan B, Throndset W, et al.  Pirfenidone: a novel antifibrotic agent with 
implications for the treatment of obliterative brochiolotis.  Transplantation Proceedings 30:1910-
1911, 1998. 
 
Estey E, Hoth D, Simon R, Marsoni S, Leyland-Jones B, Wittes R.Therapeutic Response in 
phase I trials of antineoplastic agents. Cancer Treat Rep 70: 11051115, 1986. 
 
Evans D, Baser M, McGaughran J, Sharif S, Howard E, Moran A. Malignant peripheral nerve 
sheath tumors in neurofibromatosis 1. J Med Genet 39: 311-314, 2002. 


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52
 
Gupta A, Cohen BH, Ruggieri P, Packer RJ, Phillips PC. Phase I study of thalidomide for the 
treatment of plexiform neurofibroma in neurofibromatosis 1. Neurology 60:130-132, 2003. 
 
Gurujeyalakshmi G, Hollinger MA, Giri SN.  Pirfenidone inhibits PDGF isoforms in bleomycin 
hamster model of lung fibrosis at the translational level.  American J Physiol 276:L311-318, 
1999. 
 
Huson SM, Harper PS, Compston DAS.  Von Recklinghausen neurofibromatosis.  A clinical dn 
population study in southeast Wales.  111:1355-1381, 1988. 
 
InterMune. Clinical Investigator’s Brochure, edition 3, April 2007, Brisbane, CA 
 
Iyer SN, Gurujeyalakshmi G, Giri SN.  Effects of pirfenidone on procollagen gene expression at 
the transcriptional level in bleomycin hamster model of lung fibrosis.  J Pharmacol & Exper 
Therapeutics 189:211-218, 1998. 
 
Iyer SN, Margolin SB, Hyde DM and Giri SN.  Lung fibrosis is ameliorated by Pirfenidone fed 
in diet after the second dose in a three-dose bleomycin-hamster model.  Exp Lung Res 24:119-
132, 1998. 
 
Iyer SN, Wild JS, Schiedt MJ et al.  Dietary intake of Pirfenidone ameliorates bleomycin-
induced lung fibrosis in hamsters.  J Lab Clin Med 125:779-785, 1995. 
 
Kadano T, Soma Y, Takehara K, et al.  The growth regulation of neurofibroma cells in 
neurofibromatosis type-1: increased responses to PDGF-BB and TGF-beta 1.  Biochem & 
Biophys Res Comm 198:827-834, 1994. 
 
Kaneko M, Inoue H, Nakazawa R, et al.  Pirfenidone induces intercellular adhesion molecula-1 
(ICAM-1) down-regulation on cultured human synovial fibroblasts.  Clin Exper Immunol 
113:72-76, 1998. 
 
Kehrer JP, Margolin SB. Pirfenidone diminishes cyclophosphamide-induced lung fibrosis in 
mice. Toxicology Letters  90:125-132, 1997. 
 
Kitano Y, Okamoto E, Saito K, Okano Y.  Effects of several growth factors oncultured 
neurofibroma cells.  Science 3:137-144, 1992. 
 
Konomi H, Arima M, Tanaka H, et al.  Increased deposition of types III and V collagens in 
neurofibroma tissue from patients with von Recklinghausen’s disease.  Brain Dev 11:378-382, 
1989. 
 
Korf BR.  Plexiform neurofibromas.  Am J Med Genet 89:31-37, 1999. 
 
Korf BR.  Malignancy in neurofibromatosis type 1.  The Oncologist 5:477-485, 2000. 
 


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Krishnan S, Goble J, et al. Inhibitory effect of pirfenidone on glioblastoma cell lines: 
implications for treatment of neurofibromatosis. J Appl Res 7(1):58-68, 2007. 
 
Lee BS Margolin SB, Nowak RA. Pirfenidone: a novel pharmacological agent that inhibits 
leiomyoma cell proliferation and collagen production. J Clin Endocr Metab 83:219-223, 1998.. 
 
Lefkowitz S and Margolin SB. Pirfenidone inhibition of formation of collagen by human lung 
fibroblasts (W138) in cell cultures. School of Medicine, Texas Tech University, Lubbock, Texas, 
1993. 
 
Lindor NM, Dozois R, Nelson H, Wolff B, King J, Boardman L, Wilson M, Greene MH, Karnes 
W, Mesa R, Welch T, Edmonson J, Limburg P. The American Journal of Gastroenterology 
98:1868-1874, 2003. 
 
Margolin SB.  Investigational new drug brochrue for Pirfenidone, Marnac Inc., Dallas, Texas, 
2001. 
 
Needle MN, Cnaan A, Dattilo J, et al.  Prognostic signs in the surgical management of plexiform 
neurofibroma: The Children’s Hospital of Philadelphia experience, 1974-1994.  J Pediatr 131(5): 
678-682, 1997. 
 
Okada Y.  Investigational Study of Clinical Indications for Pirfenisone Ointment, Report from 
Japan on Human Topical Dermal Trials, 1993. 
 
Peltonen J, Martala T, Vihersaari T, Renvall S, Pentinnen R.  collagen synthesis in cells cultured 
from v.Recklinghausen’s neurofibromatosis.  Acta Neuropathol 55:183-187, 1985. 
 
Raghu G, Johnson WC, Lockhart D, Mageto Y.  Treatment of idiopathic pulmnary fibrosis with 
a new antifibrotic agent, pirfenidone: results of a prospective, open-label Phase II study.  Am J 
Respir & Crit Care Med 159:1061-1069, 1999. 
 
Rasmussen SA, Yang Q, Friedman JM.  Mortality in neurofibromatosis 1: an analysis using U.S. 
death certificates.  Am J Hum Genet 69:1110-1118, 2001. 
 
Sasaki T, Arai K, Nagai Y.  Growth and collagen synthesis of cultured neurofibroma fibroblasts. 
J Dermatol 19:598-601, 1992. 
 
Schelegle ES, Mansoor JD, Giri S.. Pirfenidone attenuates bleomycin-induced changes in 
pulmonary function in hamsters. Proceedings of the Society for Experimental Biology and 
Medicine 1997; 216:392-397, 1997. 
 
Shetlar MR, Shetlar CL. Effect of antifibrosis drug on the survival of keloid transplants in 
athymic mice. FASEB  9:A967, 1995. 
 
Shetlar MR, Shetlar DJ, et al. Involution of keloid implants in athymic mice treated with 
pirfenidone or with triamcinolone. J Lab Clin Med 132(6):491-496, 1998. 


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Shimizu F, et al. Pirfenidone prevents the progression of irreversible glomerular sclerotic lesions. 
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Shimizu T, Furugawa M, Kuroda T, Hata S, Iwasaki Y, Nemoto M, Shirai K, Yamauchi S, 
Margolin SB, Shimzu F, Kurokawa K. Pirfenidone prevents collagen accumulation in the 
remnant kidney in rats with partial nephrectomy. Kidney International 63:S239-243, 1997 
 
Shimizu T, et al.  Pirfenidone improves renal function and fibrosis in the post-obstructed kidney.  
Kidney International 54:99-109, 1998. 
 
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Institutes of Health Consensus Development Conference.  Arch Neurol 45:575-578, 1988. 
 
Suga H, Teraoka S, Ota K, et al.  Preventive effect of Pirfenidone against experimental 
sclerosing peritonitis in rats.  Experimental and Tox Path 47:287-291, 1995. 
 
Teraoka S et al. Preventive effect of oral Pirfenidone against experimental liver  
cirrhosis in rats. L994. Investigational new drug brochure “Pirfenidone”, Marnac, Inc. Dallas, 
Texas, 1996. 
 
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Glabbeke M, van Oosterom A, Christian M, Gwyther S. New guidelines to evaluate the response 
to treatment in solid tumors. J NCI 92: 205-216, 2000. 
 
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epithelial cells.  Austr N Zealand J Ophth 26(suppl1):S74-76, 1998. 
 


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11.0 
APPENDICES 
APPENDIX 1:  ELIGIBILITY CHECKLIST FOR PIRFENIDONE PHASE II PROTOCOL  
Patient initials and ID number: 
  
Date of birth:  
Race: 
 
Gender:  
Patient measurements: 
(Average of 3 measurements): 
Weight (kg):  
Height (cm):  
BSA (m2):  
Institution:  
Physician:  
NF1 diagnostic criteria: 
Plexiform 
neurofibroma: 
 
≥6 Café-au-lait spots:  
 
Freckling:  
Optic glioma:  
 ≥ 2 Lisch nodules:  
Bony dysplasia:  
 
1st degree relative with NF1:  
Disease progression by either 3-D (≥20%), 2-D (≥ 13%), or 1-D (≥6%) measurements:  
≥20% increase in tumor volume: %:  
≥ 13% increase in product of 
two longest perpendicular 
diameters: 
 
%:
 
Progressive Plexiform  
Neurofibroma Over  
Prior Two Scans: 
≥6% increase in longest 
diameter: 
%:  
 
Date of scans: 1.  
2.  
 
Tumor Measurements: cm:  
cm:  
 
Inoperable: Yes:  
No:  
 
Lesion of at least 3 cm in 1D: Yes:  
No:  
 
Measurable: Yes:  
No:  
 
Potential for morbidity: Yes:  
No:  
 Location: 
 
 
 
 
Recovered from tox. of prior Rx: 
Yes:  
No:  
 
Date of last dose of (NA if none): 
Radiation:  
Chemo: GCSF: 
 
Performance score: 
 Life expectancy ≥12 mo: 
Yes:  
No:  
Hematologic parameters: 
ANC: 
 
Hgb: 
 
Plt: 
 
Liver function tests: 
SGPT:  
ULN:  
Bili:  
ULN:  
Renal function: Creat: 
 Normal range: 
 Or  Creat clear.: 
 
Signed informed consent: 
Yes:  
Date:  
No:  
Pregnant or breast feeding: 
Yes:  
No:  
Pregnancy test date: 
Other significant illnesses: 
Yes: 
 
No: 
 
Prior pirfenidone: 
Yes: 
 
Investigational agent last 30 days: 
Yes:  
No:  
 
 No: 
 
Active MPNST or other cancer: 
Yes:  
No:  
 
Ongoing XRT, chemo, GCSF, 
hormonal, immuno, biological Rx: 
 
Yes: 
 
 
No: 
 
 
Agrees to return for follow-up: 
Yes:  
No:  
 
Able to take oral medication: 
Yes:  
No:  
 
Willing to practice birth control: 
Yes:  
No:  
N/A:  
Able to undergo MRI and no 
contraindication:  
Yes: 
 
No: 
 
 
 
Name of person completing form:  
Signature/Date: 
 


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APPENDIX 2: PERFORMANCE STATUS SCALES/SCORES  
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Sco
re 
Description 
Scor
e 
Description 
Sco
re 
Description 
100 
Normal, no complaints, 
no evidence of disease 
100 
Fully active, normal. 
0 
Fully active, able to 
carry on all pre-disease 
performance without 
restriction. 
90 
Able to carry on 
normal activity, minor 
signs or symptoms of 
disease. 
90 
Minor restrictions in 
physically strenuous 
activity. 
80 
Normal activity with 
effort; some signs or 
symptoms of disease. 
80 
Active, but tires more 
quickly 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to 
carry out work of a 
light or sedentary 
nature, e.g., light 
housework, office 
work. 
70 
Cares for self, unable 
to carry on normal 
activity or do active 
work. 
70 
Both greater restriction 
of and less time spent in 
play activity. 
60 
Required occasional 
assistance, but is able 
to care for most of 
his/her needs. 
60 
Up and around, but 
minimal active play; 
keeps busy with quieter 
activities. 
2 
Ambulatory and 
capable of all self-care 
but unable to carry out 
any work activities.  Up 
and about more than 
50% of waking hours 
50 
Requires considerable 
assistance and frequent 
medical care. 
50 
Gets dressed, but lies 
around much of the day; 
no active play, able to 
participate in all quiet 
play and activities. 
40 
Disabled, requires 
special care and 
assistance. 
40 
Mostly in bed; 
participates in quiet 
activities. 
3 
Capable of only limited 
self-care, confined to 
bed or chair more than 
50% of waking hours.  
30 
Severely disabled, 
hospitalization 
indicated.  Death not 
imminent. 
30 
In bed; needs assistance 
even for quiet play. 
20 
Very sick, 
hospitalization 
indicated.  Death not 
imminent. 
20 
Often sleeping; play 
entirely limited to very 
passive activities. 
4 
Completely disabled.  
Cannot carry on any 
self-care. Totally  
confined to bed or 
chair. 
10 
Moribund, fatal 
processes progressing 
rapidly. 
10 
No play; does not get out 
of bed. 
*The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes 
only. 


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57
 
APPENDIX 3: REQUIRED STUDY EVALUATIONS PRIOR TO STARTING TREATMENT, DURING, AND POST TREATMENT WITH 
PIRFENIDONE 
 
Observation 
Pretreatment 
 
Pre Cycles 
2, 3, 4, 7 
Pre Cycle 10, and 
then  after every six 
cycles 
Post Study 
History & physical exam 
X 
X 
after every 3 cycles 
X 
Performance status 
X 
If changed 
If changed 
X 
Body surface area 
X 
X 
after every 3 cycles 
 
CBC, platelets, differential∗ 
X 
X 
X 
X 
Electrolytes, creatinine, BUN  
X 
X 
X 
X 
Glucose, Ca+2, Mg+2, PO4
∗ 
X 
X 
X 
X 
SGOT, SGPT, gamma-GTP,  
AP, bilirubin 
X 
X 
X 
X 
Urine pregnancy test 
Females  
 
 
 
3D-MRI of index lesions 
X 
Cycles 4 & 7 
only 
X 
X 
QOL assessment 
X 
Cycles 4 & 7 
only 
X 
X 
Review of Patient Diariest: 
 
X 
after every 3 cycles 
X 
∗Each blood draw for hematology and chemistries will require a maximum of 10 cc blood. 
t Review of patient diaries to include compliance and toxicity monitoring. 
 


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58
APPENDIX 4:  PROTOCOL FOR REQUIRED PRE STUDY AND ON STUDY MRI STUDIES 
Prior to starting treatment on this study all known measurable plexiform neurofibromas should 
be imaged with MRI to obtain a baseline.  Tumor extent in patients with NF1 can be very extensive, 
and may not allow for all lesions to be followed using 3-D MRI.  
The goal will therefore be to use 3-D MRI only to follow the progressing plexiform 
neurofibroma(s) (a maximum of three lesions), which will be defined as index lesion(s).  
Pre-study radiographic evaluation: 
• Identify and select the progressive plexiform neurofibroma(s) (a maximum of three lesions) for 3-
D MRI evaluation based on prior imaging studies. Should there be more than 3 progressing 
plexiform neurofibromas, the three most clinically relevant plexiform neurofibromas will be 
followed by 3-D MRI analysis. 
• Perform 3-D MRI sequences on the selected index lesions as outlined in the MRI acquisition 
protocols below.  
• In addition, if possible, perform MRI of all additional measurable plexiform neurofibroma(s). 
On study radiographic evaluation: 
Unless clinically indicated otherwise obtain MRI of the index lesions only as outlined in the MRI 
acquisition protocol below prior to cycles 4, 7, 10, and then after every 6 cycles while on study. 
MRI protocols: 
Depending on the location of the index lesions the Spine, Head/Neck or Trunk/Extremities protocols 
outlined on the following pages will be used.  
The measurement of very irregular or infiltrative neurofibromas will present major challenges, and in 
some cases, it may be difficult to precisely define tumor margins.  If necessary, participating 
institutions may modify the MRI sequences to optimize differentiation of tumor and surrounding 
tissue. Modifications should be documented in the MRI protocols, and the same imaging protocol, 
and, if possible, the same MRI scanner, should be used for all subsequent MRI studies. 
Every attempt should be made to image the entire progressive plexiform neurofibroma(s).  
A written protocol for scanning each patient has to be established at the time of study entry to allow 
for reproducibility of follow-up studies.  
All MRI studies requested per protocol will be submitted to the NCI POB within 2 weeks of 
acquisition for volume analysis. At the same time, a copy of the MRI protocol used to obtain the MRI 
study will be sent to the NCI POB, or faxed to Ms. Anne Goodwin or Ms. Wendy Goodspeed (301-
480-8871). 


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59
MRI Protocol- Spine 
 
PATIENT ID NUMBER: _________ 
Note: Only the series outlined below are required for volumetric analysis of plexiform neurofibromas and must be 
performed within protocol specifications as indicated below.  Additional series may be obtained as indicated per 
institutional PI.   
 
1. AXIAL FSEIR 
Axial FSEIR 
Protocol 
Specifications 
Actual 
Specifications 
Reason For Change 
Echo Train Length 
5 
 
 
TR 
6000 
 
 
TE 
34 
 
 
TI 
150 
 
 
Slice Thickness 
5 mm 
 
 
Skip 
0 
 
 
Matrix 
256x256 
 
 
FOV 
22 cm 
 
 
NEX 
1 
 
 
Frequency Direction 
R→L 
 
 
Options 
Tailored RF, FC, PC, 0.75 FOV 
2. CORONAL FSEIR 
Coronal FSEIR 
Protocol 
Specifications 
Actual 
Specifications 
Reason For Change 
Echo Train Length 
5 
 
 
TR 
6000 
 
 
TE 
34 
 
 
TI 
150 
 
 
Slice Thickness 
5 mm 
 
 
Skip 
0 
 
 
Matrix 
256x256 
 
 
FOV 
22 cm 
 
 
NEX 
1 
 
 
Frequency Direction 
S→I 
 
 
Options 
Tailored RF, FC, PC 
 
 
 
Date:_________Signature (responsible MRI technician):_____________________________ 
Fax completed form to: Ms. Anne Goodwin at: 301-480-8871 (phone: 301-594-4762) 


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MRI Protocol- Head/Neck 
 
PATIENT ID NUMBER: _________ 
Note: Only the series outlined below are required for volumetric analysis of plexiform neurofibromas and must be 
performed within protocol specifications as indicated below.  Additional series may be obtained as indicated per 
institutional PI. 
 
1. AXIAL FSEIR 
Axial FSEIR 
Protocol 
Specifications 
Actual 
Specifications 
Reason For Change 
Echo Train Length 
5 
 
 
TR 
6000 
 
 
TE 
34 
 
 
TI 
150 
 
 
Slice Thickness 
4 mm 
 
 
Skip 
0 
 
 
Matrix 
256x256 
 
 
FOV 
22 cm 
 
 
NEX 
1 
 
 
Frequency Direction 
A→P 
 
 
Options 
Tailored RF, FC, 0.75 FOV 
2. CORONAL FSEIR  
Coronal FSEIR 
Protocol 
Specifications 
Actual 
Specifications 
Reason For Change 
Echo Train Length 
5 
 
 
TR 
6000 
 
 
TE 
34 
 
 
TI 
150 
 
 
Slice Thickness 
5 mm 
 
 
Skip 
0 mm 
 
 
Matrix 
256x192 
 
 
FOV 
22 cm 
 
 
NEX 
1 
 
 
Frequency Direction 
S→I 
 
 
Options 
Tailored RF, PC 
 
Date:_________Signature (responsible MRI technician):_____________________________ 
 
Fax completed form to: Ms. Anne Goodwin at: 301-480-8871 (phone: 301-594-4762) 


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61
MRI Protocol-Trunk/Extremities 
 
PATIENT ID NUMBER: _________ 
Note: Only the series outlined below are required for volumetric analysis of plexiform neurofibromas and must be 
performed within protocol specifications as indicated below.  Additional series may be obtained as indicated per 
institutional PI. 
 
1. AXIAL PLANE-STIR 
Axial Plane STIR 
Protocol 
Specifications 
Actual 
Specifications 
Reason For Change 
Coil: Body 
 
 
 
Sequence:  Fast Spin Echo (Turbo) FSEIR 
 
 
Echo Train Length 
5 
 
 
TR 
6000 
 
 
TE 
15 
 
 
TI 
150 
 
 
Slice Thickness 
10 mm 
 
 
Skip 
0 
 
 
Matrix 
512x160 
 
 
FOV 
40x30 
 
 
No. of Excitations/ 
Sequence 
0.5 
 
 
No. of Acquisitions 
1 
 
 
Saturation 
None 
 
 
2. CORONAL PLANE STIR  
Coronal Plane STIR 
Protocol 
Specifications 
Actual 
Specifications 
Reason For Change 
Coil:  Body 
 
 
 
Sequence:  Fast Spin Echo (Turbo) FSEIR 
 
 
Echo Train Length 
5 
 
 
TR 
3400 
 
 
TE 
15 
 
 
TI 
150 
 
 
Slice Thickness 
5 mm 
 
 
Skip 
0 
 
 
Matrix 
512x160 
 
 
FOV 
48x48 
 
 
No. of Excitations/ 
Sequence 
1 
 
 
No. of Acquisitions 
1 
 
 
Saturation 
None 
 
 
 
Date:_________Signature (responsible MRI technician):_____________________________ 
Fax completed form to: Ms. Anne Goodwin at: 301-480-8871 (phone: 301-594-4762) 


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62
Data Analysis:  
• All MRI data will be analyzed at the Pediatric Oncology Branch of the NCI under guidance of 
Dr. Nicholas Patronas (head neuroradiologist).  After review of the MRI studies with Dr. 
Patronas to define tumor containing areas, the MRI data from each scan will be processed to 
assess the volume of the index plexiform neurofibroma(s). The tumor will be traced on 
subsequent contiguous MR slices, the numbers summed and then multiplied by the slice 
thickness to obtain a numerical volume measurement.  The tumor will be identified by high 
signal on the STIR images not corresponding to known normal anatomic structures and 
corresponding with the course of known nerves. Each patient’s volumetric measurement 
obtained from the initial MRI will serve as the baseline against which to assess incremental 
changes in volume that occur during the subsequent intervals.  Volumetric measurements and 
1-D , and 2-D data analysis will be done by 3 physicians trained in 1-D, 2-D, and 3-D MRI data 
analysis at the Pediatric Oncology Branch, NCI at an Image Review Workstation using MEDx 
software (Sensor Systems Inc.). Volumetric measurements will be used to determine disease 
progression as outlined in Sections 1.2.2, 3.1.2, and 3.1.3.  The Principal Investigator will 
inform the Participating Investigators about the results of the MRI study by written report. 
• The results of volumetric MRI measurements will be compared with 1-D and 2-D MRI 
measurements, the physical examination, and the study subject’s subjective impression 
following clinical variables.  
Image And Data Acquisition: 
In order to perform quantitative analysis the Pediatric Oncology Branch must receive the 
imaging data from the investigator sites. All MRI studies requested per protocol will be submitted to 
the NCI POB within 2 weeks of acquisition for volume analysis. At the same time, a copy of the MRI 
protocol used to obtain the MRI study will be sent to the NCI POB, or faxed to Ms. Anne Goodwin or 
Ms. Wendy Goodspeed. 
Arrangements for distribution of images from all participating institutions to the POB, NCI will 
be made by InSite One. 
InSite One will: 
• Contact participating institutions to determine the best mode of electronic data transfer 
• Prepare each site for electronic data transfer via network access device, File Transfer Protocol 
(ftp), optical disk or modem depending on the investigator site. 
• Provide training and technical support for each site 
• Ensure complete, secure and timely data transfer to the POB, NCI. 
The Pediatric Oncology Branch will check all materials received for completeness and will notify 
the site if data, images, or information are missing or incomplete.   


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63
APPENDIX 5: PATHOLOGY ANALYSIS OF PLEXIFORM NEUROFIBROMAS 
Pathological analysis of plexiform neurofibromas: 
The plexiform neurofibroma analysis component consists of three parts: (1) the central diagnostic 
neuropathology review with accompanying light- and electron-microscopic effort to identify the 
actual cell populations comprising the tumor, (2) immunohistochemical and FISH analysis of tumor 
specimens, and (3) mRNA gene expression profiling.  All tissues received from surgical biopsies 
and/or resections will be reviewed by Dr. Arie Perry. 
With this combined approach, the range of cellular constituents and their neoplastic properties will 
be carefully documented in plexiform neurofibromas.  Along with related assays being developed 
(see below), we will provide a better understanding of histogenesis, growth potential, and malignant 
transformation of these tumors, thus facilitating a rational approach for guiding patient management. 
Contribution of Tumor Specimens to a Central Tumor Repository: 
All tumor samples not required for routine clinical analysis obtained on this study will be sent to the 
tissue procurement facility. 
Tissue Acquisition:  To assist in the collection of tissue specimens, the project’s Tissue Procurement 
Facility will provide submitting centers with a complete specimen shipping kit after notification by 
the Pediatric Oncology Branch.  This kit will be sent to the submitting institution several days before 
the planned tissue resection.  The kit will contain all materials and instructions for the proper 
collection and shipping of specimens to the Tissue Procurement Facility.  
Tissue shipment:  All patient specimens and a copy of the patient consent will be sent by overnight 
express courier to Dr. Mark Watson at the Tissue Procurement Facility.  After performing the local 
institutional evaluation and issuing a pathology report, a copy of the pathology report, and all 
paraffin blocks should be sent to the tissue procurement facility.  If submission of all paraffin blocks 
is not possible or prohibited by participating pathology departments, 5 unstained slides from each 
block will be sent instead.  These slides will then be stained and reviewed by Dr. Perry, who will then 
select 1 or 2 appropriate blocks to be sent for further study.  Blocks will be returned to the submitting 
institutions upon completion of studies or within 24 hours of written request by the submitting 
institution. 
Upon entry to the Tissue Procurement Facility, all specimens will be coded and recorded in the 
facility database.  The Tissue Procurement Facility will forward appropriate coded specimens to Dr. 
Perry for centralized pathology review and other studies described above, and to Dr. Tobey 
MacDonald (gene expression analysis) for investigations related to the protocol.  The remainder of 
the specimens (including paraffin blocks) will be stored by the Tissue Procurement Facility until 
needed for future research studies or recall by the submitting institution. Any future research done 
with these samples will be conducted under a protocol approved by the Institutional Review Board 
with oversight of the tissue bank. Study participants will not receive further notice of future uses of samples, 
unless a future use could involve more than minimal risk to the study participant. All research results will be 
kept confidential. Biospecimens will be stored until they have been exhausted by use in IRB-approved research 
studies, or until the patient elects to withdraw their consent, at which time the biospecimens will be destroyed.  
The exception to this is paraffin embedded tissue blocks, which are regarded as diagnostic material.  In these 
cases, upon patient withdrawal or on request by the submitting institution, specimens will be returned to the 
medical center from which they were collected. Figure 1 diagrams the proposed flow of information and 
specimens, the coding scheme, and the residence of each data set.  This is a coded, double-broker 
model designed to maintain patient confidentiality while making meaningful research studies 
possible.  All tumor samples remain linked to the patient data by the study number.  Only the 
coordinating Center (POB) will have access to the clinical data.  Communication between the central 
tissue repository and the POB will use the patient study number.  Communication between research 
laboratories and the tissue bank will use the 
specimen code number.   


 4/6/2008 
 
 
 
 
 
 
 
 
64
Figure 1: Proposed Scheme for Specimen and data exchange, and specimen and data encoding 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trial coordinating 
Center: POB, NCI 
Patient Identifiers 
Clinical Data 
Study Number 
Participating Institution 
Diagnostic block 
Pathology report 
Patient consent 
Tumor specimens 
Neuropath Review and 
Database (Dr. Perry, Dr. 
Gutmann) 
Coded specimens 
Anonymized institutional path 
data 
Communication and data linkage by study number 
Communication and 
data linkage by 
specimen code 
number 
Communicatio
n and data 
linkage by 
specimen code 
number 
Tissue Procurement and Specimen 
Bank 
Delete identifiers 
Maintain study number 
Code specimens 
Anonymize institutional pathdata 
RNA Extraction 
  Ship RNA to: 
   Dr. Tobey Macdonald 
   Children’s National Medical 
Center 
Research Laboratory 
Coded specimens for IRB 
approved research questions 
Communication and data 
linkage by specimen code 
number 


 4/6/2008 
 
 
 
 
 
 
 
 
 
65
APPENDIX 5A: INSTRUCTIONS FOR TISSUE ACQUISITION OF DISCRETE AND PLEXIFORM 
NEUROFIBROMAS 
Five to seven days prior to the planned tumor biopsy please notify Ms Anne Goodwin 
or Ms. Wendy Goodspeed at the POB, NCI, about the planned biopsy: Phone: 301-594-
4762, Fax: 301-480-8871, e-mail: gillesan@mail.nih.gov.  To assist in the collection of 
tissue specimens, a specimen shipment kit will be sent to participating institutions: 
• The project’s Tissue Procurement Facility will provide submitting centers with a 
specimen shipping kit for shipment of tumor samples.  The kit will contain all 
materials and instructions for the proper collection and shipping of specimens to 
the Tissue Procurement Facility.   
Steps for tissue collection are as follows: 
1. To enable future molecular and biochemical analyses with the specimen, the 
participating institutional pathologist must receive the tumor tissue fresh, rather 
than “fixed in formalin”.  After resection, the tissue should be transported from the 
O.R. to the pathologist within 30 minutes.  The specimen must not be placed in 
formalin, but may be placed in normal saline, Ringer’s solution, or any other 
physiologic buffer solution. 
2. A representative and sufficiently large piece of the specimen should be fixed in 
formalin for paraffin processing as per the institution’s standard policies and 
procedure. Pathologists will be instructed to thoroughly sample the surgical 
specimen (at least one block per centimeter in greatest dimension).  This material 
will be used to make the clinical diagnosis and, later, sent for central pathology 
review. 
3. If tissue remains, an additional piece of tissue 0.5-1 cm3 in size will be snap frozen in 
liquid nitrogen or a –50oC histological bath.  This material will be shipped to the 
Tissue Procurement Facility on dry ice for future molecular and genetic research 
studies. 
4. If tissue still remains, 2-4 2 mm fragments, preferably from various sites 
representing a spectrum of gross appearances, will be placed in the provided 
gluteraldehyde container.  These specimens will be used for electron microscopy 
studies. 
5. If tissue still remains, another representative specimen will be placed in the 
provided formaldehyde container.  This specimen will be embedded at the Tissue 
Procurement Facility and used in the event that the submitting institution’s 
specimen block is not available. 
6. If tissue still remains, the remainder of the specimen will be divided into 1 cm3 
segments and snap frozen as described in (3). 
Shipments should not be sent on Fridays or on the day preceeding a holiday. 
At the time of resection, tissue should be IMMEDIATELY transported from the 
operating room to the attending surgical pathologist.  Material should be handled as 
outlined in the instructions, which will be provided with the kit. 


 4/6/2008 
 
 
 
 
 
 
 
 
 
66
Tumor specimens (snap frozen tissue, tissue in glutaraldehyde, and formaldehyde 
container) should be placed in the specimen kit provided by the Tissue Procurement 
Facility, and shipped on dry ice to:  
M. Watson, M.D., Ph.D. 
Division of Laboratory Medicine / Box 8118 
Alvin J. Siteman Cancer Center / Box 8100 
Washington University School of Medicine 
660 S. Euclid Avenue, St. Louis, MO 63110 
Phone: (314)-454-7919, Fax: (314)-454-5525 
Snap frozen tissue has to be maintained in the cryobath or a –70 degree freezer until it is 
ready for shipment.  It is very important that: (1) Tissue be frozen as soon as possible 
after resection; (2) Tissue be frozen rapidly; and (3) Tissue be maintained at or below –
50 degrees until shipment. 
Please notify Dr. Watson prior to shipment, and contact him with any questions you 
may have regarding these samples. 
 


 4/6/2008 
 
 
 
 
 
 
 
 
 
67
APPENDIX 6: PATIENT DIARY FOR PIRFENIDONE PHASE II 
 
Patient ID number:  
 
Dose: 
  
Cycle Number:    Cycle Start Date: 
  
Date → 
 
 
 
 
 
 
 
Dose: 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
Time pirfenidone dose taken → 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of capsules taken* → 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Indicate reason for missed doses → 
 
 
 
 
 
 
 
SIDE EFFECTS 
 
 
 
 
 
 
 
Nausea (see scale below)† → 
 
 
 
 
 
 
 
Vomiting (# of times in 24 hr) → 
 
 
 
 
 
 
 
Diarrhea (# of times in 24 hr)  → 
 
 
 
 
 
 
 
Skin rash  → 
 
 
 
 
 
 
 
OTHER SIDE EFFECTS (list below) 
 
 
 
 
 
 
 
→ 
 
 
 
 
 
 
 
→ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OTHER MEDICATIONS (Name) 
Dose 
Frequency 
Start Date 
Stop Date 
Reason for Use of Medication 
 
 
 
 
 
 
 
 
 
 
 
 
* For each dose write down number of capsules taken. If you miss a dose write “M” in the box. 
† 
Rate nausea mild if you are able to eat and drink a reasonable amount, moderate if you can eat and drink but the amount is substantially 
decreased, or severe if you are unable to eat and drink. 
  
 
 
 
 
 
 
 
 
Physicians should fax completed form to Ms Anne Goodwin at 301-480-8871, call with questions: 301-594-4762 Parent/patient initials:_______ 


 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE: 
National Cancer Institute 
 
 
STUDY NUMBER: 
04-C-0080 
PRINCIPAL INVESTIGATOR:  Brigitte Widemann, M.D. 
 
 
STUDY TITLE: 
Phase II Trial of Pirfenidone in Children, Adolescents, and Young Adults with Neurofibromatosis 
Type 1 and Progressive Plexiform Neurofibromas 
 
 
Continuing Review Approved by the IRB on 06/25/07 
Amendment Approved by the IRB on 04/17/08 (D) 
 
 
 
Date Posted to Web: 04/29/08 
Standard 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (4-97) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
 
First, we want you to know that: 
 
Taking part in NIH research is entirely voluntary. 
 
 
You may choose not to take part, or you may withdraw from the study at any time.  In either case, you will not 
lose any benefits to which you are otherwise entitled.  However, to receive care at the NIH, you must be taking 
part in a study or be under evaluation for study participation. 
 
 
You may receive no benefit from taking part.  The research may give us knowledge that may help people in the 
future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments 
they would want to receive (such as blood transfusions).  If you have such beliefs, please discuss them with your NIH 
doctors or research team before you agree to the study. 
 
Now we will describe this research study.  Before you decide to take part, please take as much time as you need to ask 
any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other 
health professional. If you are signing for a minor child, “you” refers to “your child” throughout the consent document. 
 
You have neurofibromatosis type I (also called NF1). The underlying cause of NF1 is a defective gene.  Genes carry the 
information for the body composition and characteristics.  For example, genes determine the color of the eyes. In NF1 
the defective gene is neurofibromin. The defect in the neurofibromin gene can result in formation of several types of 
tumors including neurofibromas (tumors involving a nerve) or plexiform neurofibroma(s) (tumors involving a nerve and 
the branches of that nerve). You have one or more plexiform neurofibroma(s) that appear(s) to be increasing in size over 
the past year and has/have the potential to cause serious medical problems. 
 
The only known effective treatment for plexiform neurofibromas is surgery, but many times complete surgical removal of 
all of the plexiform neurofibromas is not possible, because of the number or location of the tumors.  There are no 
medical treatments, which are known to be effective for patients with NF1 and plexiform neurofibromas. 
 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
04-C-0080 
CONTINUATION:  page  2  of  8  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
A new experimental drug called pirfenidone, has been found to be effective in treating a variety of fibrosing (scarring) 
conditions, and this drug targets the same growth factors that are also present in plexiform neurofibromas.  Pirfenidone 
may therefore provide a means of controlling tumors in patients with NF1. In preliminary studies in adults with a variety 
of diseases pirfenidone has been well tolerated and can be given by mouth.  Pirfenidone is currently undergoing testing in 
adults and a small number of children with NF1 and plexiform neurofibromas. 
 
We do not know if this drug will be effective in your plexiform neurofibroma(s). Pirfenidone is not approved by the Food 
and Drug Administration (FDA) for commercial use, but the FDA has permitted its use in this research study. 
 
DESCRIPTION OF RESEARCH STUDY 
The main purposes of this research study are (1) to determine if pirfenidone can slow down the growth rate of plexiform 
neurofibromas in patients with NF1, (2) to determine if pirfenidone can result in shrinkage of progressive plexiform 
neurofibromas, and (3) to determine the types of side effects that can be produced by pirfenidone in children and young 
adults with NF1.  
 
We will follow you closely throughout the study for signs of increase of the plexiform neurofibroma by regular physical 
examinations, laboratory tests, and MRI scans, as described in more detail below. Should the tumor be stable or decrease 
in size, you will continue to receive the pirfenidone for as long as it is well tolerated. You will be removed from the study 
if growth of the plexiform neurofibroma is noted based on the MRI scan. At that time we will perform a thorough clinical 
evaluation, in addition to a MRI study, and arrange for necessary follow-up care by your physician. Other reasons for 
removal from the protocol could be if you did not tolerate pirfenidone because of side effects of the drug, if you 
developed another serious medical condition, which would not allow the administration of pirfenidone, or if you were 
unable to complete the physical exams, blood work, and scans requested as part of the protocol. 
 
All patients on the study will receive pirfenidone orally (by mouth) as capsules with meals three times a day 
(approximately every 8 hours) for cycles of 28 days with no rest period. During the first week of the first treatment cycle 
you will receive pirfenidone at a lower dose, as it may help preventing you from getting nauseated. After the first week of 
treatment at a reduced dose, you will receive pirfenidone at the full dose. Capsules can be opened and the content mixed 
with food for easier intake in young children. Pirfenidone will be given at a similar dose to the dose which showed activity 
in adults with conditions other than NF1. This dose has been well tolerated by children with NF1. The daily dose will be 
1500 mg/m2 body surface area, which is calculated from your height and weight. 
 
Approximately 36 patients will be entered on this clinical trial. 
 
We will provide you with a form on which you will record the time each dose is taken, any side effects that you 
experience, and any other medications that you are taking. This diary is an important part of our monitoring of this 
experimental drug. 
 
You will not be able to receive other chemotherapy, radiation therapy, immunotherapy, biologic therapy, growth factors 
or other experimental drugs while receiving pirfenidone on this trial.  
 
Prior to entering this study you will have a small amount of blood drawn to measure blood counts, blood chemistries, and 
liver and kidney function.  Females of child-bearing age will have a pregnancy test.  Blood tests will be repeated prior to 
treatment cycle number 2, 3, 4, 7, 10, and subsequently after completion of every six treatment cycles to monitor for 
possible side effects of pirfenidone.  At each of these visits, up to a maximum of 10 ml (2 teaspoons) of blood will be 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
04-C-0080 
CONTINUATION:  page  3  of  8  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
taken.  A physical examination will be performed at the same time as blood samples are obtained, but will be continued 
at intervals of every three treatment cycles after cycle number 10. 
 
An MRI of your plexiform neurofibroma will be performed prior to beginning treatment with pirfenidone. The MRI will be 
repeated prior to treatment cycle number 4, 7, 10, and after completion of every six treatment cycles thereafter. 
 
In addition, one important aspect of the study is to assess your quality of life.  We will evaluate quality of life by giving 
you a questionnaire, which you would complete prior to treatment with pirfenidone, prior to treatment cycle number 4, 7, 
and then after completion of every 6 treatment cycles. Quality of life will not be assessed and the questionnaire will not 
be given to patients older than 18 or younger than 6 years of age. You will not have to answer any questions that you 
feel uncomfortable answering.  
 
Should you have to undergo a biopsy or surgery of your plexiform neurofibroma, we would like to obtain a sample of the 
tumor. In this case we would only obtain the tumor sample after the pathologist and surgeon have determined that any 
material necessary for clinical care has been obtained. We will perform a detailed analysis of the tumor samples to better 
understand the cell components of plexiform neurofibromas. These studies may help us to better understand which 
patients may benefit from the treatment with pirfenidone.  Any results from these studies will be preliminary and will 
require further analysis for verification. Therefore, neither you nor anyone else will be informed about results of the 
studies performed on your neurofibroma tissue.   
 
Should any tumor sample be left over after performing the above studies, we would like to retain these samples in a 
central tumor repository (storage site) at Washington University in St. Louis, Missouri.  The use of your specimen(s) will 
be for research purposes only and will not benefit you. It is also possible that the stored specimen(s) may never be used. 
The tissue will be identified with a code number, and will only be possible to connect with your name through the trial 
coordinating center “Pediatric Oncology Branch of the NCI” in Bethesda, MD.  The tissue may be distributed to 
investigators to help with their research on neurofibromatosis. There is a chance that the tumor sample you are providing 
for this study, may have some commercial applicability. There are no plans to provide financial compensation to you, 
should this occur. Any future research done with these samples will be conducted under a protocol approved by the 
Institutional Review Board with oversight of the tissue bank. You will not receive further notice of future uses of your 
sample, unless a future use could involve more than minimal risk to you. Any results from these studies will be 
preliminary and will require further analysis for verification. Therefore, neither you nor anyone else will be informed about 
results of the studies performed on your neurofibroma tissue. It might help people who have NF1 in the future. All 
research results will be kept confidential.  You can decide not to allow us to obtain a tumor sample and/or store your 
tumor sample at the tissue repository (please see below), or withdraw your specimen from the tissue repository at any 
time. Just contact us and let us know that you do not want us to use your tumor sample. Then any sample that remains 
will be destroyed. 
 
Donation of a tumor sample is optional, and if you decide not to have a tumor sample taken and/or stored, you can still 
participate in the treatment part of this study (please see below), and your care will not be affected. 
 
Should significant new findings regarding the treatment of NF1 become available during the course of this study, which 
may influence your decision to continue on this study, we will provide you with that information. 
 
Pirfenidone will be provided without charge, as will all examinations and studies performed at the NIH. The NIH will 
usually not pay for physical examinations or laboratory tests required for the study, which are performed outside of the 
NIH. 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER:  
04-C-0080 
CONTINUATION:  page  4  of  8  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
 
Please  
indicate  below  
if  you  agree  or  disagree  
to  
the  
following  study procedures for  you  
in  case  you  were  
to  undergo 
surgery of your plexiform neurofibromas for clinical purpose (not research): 
 
Obtain tumor sample for detailed pathological analysis: 
Agree:   
Disagree:   
Initials: 
Storage of the tumor sample in a central tumor repository for future neurofibromatosis type 1 research: 
 
  
Agree:   
Disagree:   
Initials: 
 
ALTERNATIVE APPROACHES OR TREATMENTS 
You  will  only  be  eligible  for  this  trial  
if  complete  surgical removal of the progressive  plexiform  neurofibroma(s)  
is  not 
feasible.    Alternatives  to  this  treatment  may  include  partial  surgical  removal  of  the  plexiform  neurofibroma,  other 
experimental therapies, or you may decide not to receive any treatment at this point in time. 
 
RISKS OR DISCOMFORTS OF PARTICIPATION 
The  side  effects  of  pirfenidone  have  been  studied  in  animals,  in  healthy  adults,  in  adults  with  fibrosing  (scarring) 
conditions, and in adults and a small number of children with NF1.  
 
In animal studies, which use much higher doses of pirfenidone than are to be used in this study, deaths occurred due to 
respiratory  (breathing)  failure.    Other  side  effects  noted in  animals  included  unsteadiness  and  weakness.  Long-term 
studies  
in  
rats  and  mice  
treated  with  pirfenidone  showed  
that  animals  developed  
tumors  of  
the  
liver.  In  addition,  
rats 
developed tumors of the uterus. The relevance of these tumors to humans is not known at this time. No reports of liver 
or uterine tumors in patients participating in clinical trials with pirfenidone have been reported to date. 
 
Pirfenidone has been studied in approximately 850-1000 adults taking this drug on an experimental basis in other studies 
for  other  conditions.  The  
following  risks/side  effects,  which are  believed  
to  be  associated  with  pirfenidone,  have  been 
infrequently  observed:  Rash,  skin  photosensitivity  (skin  rash  in  light  exposed  areas),  temporary  mild  stomach  upset, 
nausea,  decreased  appetite,  heartburn,  diarrhea,  abdominal  distension  (bloating),  abdominal  discomfort,  dyspepsia 
(indigestion), headache, tiredness, somnolence (feeling abnormally sleepy), palpitations (fast or irregular heart rate), and 
elevated  gamma-GTP  (an  enzyme  measured  
in  the  blood,  that  may  
indicate  a  problem  with  the  
liver  or  bile  system). 
Because pirfenidone can make you more sensitive to sun exposure, you should wear protective clothing and sunscreen 
during  exposure  in  the  sun.  Few  patients,  who  received  radiation  treatment  in  addition  to  pirfenidone,  developed 
lightheadedness and passed out. Overall, pirfenidone has also been well tolerated in a small number of children with NF1. 
The following side effects related to pirfenidone were observed in few of these pediatric patients: Diarrhea, mild nausea 
and  vomiting  of  
the  
initial  doses  of  pirfenidone,  
tiredness,  upset  stomach,  (gastritis), abdominal  pain,  and  palpitations 
(fast  or  
irregular  heart  
rate).  One  patient  developed  a  decrease  
in  
the  white  blood  cell  count.  
In  addition  
two  patients 
developed a side effect with uncertain relationship to pirfenidone: One patient with preexisting brain tumor developed a 
seizure, and one child experienced a decrease in the blood potassium level while on pirfenidone. Few patients were noted 
to develop behavioral changes (decreased attention, acting more defiant, immature, and impulsive), which were felt to be 
unlikely related to pirfenidone.  
 
You may have an allergic reaction to the pirfenidone, which may cause a rash, itching, hives or wheezing.  There have 
been no serious or irreversible side effects in adults taking this drug. Since this is a new experimental treatment, other 
presently unknown side effects may occur. These side effects could potentially be serious and even fatal.  
 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
04-C-0080 
CONTINUATION:  page  5  of  8  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
You will be watched closely, and the drug will be discontinued if serious side effects develop. If these symptoms resolve 
within 2 weeks after the therapy is stopped, you may continue therapy with pirfenidone, but the dosage of medication 
will be decreased.  If you continue to have side effects after stopping pirfenidone for two weeks, or experience side 
effects on a decreased dosage of pirfenidone, the medication will be stopped and you will not be able to further 
participate in this study.  Taking other medications (including over-the-counter medications, etc.) in combination with 
pirfenidone may produce or worsen side effects not produced by either alone. Before taking another medication, you 
must talk to your study doctor. 
 
The risks from the blood drawing to assess the effect of pirfenidone in the body include the discomfort from having 
needle sticks if required and a small risk of infection. 
 
Participation in the present study may render you ineligible to participate in other research studies that limit the number 
or type of treatments that patients may have received, and in some cases, the types of side effects that patients may 
have experienced. 
 
MRI:  Magnetic resonance imaging (MRI) is a standard procedure used for imaging plexiform neurofibromas. 
Administration of a contrast agent is not required for analysis of plexiform neurofibromas on this research protocol. When 
having a MRI, you will lie motionless on a table that slides into a tunnel slightly wider than your body for about one hour.  
There is very little room in the MRI, however you will easily be able to hear and speak to research staff.  As images are 
taken, the MRI makes loud banging noises as though it was being pounded on the outside with a hammer.  Earplugs will 
be offered to help reduce the noise.  MRIs use powerful magnets. There are no known or foreseeable risks associated 
with exposures to MRI provided no metal implanted prostheses (e.g., vascular clamps or pacemakers) are present. 
However, braces are not a problem. Should you have a metal prosthesis you may be excluded from participating in the 
study for your own safety.  All potential participants will be screened for the presence of such prior to the examination.  
Some participants in the study may require sedation or anesthesia to perform MRI.  Consent for this will be obtained prior 
to the MRI.  There are risks associated with sedation and anesthesia, including the risk of death in rare instances. Most of 
the MRI studies performed on this study would also be done as normal follow up for your plexiform neurofibroma, and 
not just for the study.  
 
Pirfenidone may be harmful to an unborn child. If you are a female and old enough to get pregnant, you will be given a 
pregnancy test before you begin the treatment, in order to make sure that you are not pregnant. If there is a chance that 
you could become pregnant during this study, you should not participate in the study.  If you are sexually active, you 
must use an appropriate and effective method of birth control while you are taking part in this study. If you become or 
are found to be pregnant while you are taking part in this study, you must notify one of the doctors listed on this form 
right away so the treatment can be discussed, and you will be withdrawn from the study. Breast-feeding mothers must 
stop breast-feeding. The effects of pirfenidone on female fertility are unknown. 
 
If you are a male, you should also use a means of birth control while you are taking part in this study (if sexually active), 
because we do not know what effect the experimental drug may have on your sex cells or your fertility and what effect 
this would have upon the development of an unborn child. 
 
Tumor Studies: A tumor sample will only be obtained if you have to undergo surgery or a biopsy of the plexiform 
neurofibroma for clinical reasons. With your permission, left over tumor will be sent to a central tumor repository.  
Although there is no immediate plan to perform studies from any tumor samples obtained, tumor material will be stored 
for future research.  It is expected that the tissue samples will be stored indefinitely in the repository.  The sample will be 
identified by a code number that can be traced to you only by contact with the trial coordinating center “Pediatric 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
04-C-0080 
CONTINUATION:  page  6  of  8  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Oncology Branch, NCI” in Bethesda, MD. Neither you, nor anybody else will be informed about results of testing 
performed on your tumor tissue. Every effort will be made to keep test results confidential. However, as the tumor and 
sample can be linked to your name, a small risk persists that unauthorized persons could gain access to the information. 
Some testing may eventually reveal information that, in some cases, may result in discrimination with health or life 
insurance or employment.  We believe that these risks are minimal since it is already known that you have 
neurofibromatosis. 
 
POTENTIAL BENEFITS OF PARTICIPATION 
 
The potential benefit of this treatment with pirfenidone is that it may cause your neurofibroma to stop growing or shrink 
for a period of time or it may lessen the symptoms, such as pain, that are caused by the tumor. It is our intent to benefit 
each participant in the trial. However, because there is not much information about the drug’s effect on plexiform 
neurofibromas in humans, we do not know if you will benefit from taking part in this study, although the knowledge 
gained from this study may benefit others. The MRI data in this study will be analyzed by a special approach called 
“volumetric MRI,” in addition to being read in a standard manner by a radiologist.  It is expected that the volumetric MRI 
approach will provide more precise measurement of the size of plexiform neurofibromas, and therefore will give more 
complete and objective information on which to base any possible future treatment decisions.  Volumetric MRI is 
currently not available on a routine clinical basis. Data obtained in this study will help determine an optimal dose of 
pirfenidone in children and young adults with NF1 and plexiform neurofibromas.  If the pirfenidone medication proves to 
be effective in NF1, you and other children with NF1 will have benefit of this new therapy. 
 
RESEARCH SUBJECT'S RIGHTS 
 
Joining this research study is voluntary. You may ask the doctors and nurses any questions about this treatment.  If you 
decide at any time that you do not want to receive this treatment any more, then tell us (Dr. Brigitte Widemann, phone 
301-496-7387, Dr. Frank Balis phone 301-496-0085, or Ms. Andy Gillespie, RN, phone 301-402-1848) and we will 
discontinue it. You may be eligible to receive experimental therapy other than the drug described here, or can receive 
therapy consisting of symptomatic treatment only. 
 
Your medical record may be reviewed by qualified representatives from the National Cancer Institute, by representatives 
from Solanan Inc/Marnac Inc, and by Dr. Dusica Babovic-Vuksanovic, who sponsors the clinical trial, and by the Food and 
Drug Administration (FDA). It should be noted that representatives of the U.S. Army Medical Research and Materiel 
Command are eligible to review research records as part of their responsibility to protect human participants in research. 
 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
04-C-0080 
CONTINUATION:  page  7  of  8  pages 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (5-98) 
 
P.A.: 09-25-0099 
 
FAX TO:  (301) 480-3126 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any information about 
your research involvement without your written permission.  However, if you sign a release of information form, for 
example, for an insurance company, the NIH will give the insurance company information from your medical record.  
This information might affect (either favorably or unfavorably) the willingness of the insurance company to sell you 
insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you should know that the 
Act allows release of some information from your medical record without your permission, for example, if it is required 
by the Food and Drug Administration (FDA), members of Congress, law enforcement officials, or other authorized 
people. 
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term medical care for any 
injury resulting from your/your child’s participation in research here.  Neither the National Institutes of Health nor 
Clinical Center will provide long-term medical care or financial compensation for research-related injuries, except as 
may be provided through whatever remedies are normally available under law. This study is being funded by the 
Department of Defense and conducted by the United States Army.  Army regulations provide that, as a volunteer in a 
study by the United States Army, you are authorized all necessary medical care for any injury or disease that is a direct 
result of your participation in the research. If you are hurt or get sick because of this research study, you can receive 
medical care at an Army hospital or clinic free of charge.  You will only be treated for injuries that are directly caused 
by the research study.  The Army will not pay for your transportation to and from the hospital or clinic.  If you have 
questions about this medical care, talk to the principal investigator for this study (Brigitte Widemann, phone 301-496-
7387).  If you pay out-of-pocket for medical care elsewhere for injuries caused by this research study, contact the 
principal investigator.  If the issue cannot be resolved, contact the U.S. Army Medical Research and Materiel Command 
(USAMRMC) Office of the Staff Judge Advocate (legal office) at (301) 619-7663/2221.  The Principal Investigator or his 
designee will assist you/your child in obtaining appropriate medical treatment under this provision if it is required.  If 
you/your child have any questions concerning your/your child’s eligibility for Army funded medical treatment you/your 
child should discuss this issue thoroughly with the Principal Investigator or his designee before you/your child enroll in 
this study.  This is not a wavier or release of your/your child’s legal rights.   
 
3. Payments.  The amount of payment to research volunteers is guided by the National Institutes of Health policies.  
In general, patients are not paid for taking part in research studies at the National Institutes of Health. 
 
4. Problems or Questions  If you have/your child has any problems or questions about this study, or about 
your/your child’s rights as a research participant, or about any research-related injury, contact the Principal 
Investigator, Brigitte Widemann, M.D.;  Building 10, Room 13N240, Telephone:  (301) 496-7387.  Other researchers 
you/your child may call are:  Frank M. Balis, M.D. at (301) 496-0085; Ms. Wendy Goddspeed, RN, or Ms. Anne 
Goodwin, R.N. at (301) 594-4762, or if you may have any questions about the use of your tissue for future research 
studies, you may also contact the Office of the Clinical Director of the National Cancer Institute at (301) 496-4251. 
 
 You/your child may also call the Clinical Center Patient Representative at (301) 496-2626. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
04-C-0080 
CONTINUATION:  page  8  of  8  pages 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (5-98) 
 
P.A.: 09-25-0099 
 
FAX TO:  (301) 480-3126 
 
File in Section 4:  Protocol Consent 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and have 
been given the opportunity to discuss it and to ask 
questions.  I hereby consent to take part in this study. 
I have read the explanation about this study and have 
been given the opportunity to discuss it and to ask 
questions.  I hereby give permission for my child to take 
part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/Legal Representative Date 
Signature of Parent(s)/Guardian 
Date 
 
 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
 
 
  
 
 
Signature of Parent(s)/Guardian 
Date 
 
 
 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JUNE 25, 2007 THROUGH JUNE 24, 2008. 
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 


 
 
MINOR PATIENT’S ASSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
   •  Attach to NIH-2514-1, Consent to Participate in a Clinical Research Study 
 
 
INSTITUTE: 
National Cancer Institute 
 
 
STUDY NUMBER: 
04-C-0080 
PRINCIPAL INVESTIGATOR:  Brigitte Widemann, M.D. 
 
 
STUDY TITLE: 
Phase II Trial of Pirfenidone in Children, Adolescents, and Young Adults with Neurofibromatosis 
Type 1 and Progressive Plexiform Neurofibromas 
 
 
Continuing Review Approved by the IRB on 06/25/07 
Amendment Approved by the IRB on 04/17/08 (D) 
 
 
 
Date Posted to Web: 04/29/08 
Minor 7 through 12 years of age 
 
 
PATIENT IDENTIFICATION 
MINOR PATIENT’S ASSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
NIH-2514-2 (4-97) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (2) 
 
 
We would like to invite you to take part in a research study at the National Institutes of Health (NIH).  
You have neurofibromatosis type 1.  We will call it NF1 for short.  NF1 can cause lumps that are called tumors to grow 
inside of your body and these tumors can cause pain or other problems.  Sometimes the tumors can be taken out with an 
operation, but if they can’t then doctors don’t have other ways to make them stop growing or make them go away.  
We are trying to find new medicines that can slow down or stop NF1 tumors from growing. Your tumor cannot be safely 
removed by surgery, and we are asking you to help us test one of these new medicines that is called pirfenidone.  
The reason for this study is to find out if this medicine may slow down the growth of your tumor, or shrink it, or make 
you feel better, but we don’t know yet whether this new medicine will work. 
We can measure the size of your tumor and check to see if your tumor is growing by doing scans that can take a picture 
of the inside your body without hurting you. This is called an MRI scan. For the MRI scan you will lay on the bed, the bed 
slides into a long tube of the MRI scanner. The space in the tube of the MRI scanner is small and the MRI scanner makes 
a loud banging noise when you are getting the scan.  Some people do not like being in small places or do not like the 
loud noise.  If these things bother you, please tell us.  Some people who do not like small places, do not like the loud 
noise or cannot lie still for an hour need medications to help them sleep while they get an MRI scan.  
An important part of the study is to learn how you are doing and how you are feeling while you are taking pirfenidone.  
To learn this information, you will be asked questions about things like school, activities, sleeping, books, feelings etc.  
These questions will be asked at regular times (every few months) while you are on this study. 
You will take pirfenidone by mouth as pills 3 times a day at the same time you eat your meals each day. During the first 
week you will receive fewer pirfenidone pills, as it may help preventing you from getting sick. After the first week you will 
receive the full number of pirfenidone pills. We will take small amounts of blood (less than 2 teaspoons) from you prior to 
starting pirfenidone, and regularly afterwards (initially every 4 weeks, then after every 3-6 months) to make sure that 
pirfenidone does not harm you.  We will do the MRI scans to check the size of your tumor after 3 months of treatment 
with pirfenidone, and regularly afterwards. You may be on this study and receive pirfenidone for as long as your tumor 
does not grow and you have no side effects from the pirfenidone. 
 
The new medicine might not work.  It may make you feel worse.  You could get an upset stomach or diarrhea.  Your 
heart may start beating fast.  You could have an allergy to the drug and get a rash or itchy bumps on your skin called 
hives, or it might become hard for you to breathe.  You may also feel more tired or lightheaded. Your doctor and parents 
will watch for any problems.  Be sure to tell your parents if you feel bad or if you think anything is wrong.  If these 
problems occur, they will be treated right away. 
 


 
 
 MEDICAL RECORD 
MINOR PATIENT’S ASSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
 
 
 
STUDY NUMBER: 
04-C-0040 
CONTINUATION:  page  2  of  2  pages 
 
 
PATIENT IDENTIFICATION 
MINOR PATIENT’S ASSENT TO PARTICIPATE IN A  
When you have your blood drawn or when we put a small tube (catheter) in your arm to draw blood, you might feel pain 
or there may be bruising or, rarely, an infection.   
 
The children who are part of the study will help us find out if the new medicine works. If this new medicine works, it may 
slow down or stop the growth of your tumor, and you may feel better. 
Ask your parents or your doctors or nurses if you have questions about this new medicine or the way that we are testing 
it.  We are asking for your permission and your parent’s permission before we test this new medicine on you. A copy of 
this form will be given to you and to your parents. You can decide not to take part in this study if you don’t want to and 
you can stop taking the medicine at any time, if you change your mind. 
 
We will keep your records in a safe place, and only people working on the study will know your name. 
 
 
 
CLINICAL RESEARCH STUDY 
 
NIH-2514-2 (4-97) 
 
P.A.: 09-25-0099  
FAX TO:  (301) 480-3126 
 
File in Section 4: Protocol Consent 
 
 
 
 
 
 
 
 
 
 
 
 
I have had this study explained to me in a way that I understand, and I have had the chance to ask questions.  
I agree to take part in this study. 
 
 
 
Signature of Minor Patient: 
 
Date: 
 
 
 
 
Signature of Investigator: 
 
Date: 
 
 
 
 
Signature of Witness: 
 
Date: 
 
 
 
 
Permanent address of study participant: 
 
 
_________________________________________________________________________________________________ 
 
 
_________________________________________________________________________________________________ 


 
 
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
  •  Attach to NIH-2514-2, Consent to Participate in a Clinical Research Study 
 
 
INSTITUTE: 
National Cancer Institute 
 
 
STUDY NUMBER: 
04-C-0080 
PRINCIPAL INVESTIGATOR: Brigitte Widemann, M.D.  
 
 
STUDY TITLE: 
Phase II Trial of Pirfenidone in Children, Adolescents, and Young Adults with Neurofibromatosis 
Type 1 and Progressive Plexiform Neurofibromas 
 
 
Continuing Review Approved by the IRB on 06/25/07 
Amendment Approved by the IRB on 04/17/08 (D) 
 
 
 
Date Posted to Web: 04/29/08 
Minor 13 through 17 years of age 
 
PATIENT IDENTIFICATION 
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
NIH-2514-2 (4-97) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (3) 
 
 
 
Introduction: We would like to invite you to take part in a research study at the National Institutes of Health (NIH). 
Before you decide about taking part in the study, we want you to know why we are doing the study and if it will help you. 
We also want you to know about any risks (what might go wrong) and what you will have to do. You can only be in the 
study if you and your parent(s) agree. 
 
This form gives you information about the study. Your doctor will talk to you about the study and answer questions you 
have. If you would like to take part in this study, we will ask you to sign this form to show that you understand this 
study. We will give you a copy of this form to keep. It is important that you know: 
x 
You do not have to join the study. 
x 
You may change your mind and drop out of the study at any time. 
x 
If we make important changes to the study we will tell you about it and make sure you still want to be in the 
study. 
 
Purpose of the study 
 
You have neurofibromatosis type 1 or NF1, which has caused a tumor (called a plexiform neurofibroma) to grow in your 
body.  This tumor may cause you pain, discomfort or other problems, as it gets larger.  There are no effective 
treatments, other than surgery, to make these tumors go away. Because your tumor cannot be taken out completely, we 
want to see if a new drug called pirfenidone helps to make your tumor smaller.  This drug has been given to adults and 
has been found to be effective in treating medical problems similar in some aspects to the one that you now have.  
Pirfenidone is also being tested in adults with NF1 and plexiform neurofibromas, and has been given to a small number of 
children with NF1 to find out the best dose of pirfenidone for children and teenagers with NF1. We do not know yet if 
pirfenidone is effective. We would like to see if this same medication may help children and teenagers with NF1 and 
plexiform neurofibromas. 
 
We want to answer the following questions about this new drug pirfenidone and NF1 tumors:  
1) 
Will this new drug, pirfenidone slow down how fast your NF1 tumor(s) grow(s)?  
2) 
Will pirfenidone make your NF1 tumor(s) smaller?  
3) 
How well is pirfenidone tolerated, and what are the side effects? 
 
 
 
 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
04-C-0080 
CONTINUATION:  page  2  of  5  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
Study plan 
 
If you participate in this study, you will undergo a physical examination, blood testing, and will have a magnetic 
resonance imaging (MRI) scan prior to starting pirfenidone treatment. You will be asked to complete a questionnaire 
consisting of 46 questions to determine how you are functioning and how you are feeling. All these tests will be repeated 
at regular intervals while you are on this study.  
 
You will take a medication that you have not taken before.  It is called pirfenidone and is provided as capsules, and is 
taken by mouth. You will take pirfenidone three times every day, but we define 28 days of taking pirfenidone as one 
treatment cycle. During the first week of the first treatment cycle you will receive pirfenidone at a lower dose, as it may 
help preventing you from getting nauseated. After the first week of treatment at a reduced dose, you will receive 
pirfenidone at the full dose.  
 
You will be able to receive pirfenidone for as long as you tolerate the medicine well, and your plexiform neurofibroma 
does not increase in size. Pirfenidone treatment will be stopped if your tumor grows or you have side effects from the 
pirfenidone.  
 
To measure the size of your tumor during treatment we will take a picture (called a MRI) of your tumor by using a large 
scanner. To take the picture you lay down on a bed, which slides into a tunnel in the scanner.  It may be scary if you 
don’t like small places.  You will need to lie still for approximately 1 hour.  The scanner is also very noisy while it is 
working. You may have to receive a medicine to make you sleep while you get the scans.  The medicine will be put into a 
vein in your arm through a small needle.  It will feel like a prick or bee sting when the needle is placed in your arm. The 
MRI will be performed prior to treatment with pirfenidone, prior to treatment cycle number 4, 7, 10, and after completion 
of every six treatment cycles thereafter. 
 
You will have a small amount of blood drawn for blood counts and chemistries and to measure your liver and kidney 
function. Each time, up to a maximum of 10 ml (2 teaspoons) of blood will be taken.  These blood tests will be performed 
prior to treatment with pirfenidone, and then prior to treatment cycle #2, 3, 4, 7, and after completion of every six 
treatment cycles thereafter. You will also have a physical examination at regular intervals while you receive pirfenidone. 
 
If you are a female and are old enough to become pregnant, you will also have a pregnancy test. You cannot participate 
in the study if there is a chance that you may become pregnant. 
 
Should you have to undergo a biopsy or surgery of your plexiform neurofibroma, we would like to obtain a sample of the 
tumor. We would perform a detailed analysis of the tumor in order to better understand these tumors. Should any tumor 
sample be left over after performing these studies, we would like to store these samples in a central place. Your sample 
would be identified only by a number, not by your name. Donating a tumor sample is optional. You can decide not to 
allow us to obtain a tumor sample and/or store your tumor sample or have the sample removed at any time. . This will 
not affect your care. Donating a tumor sample will be for research purpose only and will not help you, but might help 
others in the future. 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER:  
04-C-0080 
CONTINUATION:  page  3  of  5  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
Please mark below if you agree or disagree to the following in case you were to undergo surgery of your plexiform 
neurofibromas for clinical reasons: 
 
1) Obtain tumor sample for detailed analysis: 
Agree:   
Disagree:   
Initials: 
2) Storage of the tumor sample in a central tumor repository for future neurofibromatosis type 1 research: 
 
  
Agree:   
Disagree:   
Initials: 
 
Risks or side effects: 
 
Pirfenidone  has  been  studied  in  approximately  850-1000  adults taking  this  drug  in  studies  for  other  conditions.  The 
following risks/side effects have  been  infrequently  observed:  Rash,  skin  photosensitivity  (skin  rash  in  light  exposed 
areas), temporary mild stomach upset, nausea, decreased appetite, heartburn, diarrhea, abdominal distension (bloating), 
abdominal discomfort, dyspepsia (indigestion), headache, tiredness, somnolence (feeling abnormally sleepy, palpitations 
(fast or irregular heart rate), and elevated gamma-GTP (an enzyme measured in the blood, that may indicate a problem 
with  the  liver  or  bile  system).  Because  pirfenidone  can  make  you  more  sensitive  to  sun  exposure,  you  should  wear 
protective clothing and sunscreen during exposure in the sun. Few patients, who received radiation treatment in addition 
to pirfenidone, developed lightheadedness and passed out. 
 
Overall, pirfenidone has also been well tolerated in a small number of children with NF1. The following side effects related 
to  pirfenidone  were  observed  
in  
few  of  these  pediatric  patients:  Diarrhea,  nausea  and  vomiting  of  
the  
initial  doses  of 
pirfenidone,  tiredness,  upset stomach  (gastritis),  abdominal  pain,  and  palpitations (fast  or  irregular  heart  rate).  One 
patient  developed  a  decrease  in  the  white  blood  cell  count. In  addition  two  patients  developed  a  side  effect  with 
uncertain  relationship  to  pirfenidone:  One  patient  with preexisting  brain  tumor  developed  a  seizure,  and  one  child 
experienced a decrease in the blood potassium level while on pirfenidone. Few patients were noted to develop behavioral 
changes  
(decreased  attention,  acting  more  defiant,  
immature,  and  
impulsive),  which  were  
felt  
to  be  unlikely  
related  
to 
pirfenidone 
 
However, since this is a new experimental treatment, other presently unknown side effects may occur. These side effects 
could potentially be serious and even cause death. If you experience any severe side effects, the pirfenidone therapy will 
be stopped.  Any side effects of the drug will be immediately treated.  If these symptoms resolve within 2 weeks after the 
therapy is stopped, you may continue therapy with pirfenidone, but the dosage of medication will be decreased. 
 
Taking  Pirfenidone  might  be  harmful  
to  an  unborn  child.  
  Birth  control  measures  must  be  used  by  all females of child-
bearing  age  
(those  
females  who  are  older  
than  9  or  have begun  puberty)  who  can  become  pregnant  and  are  sexually 
active or by their sexual partners while in this study. These birth control measures can include contraceptive pills or use 
of condom and spermicide cream. Effects of pirfenidone upon an unborn child are unknown and may possibly result in 
serious birth defects of the unborn child.  Breast-feeding mothers must stop breast-feeding their child. 
 
During your blood tests, you may feel a small prick at the site where the needle is entering your arm.  A little while after 
your blood draw your arm may appear bruised around where the needle was inserted.  This bruising will go away within a 
few days.  When the catheter/heparin lock is inserted, it may also cause bruising, pain or, rarely, infection. 
 
We will let you know about any new findings during the course of your participation in this study, which may relate to 
your willingness to continue to participate in the study. 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
04-C-0080 
CONTINUATION:  page  4  of  5  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
Potential Benefits: 
 
Pirfenidone might slow the growth of your tumor or even might decrease its size; however, this study may not make your 
health improve. 
 
Information obtained in this study will help determine an optimal dose of pirfenidone in children with NF1 and plexiform 
neurofibromas.  If the pirfenidone medication proves to be effective in NF1, you and other children with NF1 will have 
benefit from this new therapy.  
 
Alternatives to Participation 
 
The only known effective treatment for plexiform neurofibromas is surgery. In many cases the tumor cannot be removed 
completely, and in some cases surgery cannot be safely done. Participation in this study will only be offered to you if your 
tumor cannot be safely removed. 
 
Confidentiality 
 
We will keep the records of this study confidential. Only people working on the study will know your name. 
 
Please ask your doctor or research nurse any questions you might have about this study.  Keep asking until you 
understand.  You can decide not to take part in this study if you don’t want to.  Your doctors and nurses will understand 
if you don’t want to participate.  If you agree to go on this study, know that you can stop whenever you choose.   
 
We are asking for your permission and your parent’s permission before we test this new medicine on you. A copy of 
this form will be given to you and to your parents.  
 
By signing this form, you agree that you have talked to your doctor about the study and understand it, and want to be 
in the study. You also agree that we have talked to you about the risks and benefits of the study, and about other 
choices. You may drop out of the study at any time and no one will mind. Please call the Principal Investigator Dr. 
Brigitte Widemann, M.D., at 301-496-7387 if you have any questions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
  
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
  MEDICAL RECORD 
 
STUDY NUMBER: 
04-C-0080 
CONTINUATION:  page  5  of  5 pages 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I have had this study explained to me in a way that I understand, and I have had the chance to ask questions.  
I agree to take part in this study. 
 
 
 
Signature of Minor Patient: 
 
Date: 
 
 
 
 
Signature of Investigator: 
 
Date: 
 
 
 
 
PATIENT IDENTIFICATION 
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A 
 
CLINICAL RESEARCH STUDY 
 
NIH-2514-2 (4-97) 
 
P.A.: 09-25-0099  
FAX TO:  (301) 480-3126 
 
File in Section 4:  Protocol Consent