Clinical trial NCT02096471
Conditions: Neurofibromatosis Type 1 and Growing or Symptomatic, Inoperable PN
Keywords: Neurofibromatosis Type 1 (Neurofibromas) PD-0325901 Radiographic Response Inoperable Plexiform Neurofibromas
Sponsor: University of Alabama at Birmingham
Start date: 2014-06-01; Completion date: 2018-08-01
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II open label study will evaluate adolescents (≥ 16 years of age) and adults with neurofibromatosis type-1 (NF1) and plexiform neurofibromas treated with the MEK inhibitor PD-0325901. The primary aim of the study will be to assess quantitative radiographic response in a target lesion. Subjects will receive PD-0325901 by mouth on a bid dosing schedule of 2 mg/m2/dose with a maximum dose of 4 mg bid. Each course is 4 weeks duration, and subjects will receive drug on a 3 week on/1 week off schedule. Subjects may receive additional courses beyond course 8 only if there is at least 15% reduction in volume of the target tumor. Subjects who have a 20% or greater reduction in target tumor volume at the end of 12 courses can continue on therapy for up to an additional year (maximum of 24 total courses). However, subjects who do not achieve at least 15% reduction in volume of the target tumor after 8 courses (\~8 months) will be considered treatment failures and taken off study.

The Primary purpose of this protocol is to determine whether PD-0325901 results in objective radiographic responses based on volumetric MRI measurements in adolescents and adults with NF1 and growing or symptomatic inoperable PN.

There are several secondary aims of this protocol:

To evaluate the feasibility and toxicity of chronic PD-0325901 administration in this patient population

To estimate the objective response rate of up to 2 non-target plexiform neurofibromas to PD-0325901 by MRI

To characterize the pharmacokinetic profile of PD-0325901 when administered to this patient population

To evaluate quality of life and pain during treatment with PD-0325901

Detailed description:
This phase II open label study will evaluate adolescents (≥ 16 years of age) and adults with neurofibromatosis type-1 (NF1) and plexiform neurofibromas treated with the MEK inhibitor PD-0325901. The primary aim of the study will be to assess quantitative radiographic response in a target lesion. Subjects will receive PD-0325901 by mouth on a bid dosing schedule of 2 mg/m2/dose with a maximum dose of 4 mg bid. Each course is 4 weeks duration, and subjects will receive drug on a 3 week on/1 week off schedule. Subjects may receive additional courses beyond course 8 only if there is at least 15% reduction in volume of the target tumor. Subjects who have a 20% or greater reduction in target tumor volume at the end of 12 courses can continue on therapy for up to an additional year (maximum of 24 total courses). However, subjects who do not achieve at least 15% reduction in volume of the target tumor after 8 courses (\~8 months) will be considered treatment failures and taken off study.

Subjects will have retinal screening performed before starting PD-0325901 and regularly while on study drug. Patients with glaucoma, intraocular pressure \>21 mmHg, or any other significant abnormality (excluding chronic, stable ophthalmological findings secondary to Optic Pathway Glioma) on ophthalmic examination (performed by an ophthalmologist) will not be eligible. Patients who have received radiation or cytotoxic therapy within 4 weeks of study entry and patients who have received radiation to the orbit at any time previously, will not be eligible for the study. Patients with other concurrent severe and/or uncontrolled medical disease will also be excluded. In addition, pregnant women will not be eligible for enrollment and subjects of reproductive age will be required to practice birth control while on treatment.

Subjects entered on the trial will be carefully monitored for the development of PD-0325901 associated toxicities.

In all consenting subjects entered on this trial, a complete pharmacokinetic profile of PD-0325901 after administration will be evaluated during course 1. Involvement with this part of the study will be required.

Consenting subjects with dermal neurofibromas will have punch biopsies of dermal neurofibromas at two time points to determine if the PD-0325901 is affecting the biologic target. Involvement with this part of the study will be optional.

Since plexiform neurofibromas may significantly impact the lives of patients with NF1, this study will evaluate the effects of the disease and treatment with PD-0325901 on the quality of life (QOL) of adolescents and adults. Involvement in this part of the study will be required. The Pediatric Quality of Life Inventory (PedsQL) Neurofibromatosis Type 1 Module will be used to assess the QOL of subjects. The PedsQL NF1 Module is a self-reported disease-specific QOL scale developed for adolescents and adults with NF1. It assesses 16 domains of functioning including physical functioning, emotional functioning, social functioning, cognitive functioning, physical appearance, worry, pain and hurt, fatigue, and daily activities. Preliminary data collected on this scale indicates good reliability and validity in adults. The preliminary data in a small sample of adolescents also looks promising. Data collected from this trial may be used toward validating this instrument since no disease specific QOL measure for NF1 currently exists, but such a tool is critically needed. Pain will be assessed using the Numeric Rating Scale-11 (NRS-11), which is an 11-point self-report scale of pain intensity. In addition, the Brief Pain Inventory Pain Interference Scale is a 7-item self-report questionnaire that measures the extent to which pain interferes with daily functioning. Both of these brief measures have been recommended to assess different aspects of pain in clinical trials.

For subjects who respond to PD-0325901 (≥20% tumor volume reduction of target lesion by 12 courses), an MRI scan of the target lesion is requested (but not required) at 4 and 12 months after stopping drug (as long as the subject is still on protocol) in order to determine whether response is maintained post-therapy. These studies will not be requested from subjects who experience disease progression while on study drug.

Before the subject can be enrolled, the responsible institutional investigator must sign and date the completed eligibility checklist. The completed eligibility checklist should be faxed to the NF Operations Center to confirm eligibility prior to subject enrollment.

Arms: arm 1: The primary aim of the study will be to assess quantitative radiographic response in a target lesion. Subjects will receive PD-0325901 by mouth on a bid dosing schedule of 2 mg/m2/dose with a maximum dose of 4 mg bid. Each course is 4 weeks duration, and subjects will receive drug on a 3 week on/1 week off schedule. Subjects may receive additional courses beyond course 8 only if there is at least 15% reduction in volume of the target tumor. Subjects who have a 20% or greater reduction in target tumor volume at the end of 12 courses can continue on therapy for up to an additional year (maximum of 24 total courses). However, subjects who do not achieve at least 15% reduction in volume of the target tumor after 8 courses (\~8 months) will be considered treatment failures and taken off study.
Interventions: intervention 1: PD-0325901
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
NF Protocol #106 - Version 1.3 
07/20/2018 
 
1 
 
Neurofibromatosis (NF) Consortium 
 
NF PROTOCOL 106 
A Phase 2 Trial of the MEK Inhibitor PD-0325901 in Adolescents and 
Adults with NF1- Associated Morbid Plexiform Neurofibromas 
 
 
Sponsored by: 
 
Department of Defense 
USAMRMC 
And the 
Office of the Congressionally Directed Medical Research Programs 
(CDMRP)  
 
 
 
 
 
Protocol Chairs 
Brian Weiss, MD, Chair 
Scott Plotkin, MD, Co-Chair 
Brigitte Widemann MD, Co-Chair 
 
 
Medical Monitor 
Julia Glade Bender, MD 
 
 
 
 
 
 
 
 
 
 
 


NF Protocol #106 - Version 1.3 
07/20/2018 
 
2 
 
PROTOCOL ROSTER 
Study Chair 
Brian Weiss, MD 
Cincinnati Children’s 
Hospital 
3333 Burnet Avenue 
MLC-7015 
513-636-9863 Phone 
Brian.weiss@cchmc.org 
Medical Monitor 
Julia Glade Bender, MD 
Columbia University 
Division of Ped Oncology 
161 Frt Washington Ave, IP-
7 
New York, NY 10583 
Jg589@cumc.columbia.edu 
Research Compliance Manager 
Roy McDonald, MPH 
University of Alabama at 
Birmingham – Kaul 230 
Birmingham, AL 35294-0024 
205-975-4075 Phone  
205-975-3542 Fax  
rmcdonald@uab.edu  
Study Co-Chairs 
Brigitte Widemann, MD 
Pediatric Oncology Branch, 
NCI, CCR 
10 Center Drive Bldg 10-
CRC, RM 1-5750 
Bethesda, MD 20892 
301-496-7387  Phone 
301-480-8871  Fax 
widemanb@mail.nih.gov 
Co-Investigators 
Eva Dombi, MD 
National Cancer Institute 
10 Center Drive 
Bldg 10-CRC, 
Rm 1-5750 
Bethesda, MD 20892 
301-451-7023 Phone 
301-402-1734 Fax 
dombie@mail.nih.gov 
Study Statistician 
Gary Cutter, PhD 
Department of Biostatistics 
U. of Alabama at Birmingham 
1667 Univ Blvd - Ryals 410 
Birmingham AL  35243 
205-975-5048 Phone 
295-975-2531 Fax  
cutterg@uab.edu 
Scott Plotkin, MD, PhD 
Yawkey 9E 
Massachusetts General 
Hospital 
55 Fruit Streettt 
Boston, MA 02114 
617-726-3650 Phone 
617-643-2591 Fax 
splotkin@partners.org 
 
David Gutmann. MD, PhD. 
Washington University 
School of Medicine 
600 South Euclid Avenue 
Box 8111 
St. Louis, MO 63110 
314-362-7379 Phone 
314-362-2388 Fax 
gutmannd@neuro.wustl.edu 
 
Department of Defense 
Meropi Athanasiou, PhD  
Science Officer (General 
Dynamics IT)  
Congressionally Directed Medical 
Research Programs  
1053 Patchel Street  
Frederick, MD 21702  
301-619-7319  Phone 
meropi.athanasiou.civ@mail.mil 
Study Committee 
Bruce Korf, MD, PhD 
University of Alabama  
at Birmingham 
1530 3rd Avenue South 
230 KAUL 
Birmingham, Alabama  
35294-0024 
205-934-9411 Phone  
205-934-9488 Fax  
bkorf@uabmc.edu 
Program Director 
Karen A. Cole-Plourde, BS 
University of Alabama at 
Birmingham 
1530 3rd Avenue South – 230 
KAUL 
Birmingham, AL 35294-0025 
205-934-5140 Phone 
205-975-3543 Fax 
kplourde@uab.edu 
 
Clinical Nurse Manager  
Vivien Phillips, RN 
University of Alabama at 
Birmingham 
1530 3rd Avenue South – 230 
KAUL 
Birmingham, AL  35294-0024 
205-934-5376 Phone 
205-975-3543 Fax  
vphillip@uab.edu 
Michael Fisher, MD 
Children’s Hospital of 
Philadelphia 
3501 Civic Center Blvd 
Philadelphia, PA 19104 
215-590-2800 Phone 
215-590-4183 Fax 
fisherm@email.chop.edu 
Pam Wolters, PhD 
Pediatric Oncology Branch 
Bethesda, MD  20892-8200 
301-496-0562 Phone 
301-402-1734 Fax 
woltersp@mail.nih.gov 
 


NF Protocol #106 - Version 1.3 
07/20/2018 
 
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PARTICIPATING SITES: 
 
Bruce Korf, MD, PhD 
University of Alabama at Birmingham 
1720 2nd Ave So-  KAUL 230 
Birmingham, Alabama  35294-0024 
Phone:  205-934-9411/Fax: 205-934-9488 
bkorf@uabmc.edu 
 
 
Michael Fisher, MD 
Children’s Hospital of Philadelphia 
3501 Civic Center Boulevard 
Philadelphia, PA 19096 
Phone:  215-590-2800 
fisherm@email.chop.edu 
 
 
Roger Packer, MD 
Children’s National Medical Center 
111 Michigan Avenue, NW 
Washington, DC  20010 
Phone:  202-884-2120 
rpacker@cnmc.org 
 
Wade Clapp, MD 
Indiana University  
1044 West Walnut Street  
Cancer Center, Room 402A  
Indianapolis, IN  46202 
Phone: 317-278-9290 
dclapp@iupui.edu 
 
 
Tena Rosser, MD 
Children’s Hospital Los Angeles 
300 Medical Plaza Box 696824 
Los Angeles, CA  90095 
Phone: 323-361-2471 
trosser@chla.usc.edu 
 
 


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Elizabeth Schorry, MD  
Cincinnati Children’s Hospital Medical Center 
3333 Burnet Avenue - ML 4006 
Cincinnati, OH  45229 
Phone:  513-636-4760 
elizabeth.schorry@cchmc.org 
 
James Tonsgard, MD 
University of Chicago 
5841 South Maryland Avenue, MC 3055 
Chicago, IL  60637 
Phone:  773-702-6488 
tonsgard@midway.uchicago.edu 
 
David Viskochil, MD, PhD 
University of Utah 
50 North Medical Drive – 2C412 SOM 
Salt Lake City, UT  84132 
Phone:  801-581-8943 
dave.viskochil@hsc.utah.edu 
 
 
 
David Gutmann, MD, PhD 
Washington University School of Medicine 
660 South Euclid Avenue – Box 811 
St. Louis, MO  63110 
Phone: 314-362-7379  
gutmannd@neuro.wustl.edu 
 
Jeffrey Allen, MD 
New York Univ. Pediatrics 
160 E. 32nd Street – 2nd Floor 
Hassenfeld Children’s Center 
New York, NY 10016 
Phone: 212-263-9907 
Jeffrey.Allen@nyumc.org  
 
Nicole Ullrich, MD, PhD 
Children’s Hospital Boston – Dept. of Neurology 
300 Ongwood Avenue – Fegan 11 
Boston, MA  02115 
Phone: 617-355-2066 
Nicole.Ullrich@childrens.harvard.edu 
 
 
 


NF Protocol #106 - Version 1.3 
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Brigitte Widemann, MD 
National Institutes of Health – NCI  
10 Center Drive; Building 10-CRC: Room 1-5750 
MSC 
Bethesda, MD  20892 
Phone: 301-496-7387Widemanb@mail.nih.gov 
 
 
 
Affiliate sites  
Massachusetts General Hospital (Ullrich; Plotkin) 
Dana Farber Cancer Institute (Ullrich; Kieran) 
UCLA (Rosser; Silva) 
Johns Hopkins (Packer; Blakeley) 
Ohio State University (Schorry) 
Lurie Children's Hospital of Chicago (Tonsgard; Listernick and Goldman) 
 
 
 
 
 
 
 


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ROLES AND RESPONSIBILITY OF STUDY PERSONNEL: 
 
Roger Packer, MD: Executive Director of NF Consortium, oversight of trial coordination  
Brian Weiss, MD:  Study PI, Protocol Chair 
Scott Plotkin, MD:  Protocol Co-Chair  
Brigitte Widemann, MD:  Protocol Co-Chair 
Bruce Korf, MD, PhD:  NF Consortium PI, Protocol Co-Chair 
Gary Cutter PhD, Biostatistician & Deputy Director of NF Operations Center 
Julia Glade Bender, MD: Medical Monitor 
Eva Dombi, MD: Volumetric MRI analysis of plexiform neurofibromas on protocol 
Alan Cantor, PhD: Trial statistician  
Pam Wolters, PhD: Quality of life and pain surveys 
Vivien Phillips, RN, Clinical Nurse Manager – NF Operations Center 
Karen Cole-Plourde, BS, Program Director – NF Operations Center 
Roy McDonald, MPH, Research Compliance Manger – NF Operations Center  
 
 


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TABLE OF CONTENTS 
Protocol Roster ................................................................................................................................ 2 
Participating Sites: ........................................................................................................................... 3 
Roles and Responsibility of Study Personnel: ................................................................................. 6 
EXPERIMENTAL DESIGN SCHEMA ....................................................................................... 11 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) ...................................................... 12 
2.0 
BACKGROUND AND RATIONALE ............................................................................ 12 
2.1 
Neurofibromatosis Type 1 and Plexiform Neurofibromas ............................... 12 
2.2 
Mitogen-activated Protein (MAP) Kinase/Extracellular signal-regulated 
protein kinase (ERK), and MAPK/ERK kinase (MEK) ....................................................... 16 
2.3 
Pharmacokinetics and Dosing of PD-0325901 ...................................................... 23 
2.4 
Overview of Proposed Study ........................................................................................ 23 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES ..................................... 24 
3.1 
Informed Consent/Assent ............................................................................................. 24 
3.2 
Screening Procedures ..................................................................................................... 24 
3.3 
Study Enrollment .............................................................................................................. 25 
4.0 
PATIENT ELIGIBILITY ................................................................................................. 25 
4.1 
Inclusion Criteria for all subjects:............................................................................... 25 
4.2 
Exclusion Criteria .............................................................................................................. 27 
5.0 
REQUIRED DATA .......................................................................................................... 28 
5.1 
Tests and Observations .................................................................................................. 30 
5.2 
Records to be Kept ........................................................................................................... 30 
5.3 
Role of Data Management .............................................................................................. 30 
6.0 
TREATMENT PROGRAM ............................................................................................. 31 
6.1 
Agent Information/ PD-0325901 ............................................................................... 31 
6.2 
Treatment Overview ........................................................................................................ 35 
6.3 
Criteria for Starting Subsequent Courses ................................................................ 36 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY ............................ 36 
7.1 
Supportive Care ................................................................................................................. 36 
7.2 
Growth Factors .................................................................................................................. 36 
7.3 
Surgery .................................................................................................................................. 36 
7.4 
Concomitant Medications .............................................................................................. 37 
8.0 
MODIFICATIONS FOR ADVERSE EVENTS .............................................................. 37 
8.1 
Hematological Toxicity ................................................................................................... 37 
8.2 
Non-Hematological Toxicity ......................................................................................... 38 
8.3 
Toxicities Requiring Removal From Protocol Therapy ..................................... 38 
9.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED .......................... 38 
9.1 
Required Clinical, Laboratory and Disease Evaluation ...................................... 38 
9.2 
History and physical examination and vital signs ................................................ 39 
9.3 
Retinal Exam ....................................................................................................................... 39 
9.4 
Hematology ......................................................................................................................... 39 
9.5 
Blood chemistry ................................................................................................................ 39 
9.6 
Serum or Urine Pregnancy Test .................................................................................. 39 
9.7 
MRI for volumetric analysis of plexiform neurofibroma ................................... 40 
9.8 
PD-0325901 diary ............................................................................................................ 40 
9.9 
Pharmacokinetic profile of PD-0325901 (Required) ......................................... 40 
9.10 
Pharmacodynamic Analysis (Optional).................................................................... 41 


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9.11 
Plasma Cytokines and Growth Factors (Optional) ............................................... 41 
9.12 
Maximum blood volumes for pharmacokinetic and pharmacodynamic 
studies ................................................................................................................................................. 41 
9.13 
Quality of Life and Pain Evaluations (Required) .................................................. 41 
10.0 
Adverse Reporting Requirements..................................................................................... 43 
10.1 
Definitions ........................................................................................................................... 43 
10.2 
Common Terminology Criteria for Adverse Events (CTCAE) .......................... 43 
10.3 
Attribution: Definitions of relationship to study medication are as follows:
 
44 
10.4 
Reporting Procedures for All Adverse Events ....................................................... 44 
10.5 
Expedited Reporting Guidelines ................................................................................. 44 
10.6 
Reporting of Protocol Violations/Deviations and Unanticipated Problems
 
45 
11.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA..................................................................................................................................... 46 
11.1 
Criteria for Removal from Protocol Therapy ......................................................... 46 
11.2 
Off Study Criteria............................................................................................................... 46 
12.0 
STATISTICAL AND ETHICAL CONSIDERATIONS ................................................. 47 
12.1 
Subject Accrual .................................................................................................................. 47 
12.2 
Statistics and Feasibility ................................................................................................. 47 
12.3 
Statistical Analysis Plan .................................................................................................. 48 
12.4 
Definitions of Evaluable ................................................................................................. 50 
13.0 
Response Criteria ............................................................................................................. 50 
14.0 
Human Subjects Protection & Data Safety Monitoring PLAN ........................................ 51 
15.0 
REFERENCES ................................................................................................................. 54 
APPENDIX I:  SCHEDULE OF EVALUATIONS ...................................................................... 56 
Appendix II: Performance Status Scales/Scores ........................................................................... 57 
Appendix III:  NIH Consensus clinical Defintion of Neurofibromatosis ...................................... 58 
Appendix IV:  Protocol for Required Pre-Study and On-Study MRI Studies ............................... 59 
Appendix IVa:  MRI eligibility form ............................................................................................ 62 
Appendix V: Subject Diary On PD-0325901 Protocol ................................................................. 63 
Appendix VI: Pharmacokinetic, Pharmacodynamic and Cyotkine STUDIES .............................. 64 
Pharmacokinetic Worksheet ................................................................................................. 64 
Pharmacodynamic Worksheet .............................................................................................. 66 
Plasma Cytokines and Growth Factors ............................................................................. 67 
Appendix VII:  Consortium QOL and Pain Measures .................................................................. 68 
PAIN QUESTIONNAIRE ............................................................................................................... 70 
QOL INSTRUMENT (TEEN REPORT) ...................................................................................... 72 
For teens and young adults (16 to 20 years old) with NF-1 ........................................... 72 
QOL INSTRUMENT (ADULT SURVEY) .................................................................................. 78 


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ABSTRACT/SCHEMA 
 
Background 
 
• 
Patients with Neurofibromatosis 1 (NF1) have an increased risk of developing tumors of 
the central and peripheral nervous system, including plexiform neurofibromas (PN), which 
are benign nerve sheath tumors that are among the most debilitating complications of NF1. 
There are no standard treatment options for PN other than surgery, which is often difficult 
due to the extensive growth and invasion of surrounding tissues.  
• 
The Mitogen-activated Protein Kinase (MAPK) pathway is important for plexiform 
neurofibroma growth. 
• 
Phosphorylated Extracellular signal-regulated protein kinase (p-ERK), is detected in 
human plexiform neurofibromas at higher levels than normal human nerve. 
• 
The Dhh-Cre;Nf1fl/fl mouse model develops plexiform neurofibromas, and these tumors 
histologically mimic those of human plexiform neurofibromas 1. 
• 
Elevated phosphorylated (p)-ERK1,2 was detected in Nf1fl/fl;Dhh-cre mouse 
neurofibromas relative to Nf1fl/fl;Dhh-cre or wild type mouse nerve. 
• 
PD-0325901 is a highly specific allosteric MAPK/ERK kinase (MEK) inhibitor currently 
in clinical cancer trials that blocks MAPK signaling.  
• 
Lower doses of PD-0325901 in mice results in plasma concentrations similar to the 
concentrations achieved in adults at the dose proposed for this trial, and induced tumor 
volume reductions in 85% of mice. 
 
 
Primary Objective 
• 
To determine whether PD-0325901 results in objective radiographic responses based on 
volumetric MRI measurements in adolescents and adults with NF1 and growing or 
symptomatic, inoperable PN 
Secondary Objectives 
• 
To evaluate the feasibility and toxicity of protracted PD-0325901 administration in this 
patient population 
• 
To estimate the objective response rate of up to 2 non-target plexiform neurofibromas to 
PD-0325901 by MRI. 
• 
To characterize the pharmacokinetic profile of PD-0325901 when administered to this 
patient population 
• 
To assess quality of life and pain in patients on PD-0325901 
 
Exploratory Objectives 
• 
To characterize the pharmacodynamics profile of PD-0325901 when administered to this 
patient population by assaying host tissues (dermal neurofibromas) as a surrogate for 
plexiform neurofibroma cells before and after drug administration. 
• 
To characterize the activity of PD-0325901 on neurofibroma cell gene expression 
• 
To characterize the activity of PD-0325901 on plasma cytokines and growth factors 
• 
To correlate pERK levels with pharmacokinetic data 
• 
To validate the PedsQL NF1 QOL Module, a disease specific QOL scale, for use in this 
patient population 
• 
To determine whether subjects who respond (≥20% objective radiographic response of 
target lesion by 12 courses) to PD-0325901 will maintain that response for 1 year off 
therapy 


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Eligibility 
 
• 
Patients ≥16 years old with NF1 and PN(s) that are progressive by serial imaging OR 
causing significant morbidity, and that can be analyzed by volumetric MRI.  
 
Design 
• 
PD-0325901 will be dosed by mouth b.i.d. at a dose of 2 mg/m2/dose with a max of 4 mg 
per dose (8 mg per day max). Dosing will be on a 4 week course with a 3 week on/1 
week off schedule. 
• 
Subjects will undergo volumetric assays of their target PN using MRI after every 4 
courses for the first year and then every 6 courses. 
• 
Treatment will continue for 8 courses (approximately 8 months) as long as there is at 
least SD 
• 
Treatment beyond course 8 will only be given to those with at least 15% reduction in 
volume of the target tumor by the end of course 8. 
• 
Treatment beyond course 12 will only be given to those subjects who achieve a response 
( ≥ 20% tumor shrinkage by volumetric analysis) by the end of course 12, and will be 
continued for a maximum of 24 total courses. 
• 
Subjects will be removed for significant toxicity or objective progression (≥ 20% tumor 
growth by volumetric analysis) at any time  
 


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EXPERIMENTAL DESIGN SCHEMA 
 
 


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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1. Primary Aim 
1.1.1. To determine whether PD-0325901 results in objective radiographic responses 
based on volumetric MRI measurements in adolescents and adults with NF1 and 
growing or symptomatic inoperable PN 
 
1.2. Secondary Aims 
1.2.1. To evaluate the feasibility and toxicity of chronic PD-0325901 administration in 
this patient population  
1.2.2. To estimate the objective response rate of up to 2 non-target plexiform 
neurofibromas to PD-0325901by MRI  
1.2.3. To characterize the pharmacokinetic profile of PD-0325901 when administered to 
this patient population  
1.2.4. To evaluate quality of life and pain during treatment with PD-0325901 
 
1.3. Objective Aims 
1.3.1. To characterize the pharmacodynamic profile of PD-0325901 when administered 
to this patient population using dermal neurofibromas as a surrogate for plexiform 
neurofibroma cells. 
1.3.2. To characterize the activity of PD-0325901 on neurofibroma cell gene expression 
1.3.3. To characterize the activity of PD-0325901 on plasma cytokines and growth 
factors 
1.3.4. To correlate pERK levels to pharmacokinetic data and response 
1.3.5. To validate the PedsQL NF1 QOL Module, a disease specific QOL scale, for use 
in this patient population 
1.3.6. To determine whether subjects who respond (≥20% objective radiographic 
response of target lesion by 12 courses) to PD-0325901 will maintain that response 
for 1 year one they come off therapy 
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1 
Neurofibromatosis Type 1 and Plexiform Neurofibromas 
 
 
Neurofibromatosis type 1 (NF1) is a common autosomal dominant, progressive disorder 
with an incidence of 1:3500 (>80,000 persons affected in The United States).  NF1 is 
caused by a mutation in the NF1 tumor suppressor gene. The NF1 gene was cloned on 
chromosome 17q11.2 and compromises 60 exons spanning 350 kb of genomic DNA. 
Mutation analysis of the NF1 gene allows identification of 95% of mutations with a wide 
spectrum of mutations (Messiaen, Callens et al 2000). To date, no phenotype genotype 
correlations have been made with the exception of complete loss of the NF1 gene 
(megabase deletions), which is associated with severe intellectual disability. The 
diagnosis of NF1 is clinical and based on criteria developed at the NIH consensus 
conference (Section 4.1.1).  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%), pheochromocytomas (1%), and malignant peripheral nerve sheath 
tumors (10%) 2,3. 


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13
 
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 MPNSTs arise by malignant transformation of neurofibroma. Based on a 
recent study, the life-time risk of developing MPNST in patients with NF1 is 8-13% 4. 
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 5.  Between 20-44% 
of individuals with NF1 develop plexiform neurofibromas 6.  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 5.   
 
A subset of plexiform neurofibromas includes paraspinal plexiform neurofibromas. These 
tumors tend to originate from the dorsal root ganglion and grow bidirectionally, centrally 
towards the neural foramen and centrifugally down the peripheral nerve.  These tumors 
cause substantial morbidity by compression of the spinal cord and by peripheral growth, 
and may show progressive growth not only in young children, but also in adults.  
Individuals with substantial paraspinal neurofibroma burden may be a distinct subset of 
individuals with NF (personal communication Dr. Bruce Korf).  These patients typically 
have no or only few cutaneous neurofibromas; have few, if any, café au lait spots; have a 
large number of firm subcutaneous neurofibromas; and rarely have cognitive deficits. The 
phase II trials of tipifarnib and pirfenidone (adult and pediatric studies) allow study entry 
to patients with paraspinal plexiform neurofibromas. In these clinical trials, volumetric 
MRI analysis of paraspinal neurofibromas is used to evaluate the potential benefit of the 
investigational agent.  
 
Plexiform neurofibromas, including paraspinal neurofibromas, cause major morbidity and 
mortality in NF1 3,7,8.  There is no currently accepted effective drug therapy for plexiform 
neurofibromas.  The rate of growth of this histologically benign neoplasm has been 
described as unpredictable and often episodic 2.  Recently, Widemann et al reported the 
time to progression (TTP) of plexiform neurofibromas on the control arm of a blinded 
cross-over designed trial in which patients received either placebo or tipifarnib (personal 
communication).  The placebo arm mean TTP was 10.6 months. 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 5.  There is no 
other standard treatment modality for patients with progressive plexiform neurofibromas.  
 


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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 9, cis-retinoic acid, 
interferon alpha 2b10,11, methotrexate and vinblastine, PEG interferon alpha-2b12, the 
farnesyltransferase inhibitor tipifarnib (R115777)13,14, the antifibrotic agent 
pirfenidone15,16, the RAF kinase inhibitor Sorafenib17, the cKIT inhibitor Gleevec18, and 
the mTOR inhibitor Sirolimus (personal communication) 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. While PEG 
interferon alpha-2b increased TTP and there have been some PN shrinkage reported with 
Gleevec, to date no medical treatment has reliably resulted in objective radiographic 
response of plexiform neurofibromas. 
 
 


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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 19,20. 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 (Solomon, Warren et al. 2004).  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, the volume of each plexiform neurofibroma was also determined by each 
observer once by manually tracing the tumor borders on each MR image. The results of the 
application of the automated method and the correlation with the manual method are shown 
in the table below. 
 
Automated Volumetric MRI Analysis 
Observer 1 
Observer 2 
Mean tumor volume (ml)  
Median (range) 
291 
(80.9-1581) 
290 
(75.7-1603) 
Median Inter-day CV (%)  
(range) 
3.6 
(0.7-6.0) 
1.6 
(0.6-5.6) 
Difference in volume between observers (%) 
Median (range) 
6.4 (1.4 – 11.9) 
6.4 (1.4 – 11.9) 
Correlation automated vs. manual method, R 
0.999 
0.999 
 
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 was used in the phase II trial of the 
farnesyltransferase inhibitor tipifarnib, the phase I and II trials of pirfenidone, the phase I 
trial of peg-interferon alfa-2b, and the NF Consortium phase II trial of Sirolimus for 
children with NF1 and plexiform neurofibromas to assess changes in tumor size. Imaging 
studies on these multicenter trials are sent to the NCI, POB, where volumetric MRI analysis 
is performed. Tumor progression on these trials is defined as an increase in plexiform 
neurofibroma volume by ≥ 20%.  
 
Figure 1: Axial MRI of pelvic 
plexiform neurofibroma. Steps 
of automated volumetric 
analysis A-D. 


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This volume increase corresponds to much smaller changes in 1-D, or 2-D measurements 
as outlined in the table below: 
 
 
Response Criteria 
RECIST 
Diameter, 
2r 
WHO 
Product, (2r)2 
Current NF1 trials 
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 NF1 trials listed above. 
 
2.2 
Mitogen-activated Protein (MAP) Kinase/Extracellular signal-regulated protein kinase (ERK), 
and MAPK/ERK kinase (MEK) 
 
MEK and Cancer 
The MAPK pathway regulates multiple critical cellular functions including growth and 
senescence21. Dysregulation of the RAS-MAPK-MEK pathway occurs frequently in 
human cancer 22.   MEK1 mutations have been found in 3% of melanomas and 2.2% of 
colon cancers.  These mutations typically lead to activation of both MEK and ERK. In 
addition, malignant peripheral nerve sheath tumors (MPNST), a cancer seen commonly 
in patients with Neurofibromatosis Type 1, have aberrations in MAPK signaling23.     
 
MEK and NF1  
 
The NF1 gene encodes a protein, termed neurofibromin, which functions partly as a Ras-
GTPase activating protein (RasGAP). Accordingly, neurofibromin loss in tumor cells 
leads to Ras hyperactivation. Signaling intermediates downstream of Ras are 
hyperactivated as a result of NF1 gene inactivation and these specific proteins are critical 
for transmitting the Ras growth signal and for the development of neoplasia in patients 
with NF1. PD-0325901 is a highly specific non-competitive MEK inhibitor currently in 
clinical cancer trials.  PD-0325901 blocked MAPK signaling based on pharmacodynamic 
measurement of p-ERK in MPNST xenografts and mouse neurofibroma tissue sections at 
intervals after PD-0325901 exposure.  
 
Dhh-Cre;Nf1fl/fl Mice Develop Plexiform Neurofibromas 
 
 
The Dhh-Cre;Nf1fl/fl mouse model develops plexiform neurofibromas, and these tumors 
histologically mimic those of human plexiform neurofibromas 1. MAPK pathway 
activation was evaluated in vivo by staining tissue sections for P-ERK.  Elevated 
phosphorylated (p)-ERK1,2 was detected in Nf1fl/fl;Dhh-cre mouse neurofibromas and 
NPcis mouse sarcomas relative to Nf1fl/fl;Dhh-cre or wild type mouse nerve. P-ERK was 
also detected in all human neurofibromas (n = 6) and MPNSTs (n = 4) at higher levels 
than normal human nerve associated with a neurofibroma. In addition, malignant tumors 
showed higher levels of p-ERK relative to benign neurofibromas. 
 
PD-0325901 is a novel MEK inhibitor 
 


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PD-0325901 is an orally bioavailable, highly specific allosteric MEK inhibitor currently 
in clinical cancer trials. PD-0325901 inhibits both purified MEK and cellular activation 
of MAPK at the low nanomolar range24. PD-0325901 has shown activity against 
pancreatic, colon, breast, lung and skin cancers.  Phase 1 trials of this drug have shown 
90% suppression of MAPK phosphorylation at doses as low as 1 mg daily.   
Mouse Neurofibroma Volume is Reduced by PD0325901 
PD-0325901 blocked MAPK signaling based on pharmacodynamic measurement of p-
ERK in MPNST xenografts at intervals after PD-0325901 exposure. P-ERK disappeared 
by 30 minutes after dosing MPNST xenografts, remained low at 6h, and resembled 
pretreatment levels by 24h (see Fig 1). Pharmacodynamic assessment of PD-0325901 
was at the end of the 60 day treatment period, demonstrating that the inhibitor remained 
efficacious throughout the experiment.  
Nf1fl/fl;Dhh-Cre mice neurofibroma growth rates can be measured using serial 
volumetric magnetic resonance image (MRI) analysis. In pre-clinical studies performed 
by Ratner et al.25, twenty-eight tumor-bearing mice were randomly assigned to PD-
0325901 treatment (10 mg/kg/day; n=18) or received control vehicle (n=10) (See Fig 2). 
Because this dose of MEK inhibitor has been reported to cause toxicity in human trials 
after prolonged exposure, lower doses of PD-0325901 were also analyzed with striking 
results. Sixteen mice were treated with 5 mg/kg and 15 mice with 1.5 mg/kg PD-
0325901, with MRI volumetric analysis used to determine efficacy. The 1.5 mg/kg PD-
0325901 dose in mice results in plasma concentrations similar to the concentrations 
achieved in adults at the dose proposed for this trial. Tumor volumes were reduced in 
mice treated with 1.5 mg/kg (10/15 mice), 5mg/kg (15/16 mice), or 10 mg/kg (14/18 
mice) PD-0325901 (p<0.001 each dose). PD-0325901 was well tolerated with no 
apparent toxicity at any dose.  In addition, cellular proliferation in neurofibromas treated 
with either control, 1.5 mg/kg, 5.0 mg/kg, or 10 mg/kg of PD-0325901 for 60 days was 
assessed by quantification of Ki67+ cells.  Neurofibromas in Nf1fl/fl;Dhh-Cre mice treated 
with PD-0325901 at any dose showed a significant (***p<0.001) reduction in the 
percentage of  Ki67+ cells relative to mice treated with control vehicle (see Fig 3).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 1. p-ERK in Dhh-Cre mouse neurofibromas.  Brown staining indicates detection of 
phosphorylated (p)-ERK in paraffin tissue sections.  Nf1fl/fl;Dhh-cre  mouse p-ERK staining is robust in 
carrier treated neurofibroma (A, E) but is absent 30 minutes after treatment with 10mg/kg (B) or 1.5 mg/kg 
(F) PD-0325901.  P-ERK becomes detectable 6 hours (C) post-treatment with 10mg/kg PD-0325901 and 
returns to pretreatment levels by 24 hours (D).   P-ERK also becomes detectable 6 hours (G) post-treatment 
with 1.5 mg/kg PD-0325901 but does not return to pretreatment levels by 24 hours (H).  Scale bar = 50 µm; 
scale bar in (H) applies to (E – H); scale bar in (D) applies to (A – D). (Data from N Ratner, personal 
communication.) 
 
 
 


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FIGURE 2. PD-0325901 inhibits neurofibroma growth. (A – F) Serial MRI in Nf1flox/flox;DhhCre 
mice given vehicle (A – C) versus 10 mg/kg PD032901 (D – F).  MRI was conducted on 5 month-
old pre-treated mice (A,D), at treatment onset (B,E – Day 0; 7 months old), and at the end of 
treatment (C,F – Day 60; 9 months old).  Images show representative tumor-bearing mice given 
vehicle control (A – C) or PD-0325901 (D – F).  Note the reduction in size and intensity of bright 
bilateral neurofibromas treated with PD-0325901. (G) Volumetric measurements of vehicle-
treated or PD-0325901-treated Nf1flox/flox;DhhCre mice indicate a decrease in neurofibroma volume 
treated with 1.5 mg/kg, 5mg/kg, or 10 mg/kg PD-0325901 for 2 months.  The y-axis shows tumor 
volume in mm3 quantified by measurements of MRI scans. Each bar represents the difference in 
tumor volume in an individual animal from Day 0 (7 months) to Day 60 (9 months).  Mixed 
Effects Model analysis indicated statistical significance for each dose (p<0.001).  (Data from N 
Ratner, personal communication.) 
 
 
 


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Figure 3.  Molecular mechanism of PD-0325901 in Nf1fl/fl;Dhh-Cre neurofibromas and 
MPNST xenografts.  (A) Assessment of proliferation in neurofibromas by quantification of Ki67+ 
cells.  Neurofibromas in Nf1fl/fl;Dhh-Cre mice treated with 1.5, 5.0, or 10mg/kg PD-0325901 for 
60 days showed a significant (***p<0.001) reduction in the percentage of  Ki67+ cells relative to 
mice treated with control vehicle.  (C) Labeling of Ki67+ proliferating cells (green), CNPase+ 
(red) Schwann cells, and DAPI+ (blue) cell nuclei in Nf1fl/fl;Dhh-Cre neurofibromas (C) and 
MPNST xenografts Scale bar = 50 µm (E) Assessment of vasculature in neurofibromas and 
MPNSTs by quantification of MECA+ endothelial cells.  Number of blood vessels per high 
powered field was significantly (**p<0.01) reduced in both neurofibromas25. 
 
Neurofibromas are complex tumors, containing not only Schwann cells and vasculature, 
but also hematopoietic cells including mast cells and macrophages.  Recent data from the 
Ratner lab (Prada, C., et al., Acta Neuropath, 2012, in press) indicate that roughly 30% of 
neurofibroma cells are macrophages.  Based on this finding, it is likely that patient 
plasma contains growth factors/cytokines that attract these hematopoietic cells to 
neurofibromas.  Such factors could be biomarkers of tumor burden and/or play roles in 
tumor growth. 
 
 
 
 
 


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Figure 4 Iba1+ macrophages in nerve and neurofibroma. (A) Staining of paraffin sections with 
anti-Iba1 (brown) to mark macrophages. GEM genetically engineered mouse model. (B) 
Quantification of Iba1+ macrophages per high-powered field (hfp) (*p=0.001). Averages from 
individual mice are shown as individual dots. (C) Staining of Dhh-Cre; Nf1fl/fl sciatic nerve 
sections with anti-Iba1 to mark macrophages (red) and with anti-GFP to mark Schwann cells 
(green). (D) M2 macrophages are rare in Nf1- deficient nerves and tumors. Iba1 (brown) and 
CD163 (purple) in paraffin sections. Green arrowheads show rare double-labeled cells. In all other 
cases, cells are single labeled. (E) Staining of human plexiform neurofibroma (PNF) and 
malignant peripheral nerve sheath tumor (MPNST) paraffin sections with anti-Iba1 (brown) to 
mark macrophages. (F) Average numbers of Iba1+ cells in human neurofibroma and MPNST. (G) 
FACS shows populations of CD11b cells (macrophages) isolated from human neurofibromas after 
in vitro culture; table presents quantification. Scale bar in Fig. 1A 50 m 
 
 


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Human Trials with PD-0325901 
A pilot study in advanced solid tumor patients (adults) evaluated PD-0325901 
administered orally at 20 mg twice daily (BID) for 21 consecutive days followed by 7 
days of no treatment (n=15 patients), and later at 15 mg BID for 21 consecutive days 
followed by 7 days of no treatment (n=4 patients) when the initial dose was not tolerated 
well 26. The study was terminated early because of an unexpected high incidence of 
musculoskeletal and neurological adverse events, including gait disturbance, memory 
impairment, confusion, mental status changes, and mild to moderate visual disturbances. 
Other common toxicities were diarrhea, rash, fatigue, and nausea. One patient achieved a 
confirmed complete response and five patients had stable disease. 
A Phase 1 trial of PD-0325901 was conducted in 66 patients with advanced cancer27 to 
evaluate different doses and dosing schedules. They found that twice a day dosing 
sustained target suppression more completely than did once daily dosing.   Common 
adverse events were rash, diarrhea, fatigue, nausea, and visual disturbances including 
retinal vein occlusion (RVO; n = 3). Acute neurotoxicity (visual disturbance, balance, 
and gait disorders) was common in patients receiving ≥ 15 mg BID, regardless of 
schedule. The maximum tolerated dose, 15 mg BID continuously, was associated with 
late-onset RVO outside the dose-limiting toxicity window. An alternative dose and 
schedule, 10 mg BID 5 days on/2 days off, was therefore expanded; one RVO event 
occurred.  In contrast to the neurotoxic effects observed, all episodes of RVO presented 
quite late, after 13, 15, and 36 weeks of therapy. A retrospective analysis of relevant 
visual episodes found predisposing factors for retinopathy (hypertension, diabetes, 
hypercholesterolemia, and glaucoma) in all patients with RVO but no correlation with 
cumulative PD-0325901 dose. No patients on a 3 week on/1 week off dosing regimen 
developed RVO. Finally, they determined that doses ≥ 2 mg bid, which achieved the 
plasma levels consistent with target inhibition in xenograft mouse models, caused ≥60% 
suppression of pERK signaling in melanoma tissue from patients.  
An open-label, phase II study of PD-0325901 evaluated 15 mg bid given intermittently (3 
weeks on/1 week off) to 13 patients with advanced non-small cell lung cancer 28.  Of 13 
patients treated, three discontinued due to adverse events (blurred vision, fatigue, and 
hallucinations, respectively).  The study was then altered to 5 days on/2 days off for 3 
weeks, followed by 1 week off and another 21 patients were enrolled. Main toxicities 
included diarrhea, fatigue, rash, vomiting, nausea, and reversible visual disturbances. 
There were no objective responses. Seven patients had stable disease. Neither phase I nor 
II PD-0325901 trials have been conducted in children. 
Based on these data, on the presence of the activated pathway in patients with NF1, and on 
the availability of a targeted inhibitor, we propose a Phase 2 study of the MEK inhibitor PD-
0325901 initially limited to older adolescents and adults with NF1 and plexiform 
neurofibromas.  Development of RVO seems to be avoidable with a 3 week on/1 week off 
schedule.  In addition, toxicity is minimal when patients are given ≤ 5 mg bid. Finally, 
because murine trials show similar efficacy at the low dose of 1.5 mg/kg as at 10 mg/kg, we 
propose a low dose of PD-0325901 at 2 mg/m2 po bid (with a max dose of 4 mg bid) and a 
3 week on/1 week off schedule. 
 


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2.3 
Pharmacokinetics and Dosing of PD-0325901 
 
A major product resulting from metabolism of PD-0325901 is the carboxylic acid 
metabolite, which showed comparable efficacy to the parent compound when assayed 
against purified MEK1 but was significantly less effective at reducing ERK 
phosphorylation in tumor cells.27  Assays for measuring both PD-0325901 and its 
metabolite are well established.  In this study, we will obtain pK data on consenting 
participants and relate this to pD profiles. 
 
2.4 
Overview of Proposed Study 
 
This phase II open label study will evaluate adolescents (≥ 16 years of age) and adults 
with neurofibromatosis type-1 (NF1) and plexiform neurofibromas treated with the MEK 
inhibitor PD-0325901. The primary aim of the study will be to assess quantitative 
radiographic response in a target lesion. Subjects will receive PD-0325901 by mouth on a 
bid dosing schedule of 2 mg/m2/dose with a maximum dose of 4 mg bid. Each course is 4 
weeks duration, and subjects will receive drug on a 3 week on/1 week off schedule.  
Subjects may receive additional courses beyond course 8 only if there is at least 15% 
reduction in volume of the target tumor.  Subjects who have a 20% or greater reduction in 
target tumor volume at the end of 12 courses can continue on therapy for up to an 
additional year (maximum of 24 total courses).  However, subjects who do not achieve at 
least 15% reduction in volume of the target tumor after 8 courses (~8 months) will be 
considered treatment failures and taken off study. 
 
Subjects will have retinal screening performed before starting PD-0325901 and regularly 
while on study drug. Patients with glaucoma, intraocular pressure >21 mmHg, or any 
other significant abnormality (excluding chronic, stable ophthalmological findings 
secondary to Optic Pathway Glioma) on ophthalmic examination (performed by an 
ophthalmologist) will not be eligible. Patients who have received radiation or cytotoxic 
therapy within 4 weeks of study entry and patients who have received radiation to the 
orbit at any time previously, will not be eligible for the study.  Patients with other 
concurrent severe and/or uncontrolled medical disease will also be excluded. In addition, 
pregnant women will not be eligible for enrollment and subjects of reproductive age will 
be required to practice birth control while on treatment. 
 
Subjects entered on the trial will be carefully monitored for the development of PD-
0325901 associated toxicities. Stopping rules for toxicity are outlined in section 8.  
 
In all consenting subjects entered on this trial, a complete pharmacokinetic profile of PD-
0325901 after administration will be evaluated during course 1.  Involvement with this 
part of the study will be required.  
 
Consenting subjects with dermal neurofibromas will have punch biopsies of dermal 
neurofibromas at two time points to determine if the PD-0325901 is affecting the biologic 
target. Involvement with this part of the study will be optional.  
 
Since plexiform neurofibromas may significantly impact the lives of patients with NF1 29, 
this study will evaluate the effects of the disease and treatment with PD-0325901 on the 
quality of life (QOL) of adolescents and adults.  Involvement in this part of the study will 


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be required. The Pediatric Quality of Life Inventory (PedsQL) Neurofibromatosis Type 1 
Module will be used to assess the QOL of subjects (Nutakki et al, personal 
communication).  The PedsQL NF1 Module is a self-reported disease-specific QOL scale 
developed for adolescents and adults with NF1.  It assesses 16 domains of functioning 
including physical functioning, emotional functioning, social functioning, cognitive 
functioning, physical appearance, worry, pain and hurt, fatigue, and daily activities.  
Preliminary data collected on this scale indicates good reliability and validity in adults 
(Nutakki et al, personal communication).  The preliminary data in a small sample of 
adolescents also looks promising (N. Swigonski, personal communication, October 10, 
2012).  Data collected from this trial may be used toward validating this instrument since 
no disease specific QOL measure for NF1 currently exists, but such a tool is critically 
needed.  Pain will be assessed using the Numeric Rating Scale-11 (NRS-11), which is an 
11-point self-report scale of pain intensity.  In addition, the Brief Pain Inventory Pain 
Interference Scale is a 7-item self-report questionnaire that measures the extent to which 
pain interferes with daily functioning30.  Both of these brief measures have been 
recommended to assess different aspects of pain in clinical trials31.  A brief description of 
the QOL and pain scales being used in this protocol is attached in Appendix VII.  
 
For subjects who respond to PD-0325901 (≥20% tumor volume reduction of target lesion 
by 12 courses), an MRI scan of the target lesion is requested (but not required) at 4 and 
12 months after stopping drug (as long as the subject is still on protocol) in order to 
determine whether response is maintained post-therapy.  These studies will not be 
requested from subjects who experience disease progression while on study drug. 
 
 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
The NF Operations Center should be contacted to ensure availability of a treatment slot. 
 
3.1 
Informed Consent/Assent  
 
The investigational nature and objectives of the trial, the procedures and treatments involved and 
their attendant risks and discomforts, and potential alternative therapies will be carefully 
explained to the subject or the subject’s parent(s) or guardian if the subject is a child, and a signed 
informed consent and assent will be obtained according to institutional and federal guidelines.  
Assents will be tailored for those aged 16-17 years (or until the age of majority in the state of the 
clinical center).  In addition, study participants should sign the institution’s HIPAA Consent and 
the institution’s Release of Medical Information Waiver if not already included in the study 
consent document. 
 
3.2 
Screening Procedures 
 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial must 
only be done after obtaining written informed consent. Documentation of the informed consent for 
screening will be maintained in the subject’s research chart. Studies or procedures that were 
performed for clinical indications (not exclusively to determine eligibility) may be used for baseline 
values even if the studies were done before informed consent was obtained. 
 


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Before the subject can be enrolled, the responsible institutional investigator must sign and date 
the completed eligibility checklist. The completed eligibility checklist should be faxed or scanned 
and emailed to the NF Operations Center to confirm eligibility prior to subject enrollment. 
 
3.3 
Study Enrollment 
 
Subjects may be enrolled on the study once all eligibility requirements for the study have been 
met and a treatment number for subject treatment has been confirmed by the NF Consortium 
Operations Center. Subjects who give informed consent for the protocol in order to undergo 
screening for eligibility are not considered enrolled and should not be registered until the 
screening is completed and they are determined to meet all eligibility criteria. Treatment must 
start within 14 days of enrollment. Subjects must not receive any protocol therapy prior to 
enrollment.  
 
4.0 
PATIENT ELIGIBILITY 
 
All studies to determine eligibility must be performed within 2 weeks prior to enrollment. All 
clinical and laboratory data required for determining eligibility of a subject enrolled on this trial 
must be available in the subject's medical or research record which will serve as the source 
document for verification at the time of audit/monitoring.  
 
4.1 
Inclusion Criteria for all subjects: 
 
4.1.1 
All subjects must have EITHER the clinical diagnosis of NF1 using the NIH Consensus 
Conference criteria (see Appendix III), OR have a constitutional NF1 mutation 
documented in a CLIA/CAP certified lab.  
 
4.1.2 
Subjects must have plexiform neurofibroma(s) that are progressive (see section 4.1.2.1) 
OR are causing significant morbidity, such as (but not limited to) head and neck lesions 
that are compromising the airway or great vessels, brachial or lumbar plexus lesions that 
are causing nerve compression and loss of function, lesions causing major deformity (e.g., 
orbital lesions) or are significantly disfiguring (see section 4.1.2.2), lesions of the extremity 
that cause limb hypertrophy or loss of function, and painful lesions.  Subjects with 
paraspinal plexiform neurofibromas will be eligible for this trial. 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.  
 
4.1.2.1  For subjects enrolled for tumor progression, progression is defined as:  
• Presence of new plexiform neurofibroma on MRI or CT (documented by 
comparison with prior MRI or CT), OR 
• A measurable increase in plexiform neurofibroma size (≥ 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) documented by 
comparison of two scans (MRI or CT) in the time period of approximately one 
year or less prior to evaluation for this study. 
 
4.1.2.2 For subjects enrolled for a “major deformity” or “significantly disfiguring” tumor, 
eligible tumors will be limited to tumors of the head & neck or those on other areas of the 


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body that are unable to be concealed by standard garments.  In order to enroll a plexiform 
neurofibroma for these indications, the Study Chair or Co-Chair must be contacted to 
review subject eligibility prior to enrollment. 
 
4.1.3 
Measurable disease:  Subjects must have measurable plexiform neurofibroma(s) amenable 
to volumetric MRI analysis. For the purpose of this study, the target lesion must be seen 
on at least 3 consecutive MRI slices and the field of view must contain the entire tumor of 
interest.  Tumors must be at least 3 mL in volume (most PNs 3 cm in longest diameter will 
meet this criteria).  If the tumor is <3 cm in longest diameter, the subject may still be 
eligible.  Central review of the MRI of the target plexiform is required prior to 
enrollment to ensure that the tumor is measurable and amenable to volumetric 
analysis.  After consenting, please send the images on a CD along with the form in 
Appendix IVa to Eva Dombi (see Appendix IVa for address).  Central review will take 3-
7 days (please plan accordingly). 
 
4.1.4. Age:  Subjects must be ≥ 16 years of age at the time of study entry. 
 
4.1.5. Durable Power of Attorney: Adults who are unable to provide informed consent will 
NOT be enrolled on this study. 
 
4.1.6. Performance Level:  Karnofsky ≥ 50% (Appendix II).  Note: Subjects who are unable to 
walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory 
for the purpose of assessing the performance score. 
 
4.1.7. Prior Therapy 
Subjects are only eligible if complete resection of a plexiform neurofibroma with 
acceptable morbidity is not feasible, or if a subject with surgical option refuses surgery. 
 
Subjects 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 evaluable by volumetric analysis (see section 4.1.3). 
 
Subjects may have been previously treated for a plexiform neurofibroma or other 
tumor/malignancy, but must have fully recovered from the acute toxic effects of all prior 
chemotherapy or radiotherapy prior to entering this study. 
 
a. Myelosuppressive chemotherapy:  Must not have received within 4 weeks of entry 
onto this study.  
b. Hematopoietic growth factors: At least 7 days since the completion of therapy with a 
growth factor that supports platelet, red or white cell number or function.   
c. Biologic (anti-neoplastic agent):  At least 14 days since the completion of therapy 
with a biologic agent.  For agents that have known adverse events occurring beyond 
14 days after administration, this period must be extended beyond the time during 
which adverse events are known to occur.  These subjects must be discussed with the 
Study Chair on a case-by-case basis. 
d. Investigational Drugs:  Subjects must not have received an investigational drug 
within 4 weeks. 
e. Steroids: Subjects with endocrine deficiencies are allowed to receive physiologic or 
stress doses of steroids if necessary.   
f. 
XRT:  ≥ 6 months from involved field radiation to index plexiform neurofibroma(s); 


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≥ 6 weeks must have elapsed if subject has received radiation to areas outside index 
plexiform neurofibroma(s). Subjects who have received radiation to the orbit at any 
time are excluded. 
g. 
Surgery: At least 2 weeks since undergoing any major surgery and must be 
recovered from effects of surgery. 
 
4.1.8. Organ Function Requirements 
 
4.1.8.1. 
Adequate Bone Marrow Function Defined as: 
- 
Peripheral absolute neutrophil count (ANC) ≥ 1500/µL 
- 
Platelet count ≥ 100,000/µL 
- 
Hemoglobin ≥ 10.0 gm/dL 
 
4.1.8.2. 
Adequate Renal Function Defined as:  maximum serum creatinine 1.5 mg/dL 
OR a creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 
 
 
4.1.8.3. 
Adequate Liver Function Defined As: 
- Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal 
(ULN) for age, and 
- SGPT (ALT) ≤ 5 x upper limit of normal (ULN) for age, and 
- Serum albumin ≥ 2 g/dL. 
 
 
4.2 
Exclusion Criteria 
 
4.2.1 
Exclusion Criteria 
• 
Chronic treatment with systemic steroids or another immunosuppressive agent.  
Subjects with endocrine deficiencies are allowed to receive physiologic or stress doses 
of steroids if necessary. 
• 
Evidence of an active optic glioma or other low-grade glioma, requiring treatment with 
chemotherapy or radiation therapy.  Subjects not requiring treatment are eligible for 
this protocol. 
• 
Patients with malignant glioma, malignant peripheral nerve sheath tumor, or other 
malignancy requiring treatment in the last 12 months. 
• 
Subjects who have received radiation to the orbit at any time previously 
• 
Subjects with glaucoma, intraocular pressure >21 mmHg, or any other significant 
abnormality on ophthalmic examination (performed by an ophthalmologist). 
Ophthalmological findings secondary to long-standing Optic Pathway Glioma such as 
optic nerve pallor or strabismus will NOT be considered significant for the purposes 
of the study. 
• 
Tumor not able to be reliably evaluated by volumetric analysis. 
• 
Other concurrent severe and/or uncontrolled medical disease, which could compromise 
participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe 
infection, severe malnutrition, chronic liver or renal disease, active upper GI tract 
ulceration, congestive heart failure, etc.) 
• 
Subjects who have an uncontrolled infection. 


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• 
Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of PD-0325901 (e.g. ulcerative disease, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection).  
• 
Subjects unable to swallow capsules whole, as study drug may not be crushed or 
opened. 
• 
Women who are pregnant or breast feeding.  
• 
Males or females of reproductive potential may not participate unless they have agreed 
to use an effective contraceptive method during the period they are receiving the study 
drug and for 3 months thereafter. Abstinence is an acceptable method of birth control. 
Women of childbearing potential will be given a pregnancy test within 7 days prior to 
administration of PD-0325901 and must have a negative urine or serum pregnancy test. 
• 
History of noncompliance to medical regimens 
• 
Subjects unwilling to or unable to comply with the protocol, or who in the opinion of 
the investigator may not be able to comply with the safety monitoring requirements of 
the study 
• 
Prior treatment with a MEK inhibitor of any kind 
 
 
 
5.0 
REQUIRED DATA 
 
IRB Approvals 
 
The PI from each participating institution will provide the NF Consortium Operations Center 
with a copy of the initial IRB protocol approval and the yearly IRB continuing reviews. The 
Study Coordinator will submit these to the USAMRMC ORP HRPO. Registration will be halted 
at a participating institution if a current continuing approval is not on file at the NF Consortium 
Operations Center.  
 
 
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. 
 
Amendments and Consents 
 
The PI from each participating institution will provide the NF Consortium Operations Center with 
a copy of IRB approval of all amendments to the protocol or consent. The NF Consortium 
Operations Center will provide these institutional reviews to the USAMRMC ORP HRPO.   
 
As this trial receives funding by the US Army, substantive amendments to the research protocol 
and any amendments that could potentially increase risk to subjects must be submitted to the 
HRPO for approval prior to implementation and site distribution. The USAMRMC ORP HRPO 
defines a substantive amendment as a change in Principal Investigator, change or addition of an 
institution, elimination or alteration of the consent process, change to the study population that 
has regulatory implications (e.g. adding children, adding active duty population, etc.), significant 
change in study design (i.e. would prompt additional scientific review), or a change that could 
potentially increase risks to subjects.  
 


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Data Collection and Toxicity Reporting 
 
The trial is being conducted by the NF Consortium.  Case report forms developed by the NF 
Consortium Operations Center will be used for submitting clinical data to the Operations Center.  
Data must be submitted to the Operations Center within two weeks of completing each required 
evaluation while the subject is on study.  
 
The NCI POB will receive MRI studies electronically or on CD and completed worksheets for 
volumetric analysis, and completed QOL and pain evaluations for analysis.  When sending the 
CD, the site must provide tracking # (FedEx or UPS) by email to Eva Dombi: 
dombie@mail.nih.gov.  
 
Cincinnati Children’s Hospital Medical Center will receive pharmacokinetic and 
pharmacodynamic samples together with completed worksheets. 
 
Upon analysis of these studies, results will be transmitted to the NF Consortium Operations 
Center for entry into the study databases. 
 
Representatives from the FDA and the U.S. Army Medical Research and Material Command 
will have access to the data and research records as required.  
 
Julia Glade Bender, M. will serve as the medical monitor.  She will serve as a patient advocate 
and is independent of the clinical study team.  She 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 10.0. 
She will be automatically notified by the data entry system as soon as any SAE is entered into 
the study system. The monitor provides an unbiased written report of the event and may request 
additional information if needed for her determination.  
 
Handling of Research Samples 
 
This study is conducted at NF Consortium Sites and coordinated by the NF Consortium 
Operations Center.  Sample labeling, collection and initial processing will be conducted as 
outlined in the study Section 9, as well as in Appendix VI. Blood samples obtained for 
pharmacokinetic and pharmacodynamic studies and skin samples for pharmacodynamic studies 
will be sent to Cincinnati Children’s Hospital Medical Center for analysis. Samples will be 
stored in designated monitored freezers and will be identified by the protocol specific subject ID 
number.  Once analyzed for the studies outlined in this protocol, any remaining samples will be 
stored by the Cincinnati Children’s Hospital until the study is complete and the manuscript 
describing the study has been accepted for publication.  Any use of samples not outlined in 
Section 9 or Appendix VI will require Study Leadership approval and prospective IRB review 
and approval.  The study will remain open and status reported to the IRB until all samples have 
been analyzed, reported or destroyed. Unintentional loss or destruction of any samples will be 
reported to the IRB as part of annual continuing reviews.  MRI studies of PN will be obtained as 
described in Appendix IV and will be sent on CD to the NCI POB. MRI studies will be loaded 
on one of three Sun Workstations, which are password protected and allow access only to Drs. 
Dombi, Widemann, or associate investigators on the trial. CDs will be stored in locked filing 
cabinets.  Data results will be electronically submitted to the Operations Center for curation in 
the study database. 
 


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Data and Center Audits 
 
The trial will be monitored during the course of the study and audited periodically by the NF 
Consortium Operations Center 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 compromise the ability to safely administer study drug 
or to accurately determine study endpoints, will be included in the annual protocol review to the 
USAMRMC ORP HRPO.   
 
All unexpected and serious adverse events will be forwarded to the Medical Monitor, the Study 
PI and the USAMRMC ORP HRPO by the NF Consortium Operations Center as defined in 
Section 10.0.  
 
Volumetric MRI analysis performed by the NCI-POB will be used to determine disease 
progression, and subjects will not be removed from study based on 1-D or 2-D MRI 
measurements or based on clinical measurement of superficial lesions.  
 
5.1 
Tests and Observations   
 
See section 9.0 and Appendix I.  Unless otherwise noted, all tests to determine eligibility must be 
completed within 14 days of study entry. 
 
5.2 
Records to be Kept 
 
Subject Registration and Case Report Forms 
 
Subjects will be registered with the NF Consortium Operations Center via the electronic data 
entry system (eDES). Electronic and paper Case Report Forms will be developed by the 
Consortium Operations Center and PI.  All data must be entered into the eDES.  Sites have the 
option of maintaining a printed copy of completed forms in the subject’s study binder that have 
been initialed and dated by the study team member entering the data into the paper case report 
form. 
 
Subjects must not be identified by name on any study documents that are sent off site to any 
agency.  The Subject Identification Number received upon data entry registration and placed on 
all case report forms and regulatory documents will identify subjects. 
 
All data entered on a paper CRF must be legibly recorded in indelible ink or typed.  A correction 
should be made by striking through the incorrect entry with a single line and entering the correct 
information adjacent to it.  The correction must be initialed and dated by the investigator or 
designated qualified individual.  Any requested information that is not obtained as specified in the 
protocol should have an explanation noted on the CRF as to why the required information was not 
obtained.  The electronic CRF provides audit trail showing when data is revised. 
 
 
5.3 
Role of Data Management 
 


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5.3.1 
Instructions concerning the recording of study data on CRFs will be provided by the NF 
Operations Center. 
5.3.2 
It is the responsibility of the NF Operations Center to assure the quality of data for this 
study in partnership with the study investigators.  This role extends from protocol 
development to generation of the final study database. 
 
6.0 
TREATMENT PROGRAM 
 
6.1 
Agent Information/ PD-0325901 
 
6.1.1 
Source and Pharmacology:  
 
Absorption 
Absorption of PD-0325901 following oral administration of a single dose is moderate to 
high with an absolute bioavailability of 29.5% in rats, 103% in dogs, and 43.7% in 
monkeys. 
 
In humans, the plasma pharmacokinetics of PD-0325901 was characterized by rapid 
absorption, with peak concentrations occurring within 1 to 2 hours of dosing, generally 
dose- proportional changes in exposures, and an average elimination half-life of 8.6 hours 
(range 5 to 18 hours across dosing cohorts). The plasma half-life of the carboxylic acid 
metabolite PD-0315209 was longer than that for the parent. 
Food effects 
There was minimal effect of food on PD-0325901 pharmacokinetics. Food appeared to 
reduce PD-0325901 peak plasma concentrations, but the effect on AUC was variable. 
 
Distribution 
There was no apparent accumulation of PD-0325901 in plasma following 13 weeks of 
dosing to rats and dogs. 
Plasma protein binding for [14C]PD-0325901 was high with unbound fractions of 
<0.0129 (mouse), <0.0328 (rat), <0.00948 (dog),  <0.00905 (monkey), <0.00254 
(human). 
 
PD-0325901 showed a marked preferential distribution to plasma over red blood cells. 
Following oral administration to Long Evans rats, [14C]PD-0325901 distributed 
extensively to tissues, with concentrations in most tissues lower than that in blood; 
distribution of radio-equivalents in brain demonstrated distinct regional localization with 
highest levels in striatum, hippocampus, and olfactory bulb. Drug equivalents were not 
retained in pigmented tissues. 
Metabolism 
In vitro metabolism of [14C]PD-0325901 involves glucuronidation and oxidation of 
parent compound. A carboxylic acid metabolite (PD-0315209, M15) was found both in 
vitro and in vivo (rats, dogs, and monkeys). In rats, biliary excretion is the major route of 
elimination for the absorbed compound and/or its metabolites. 


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In vitro studies using pooled human liver microsomes demonstrated low potential of PD-
0325901 to inhibit activities of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and 
CYP3A4 based on IC50 values relative to the plasma concentration achieved in humans. 
Excretion 
After oral administration of [14C]PD-0325901 to rats and dogs, elimination of [14C]PD-
0325901-derived radioactivity occurred primarily in feces in dogs. In male and female 
bile-duct cannulated rats, the elimination of [14C]PD-0325901-derived radioactivity 
occurred predominately in the bile and via feces in non-cannulated rats. Elimination of 
[14C]PD-0325901-derived radioactivity via renal excretion plays a minor role. 
 
6.1.2 
Formulation and Stability 
The dosage form is a hard gelatin capsule. The capsule shell is composed of gelatin, 
titanium dioxide, and black iron oxide. The active composition consists of PD-0325901 
and precedented ingredients. The capsules will be packaged in appropriate packaging 
material and storage conditions. 
 
Tablet size: 1mg 
Molecular Weight: 482.19 g/mol 
 
Chemical Structure: 
 
 
 
CAS Name: N-[(2R)-2,3-dihydroxypropoxyl]-3,4-difluro-2-[(2-fluoro- 4-
iodophenyl)amino]-benzamide 
Systematic (IUPAC) Name: N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo- phenylamino)-benzamide 
Molecular Formula: C16H14N2O4F3I  
Physical Description: White to tan or pink powder 
6.1.4 
Supplier 
Pfizer 
235 East 42nd Street  
New York, NY 10017 
1-212-733-2323 
 
6.1.5 
Toxicities 


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The primary PD-0325901 toxicities in nonclinical studies are to the GI tract (rat, dog, 
rabbit, and monkey), skin (rat, dog, and monkey), cornea (rat), CNS (dog), liver (rat), 
gallbladder (monkey), bone (rat), and systemic mineralization (rat). Systemic 
mineralization in the rat was associated with dysregulation of calcium and phosphorus 
homeostasis. Injury to the mucosa of the GI tract is the dose-limiting toxicity in non-
rodents. Results of the safety pharmacology studies were generally unremarkable. PD-
0325901 was not mutagenic in bacteria or clastogenic in vitro or in vivo. 
As of 20 June 2012 (data cut-off date), 3 studies evaluating the safety, efficacy, and/or 
PK of PD-0325901 had been undertaken. Study A4581001 was a Phase 1/2 study in 
cancer patients, with 79 patients dosed (66 in Phase 1 and 13 in Phase 2). Study 
A4581002 was a Phase 2 study in patients having advanced NSCLC (N = 13). In 
addition, a formal food effect study in healthy subjects (N = 23) evaluated the effect of 
food on plasma pharmacokinetics of PD-0325901. Doses have been administered on an 
intermittent (i.e. 3 weeks on/1 week off) or continuous daily dosing schedule. Frequently 
reported treatment-related adverse events have included diarrhea, acneiform skin rash, 
edema, visual disturbances (consisting of blurred vision, reduced acuity, halos, floaters, 
colored spots or flashes of light), nausea, and fatigue. As of 20 June 2012, two patients on 
the Phase1 study were diagnosed with significant findings on eye examinations: 1 with a 
Grade 3 eye disorder, 1 with a Grade 3 retinal vein occlusion. There were also 6 patients 
with Grade 2 visual adverse events including 1 case of retinal vein occlusion, 1 case of 
optic neuropathy and 1 case of retinal hemorrhage. None of the patients on the 15-20 mg 
bid intermittent dosing Phase 2 part of the study had greater than a Grade 1 visual adverse 
event. 
Among 13 subjects enrolled on a 15 mg bid 3 weeks on/1 week off schedule (Schedule 1-
see Table 2), the most frequently reported treatment-related adverse events (AEs) were 
gastrointestinal disorders (11 subjects, 84.6%), including diarrhea (7 subjects, 53.8%), 
nausea and vomiting (each in 6 subjects, 46.2%), and dry mouth (2 subjects, 15.4%). 
Seven of 13 subjects (53.8%) experienced at least one Grade 3, treatment-related AE 
according to the CTCAE criteria. No subjects experienced treatment-related Grade 4 or 
Grade 5 AEs. Treatment-related Grade 3 AEs included inappropriate antidiuretic 
hormone secretion, diarrhea, pneumonia, hypocalcemia, confusional state, hallucination, 
dyspnea, lung infiltration, and rash, each in 1 subject (7.7%). 
Among 21 subjects enrolled on a 15 mg bid 5 days on/2 days off for 3 weeks followed by 
1 week off schedule, the most frequently reported AEs were also gastrointestinal 
disorders, which occurred in all subjects (n = 21, 100%). These AEs included diarrhea 
(16 subjects, 76.2%), vomiting (7 subjects, 33.3%), nausea (6 subjects, 28.6%), 
constipation (4 subjects, 19.0%), and abdominal pain, abdominal pain (upper), and dry 
mouth, each experienced by 3 subjects (14.3%). One subject (4.8%) experienced 
dyspepsia during this study. 6 of 21 subjects (28.6%) experienced at least one treatment-
related Grade 3 AE, and 3 subjects (14.3%) experienced at least one treatment-related 
Grade 4 AE. Treatment-related Grade 3 AEs included atrial flutter, diarrhea, hiatus 
hernia, bronchitis, alanine aminotransferase increased, aspartate aminotransferase 
increased, syncope, confusional state, dyspnea, hypoxia, and hypotension, each in 1 
subject (4.8%); and fatigue and dehydration in 2 subjects (9.5%). Treatment-related 
Grade 4 AEs included diarrhea, dehydration, pneumonia aspiration, pulmonary 
embolism, pulmonary hypertension, and deep vein thrombosis, each in 1 subject (4.8%). 


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Table 1  Adverse drug reactions occurring in patients receiving PD-0325901 in Phase 1/2 
Studies* 
 
 
System Organ Class 
Adverse Reaction 
Eye Disorders 
Retinal vein occlusion, retinal hemorrhage, 
optic ischemic neuropathy 
Nervous system disorders 
Dizziness, paresthesia 
Gastrointestinal disorders 
Diarrhea 
Skin and subcutaneous tissue disorders 
Rash 
Musculoskeletal and connective tissue 
disorders 
Muscle disorder (neck drop), muscular 
weakness 
Psychiatric disorders 
Confusional state 
*Table 7-1 in PD-0325901 Investigator Brochure September 2012  
 
Table 2:  Study A4581002 (Phase 2) Treatment-related Adverse Events Experienced by > 
10% of Subjects on Either Dosing Schedule (Maximum Grade, All Cycles)* 
 
MedDRA SOC 
Preferred term 
Schedule 1 
N (%) 
Schedule 2 
N (%) 
At least 1 AE 
13 (100.0%) 
21 (100.0%) 
Eye disorders 
9 (69.2) 
7 (33.3) 
Vision blurred 
5 (38.5) 
1 (4.8) 
Visual disturbance 
4 (30.8) 
1 (4.8) 
Gastrointestinal disorders 
10 (76.9) 
21 (100) 
Constipation 
0 (0.0) 
3 (14.3) 
Diarrhea 
7 (53.8) 
16 (76.2) 
Dry mouth 
2 (15.4) 
3 (14.3) 
Dyspepsia 
2 (15.4) 
1 (4.8) 
Nausea 
5 (38.5) 
6 (28.6) 
Vomiting 
5 (38.5) 
7 (33.3) 
General disorders and administration site 
6 (46.2) 
15 (71.4) 
conditions 
Face edema 
2 (15.4) 
4 (19.0) 
Fatigue 
4 (30.8) 
10 (47.6) 
Edema peripheral 
2 (15.4) 
4 (19.0) 
Metabolism and nutrition disorders 
1 (7.7) 
5 (23.8) 
Dehydration 
0 (0.0) 
3 (14.3) 
Nervous system disorders 
4 (30.8) 
7 (33.3) 
Dizziness 
1 (7.7) 
3 (14.3) 
Psychiatric disorders 
6 (46.2) 
6 (28.6) 
Confusional state 
4 (30.8) 
4 (19.0) 
Hallucination                                                                        2 (15.4)                   1 (4.8) 
Respiratory, thoracic and mediastinal 
5 (38.5) 
6 (28.6) 
disorders 
Dyspnea 
3 (23.1) 
2 (9.5) 
Epistaxis 
2 (15.4) 
0 (0.0) 
Skin and subcutaneous tissue disorders 
7 (53.8) 
15 (71.4) 
Dermatitis acneform 
1 (7.7) 
7 (33.3) 


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Rash 
6(46.2) 
7(33.3) 
  
 
*Table 6.2-17 in PD-0325901 Investigator Brochure September 2012 
 
6.2 
Treatment Overview 
 
This phase II study will evaluate adolescents (≥ 16 years of age) and adults with 
neurofibromatosis type-1 (NF1) and plexiform neurofibromas treated with the MEK inhibitor PD-
0325901. The primary aim of the study will be radiographic response. Subjects will receive PD-
0325901 by mouth on a bid dosing schedule of 2 mg/m2/dose with a maximum dose of 4 mg bid. 
Each course is 4 weeks duration with a 3 week on/1 week off schedule.  Subjects may receive 
additional courses beyond course 8 only if there is at least 15% reduction in volume of the target 
tumor.  Subjects who have a 20% or greater reduction in target tumor volume at the end of 12 
courses can continue on therapy for up to an additional year (maximum of 24 total courses). 
Subjects who have not had at least 15% reduction in volume of the target tumor by the end of the 
8th course will be removed from protocol therapy.  Subjects who have not had at least 20% tumor 
shrinkage by volumetric analysis by the end of the 12th course will be removed from protocol 
therapy. 
 
PD-0325901 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 the drug.  
Subjects or their parents/guardians will keep a diary to document each dose of PD-0325901 and 
potential side effects. The subject diary should be reviewed with the subject's family at each 
required clinical study evaluation.  The subjects should use the diary in Appendix V or a suitable 
document developed by the local institution. In addition, leftover study medication should be 
collected at each on study evaluation, and drug should be accounted for at this time (Appendix V).  
Food did not seem to have a significant effect on PD-0325901 pK.  Medication may be taken 
either with or without food. 
 
PD-0325901 is an antineoplastic agent and should be handled and administered with care. 
Inhalation of powder or contact with skin and mucous membranes, especially those of the 
eyes, must be avoided. Should accidental eye contact occur; copious irrigation with water should 
be instituted immediately followed by prompt ophthalmologic consultation. Should accidental 
skin contact occur; the exposed area should be irrigated immediately with copious amounts 
of water for at least 15 minutes. 
 
PD-0325901 capsules must be swallowed whole.  Subjects should not open or crush them for 
any reason. 
 
 
Starting Dosing Nomogram 
Starting dose: 2 mg/m2/dose BID maximum dose 4 mg/dose 
BSA m2 
≥0.9-1.24 
1.25-1.74 
≥1.75 
Starting Dose (mg) 
2 
3 
4 
Tablets: 1 mg 
 
PD-0325901 will be held for subjects who experience toxicity as per section 8.  
 


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6.3 
Criteria for Starting Subsequent Courses 
 
Unless the subject has developed toxicity requiring interruption or withdrawal from protocol 
therapy (see section 8.0), a course may be repeated every 28 days if the subject has at least stable 
disease and has again met laboratory parameters (when study evaluations are required) as defined 
in the eligibility section.   
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
Subjects must be instructed not to take any additional medications (including over-the-counter 
products) during the trial without prior consultation with the investigator. All medications taken 
within 30 days of screening should be recorded. If concomitant therapy must be added or changed, 
the reason and name of the drug/therapy should be recorded. 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
subject are allowed, including drugs given prophylactically (e.g. antiemetics), with the following 
exceptions: 
• No other investigational therapy should be given to subjects 
• No chronic treatment with systemic steroids or another immunosuppressive agent (see 
section 7.4) with the exception of subjects with endocrine deficiencies who are allowed 
to received physiologic or stress doses of steroids, if necessary.  
 
Concurrent Anticancer Therapy 
 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered.  
 
7.1 
Supportive Care 
 
Appropriate antibiotics, blood products, fluids, electrolytes and general supportive care are to be 
used as necessary.  Antiemetics, other than systemic steroids, are allowed. Corticosteroids are 
permissible as premedication for blood product transfusions, or as treatment for an acute allergic 
reaction. 
 
7.2 
Growth Factors 
 
Growth factors that support platelet or white cell number or function can only be administered for 
culture proven bacteremia, clinical sepsis, or invasive fungal infection with neutropenia. The 
Study Chair should be called when growth factors are initiated. 
 
7.3 
Surgery 
 
Subjects undergoing surgical procedures should have the study drug held for 2 weeks prior to the 
procedure, if feasible, and for 2 weeks after. Surgery to a non-target plexiform neurofibroma does 
not require removal from protocol therapy (i.e. subject can continue on therapy once he/she 
recovers from surgery, as described above). 
 
 
 


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7.4 
Concomitant Medications 
 
Other than for subjects receiving physiologic replacement doses of steroids due to endocrine 
deficiencies, corticosteroid therapy is ONLY permissible as premedication for blood product 
transfusions, or as treatment for an acute allergic reaction.  
 
      
 
8.0 
MODIFICATIONS FOR ADVERSE EVENTS 
 
Guidelines for Treatment Delay, Dose Reduction, or Study Drug Discontinuation for 
Toxicity 
 
Subjects will be monitored continuously for AEs throughout the study and for 30 days after the 
last dose of study treatment, and for any serious adverse event (SAE) assessed as related to study 
treatment or study procedures, even if the SAE occurs more than 30 days after the last dose of 
study treatment. 
Subjects will be instructed to notify their physician immediately of any and all AEs. Subjects 
experiencing one or more AEs due to the study treatment may require a dosing delay or 
reduction(s) in their dose in order to continue with study treatment.  
Adverse events will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) (v4.0). 
 
Any subject experiencing a toxicity (as described below in sections 8.1 and 8.2) that is possibly, 
probably, or definitely related to PD-0325901 should have the drug held until the toxicity has 
completely resolved.  In addition, the site should notify the study chair (brian.weiss@cchmc.org) 
and NF Operations Center immediately of any DLT. 
 
8.1 
Hematological Toxicity  
 
8.1.1 During All Courses: 
 
If a subject experiences, at least possibly related to the investigational drug, EITHER ≥ 
grade 3 neutropenia (ANC < 1,000), anemia (Hb < 8), or thrombocytopenia (platelets < 
50,000) OR clinically significant grade 2 neutropenia, anemia, or thrombocytopenia that 
does not resolve within 72 hours after initiation of maximal medical management, the drug 
will be withheld.  Subjects should continue to be seen and have complete blood counts 
obtained every 1-2 weeks until recovery (≤ Grade 1) is documented.  Upon resolution of 
the toxicity (≤ Grade 1), PD-0325901 may be restarted using the following nomogram: 
 
Dose reduction: 
Starting dose (mg) 
Reduced dose (mg) 
Percent decrease 
2 BID 
2 mg AM; 1 mg PM 
25% 
3 BID 
2 mg BID 
33% 
4 BID 
3 mg BID 
25% 
 


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Subjects will not have the dose re-escalated in subsequent cycles. If the subject has 
hematological toxicity (as explained above) at the reduced dose, then they should be 
removed from protocol therapy. 
 
8.2 
Non-Hematological Toxicity 
 
8.2.1 During All Courses  
 
If a subject experiences, at least possibly related to the investigational drug, EITHER ≥ 
Grade 3 non-hematological toxicity OR clinically significant grade 2 non-hematological 
toxicity that does not resolve within 72 hours after initiation of maximal medical 
management, the study drug will be withheld. Subjects should continue to be seen and 
have appropriate labs/observations obtained every 1-2 weeks until recovery (≤ Grade 1) 
is documented. Upon resolution of the toxicity (≤ Grade 1), PD-0325901 may be 
restarted using the nomogram in 8.1.1.  Subjects will not have the dose re-escalated in 
subsequent cycles.  If the subject has non-hematological toxicity at the reduced dose, then 
they should be removed from protocol therapy.  
8.3 
Toxicities Requiring Removal From Protocol Therapy 
 
Any toxicity defined in section 8.1 or 8.2 that is at least possibly related to study medication that 
recurs on a reduced dose of PD-0325901.  No subject may be dose-reduced more than once. 
 
Any ≥ Grade 3 toxicity that is at least possibly due to study drug that does not resolve to ≤ Grade 
1 within 2 weeks requires removal from protocol therapy.     
 
Development of retinal vein occlusion will also require removal from protocol therapy 
 
Development of glaucoma, intraocular pressure >21 mmHg, or any other significant abnormality 
on ophthalmic examination (performed by an ophthalmologist) while on study treatment will 
require removal from protocol therapy. Ophthalmological findings secondary to long-standing 
Optic Pathway Glioma such as optic nerve pallor or strabismus will NOT be considered 
significant for the purposes of the study. 
 
The study chair or co-chair should be contacted for any questions regarding toxicity. 
 
 
 
9.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
Pre and on study evaluations are described in Appendix I. 
 
9.1 
Required Clinical, Laboratory and Disease Evaluation 
 
All entry/eligibility studies must be performed within 2 weeks prior to enrollment into the trial 
(unless otherwise specified).  The baseline MRI study documenting disease status is required within 
4 weeks prior to study entry.  Entry/eligibility studies (laboratory and MRI) may be counted 
as the baseline (pre-study) studies as long as there has been no concerning change in 
clinical status prior to starting study drug. Study drug must start within 14 days of 


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enrollment. 
 
9.2 
History and physical examination and vital signs 
 
Physical examination will be performed prior to entry, at the end of course 1 (+1week); post 
course 2 (+1week), 3 (+1 week), 4 (+1 week), 8 (+2 weeks), 12 (+2 weeks), 18 (+2 weeks) and 24 
(+2 weeks).  In addition, at the end of treatment +2 weeks if this is not encompassed in the times 
above. The exam must comprise a total body examination (general appearance, skin, neck, 
including thyroid, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities 
and basic nervous system). Significant findings made after the start of study drug which meet the 
definition of an Adverse Event must be recorded.  
Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, 
temperature and weight.  
 
9.3 
Retinal Exam 
 
Subjects will have a retinal exam consisting of slit lamp examination with binocular indirect 
ophthalmoscopy at baseline and after the first and second course (+2 weeks), then after every two 
courses for the first year (+2 weeks), then after every third course for the second year (+2 weeks) 
while on study drug. Subjects with evidence of disease (retinal vein occlusion) will need full 
evaluation (such as fluorescein angiography and/or optical coherence tomography).  In addition, 
at the end of treatment +2 weeks if this is not encompassed in the times above. 
 
9.4 
Hematology 
 
CBC must include hemoglobin, hematocrit, platelets, total white blood cell count (WBC) and 
differential.  CBC must be performed within two weeks prior to entry on trial, at the end of 
courses 1 +1 week, 2 +1 week, 3 +1 week, 4 +1 week, 8 +2 weeks, 12 +2 weeks, 18 +2 weeks 
and 24 +2 weeks.  In addition, at the end of treatment +2 weeks if this is not encompassed in the 
times above. 
 
9.5 
Blood chemistry 
 
Blood chemistry must include sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
glucose, creatinine, blood urea nitrogen, albumin, total protein, SGOT (AST), SGPT (ALT), total 
bilirubin, alkaline phosphatase, and CPK.  Blood chemistries should be drawn within two weeks 
prior to study entry, at the end of courses 1 +1 week, 2 +1 week, 3 +1 week, 4 +1 week, 8 +2 
weeks, 12 +2 weeks, 18 +2 weeks and 24 +2 weeks.  In addition, at the end of treatment +2 
weeks if this is not encompassed in the times above. 
 
9.6 
Serum or Urine Pregnancy Test 
Standard pregnancy tests will be given to all females of childbearing age within 7 days prior to 
starting treatment medication.  In addition, tests will be administered at the end of course 4 +2 
weeks, 8 +2 weeks, 12 +2 weeks, 18 +2 weeks, and 24 +2 weeks to ensure that females are not 


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pregnant while on the study medication. In addition, at the end of treatment +2 weeks if this is not 
encompassed in the times above. 
 
9.7 
MRI for volumetric analysis of plexiform neurofibroma 
 
Evaluate the plexiform neurofibromas(s) by MRI within 4 weeks prior to course 1 and after 
courses 4 +2 weeks, 8 +2 weeks, 12 +2 weeks, 18 +2 weeks, and 24  +2 weeks while on study 
and at end of study +2 weeks.  In addition, at the end of treatment +2 weeks if this is not 
encompassed in the times above.  To evaluate the durability of response, subjects who responded 
while on treatment (>20% target lesion shrinkage by 12 cycles), will be recommended but not 
required to have a follow-up MRI scan at approximately 4 months and 12 months following 
completion of therapy.  If a subject starts another tumor-directed therapy during the one year 
follow-up time, then they are off-study (and no further MRIs requested). 
 
The imaging protocol outlined in Appendix IV will be used each time MRI examinations are 
performed to assess progression or response. In subjects with clinical suspicion of disease 
progression, MRI analysis should be performed earlier using the protocol outlined in Appendix 
IV.  If because of unforeseen reasons, an MRI time window is passed, but not yet at the time of 
the opening of the subsequent window, the MRI should be performed and the protocol violation 
noted. 
 
 
9.8 
PD-0325901 diary 
 
A diary will be kept by the subject and/or proxy (see Appendix V).  A document developed by 
the local institution can be used as a substitute for Appendix V. The diary will be reviewed with 
the treating physician at the history/physical visit after completion of courses 1+1 week, 2 +1 
week, 3 +1 week, 4 +1 week, 8 +2 weeks, 12 +2 weeks, 18 +2 weeks and 24 +2 weeks.  In 
addition, at the end of treatment +2 weeks if this is not encompassed in the times above. 
 
9.9 
Pharmacokinetic profile of PD-0325901 (Required) 
 
A complete pharmacokinetic profile will be obtained on all subjects. Involvement with this part 
of the study will be required. Plasma pharmacokinetics will be studied on day 1 of course 1.  
 
Blood samples (3 ml) will be drawn for the pharmacokinetic profile before, and during PD-
0325901 therapy on day 1 of course 1 at the following times: before the Day 1 morning dose (pre-
dose), and at 30 min, 1 hr, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, and 10-12 hrs after the Day 1 morning 
dose of PD-0325901, prior to administration of the evening dose.  
 
There will be a total of 9 samples drawn. Samples are stable for at least 8 months at -80 °C. Drug 
analysis: PD-0325901 concentrations will be analyzed in plasma by Advion Laboratories.  
Specimens will be maintained by Advion Laboratories until the end of the study, then remaining 
specimens will be destroyed.  Procedures for obtaining, processing, and shipment of blood 
samples are outlined in Appendix VI.   
 


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9.10 
Pharmacodynamic Analysis (Optional) 
 
As a marker of the effects of PD-0325901, ERK phosphorylation will be measured in dermal 
neurofibromas using methods described by Ratner et al. Dermal neurofibromas are nerve tumors 
associated with dermal and epidermal nerves.  Many NF1 patients develop dermal neurofibromas 
around the time of puberty.  The cellular composition of dermal neurofibromas is 
indistinguishable from that of plexiform neurofibromas; therefore, dermal neurofibromas may be 
useful as an accessible surrogate tissue for analysis of therapeutic efficacy. 
 
Three millimeter punch biopsies of 1-2 dermal neurofibromas (2 dermal neurofibromas per 
timepoint is preferred) will be made prior to initiating therapy with PD-0325901 and during week 
3 of course 1 at least 30 min but no more than 6 hours after taking the morning dose.  At each 
time point, one tumor will be fixed in formalin for paraffin embedding, and shipped on wet ice.  
At the same time, one tumor will be frozen in liquid nitrogen and stored at -80˚C and shipped 
separately, on dry ice.  If only one tumor is biopsied, the sample should be placed in formalin. 
Time of tumor removal after drug dose will be noted.   Any remaining specimens will be stored 
for future research with subject consent.  Details regarding sample processing and shipment are 
provided in Appendix VI. 
 
9.11 
Plasma Cytokines and Growth Factors (Optional) 
Procedure: 10 ml blood will be drawn into EDTA tubes before treatment initiation, during week 3 
of course 1 and during week 3 of course 4.  The sample will be collected at least 30 min but no 
more than 6 hours after taking the morning dose.  Any remaining specimens will be stored for 
future research with subject consent.   
 
9.12 
Maximum blood volumes for pharmacokinetic and pharmacodynamic studies 
 
Institutional guidelines will be followed for maximum blood volumes for research samples. The 
table below provides details regarding blood volumes obtained for research studies during course 
1. All subjects should have blood samples obtained for pharmacokinetic analysis.  
 
Type of test 
Volume per sample (ml) 
Number of samples 
(volume for all samples, ml) 
Pharmacokinetics 
3 
9 (27) 
Plasma Cytokine 
Measurement 
10 
3 (30) 
 
Total volume for research samples course 1 
12 (57) 
 
 
9.13 
Quality of Life and Pain Evaluations (Required) 
 
This study will evaluate quality of life, pain intensity, and pain interference in subjects during 
treatment with PD-0325901. The Pediatric Quality of Life Inventory (PedsQL) NF1 Module 
(Adult and Teen self-report forms) will be used to assess disease-specific QOL.  Pain intensity 
will be assessed by self-report with the Numeric Rating Scale-11 (NRS-11) and pain interference 
will be measured by the Brief Pain Inventory (BPI) Pain Interference Scale.  The following table 
summarizes the quality of life and pain questionnaires to be completed by age of the subjects.   


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Quality of Life and Pain Questionnaires to be Completed by Age of Subject at Study Entry 
 
Questionnaire 
Age of Subject (years) 
at Study Entry 
 
16-20* 
21+* 
Disease Specific QOL 
Subject: PedsQL NF1 Module-Teen 
      or     Peds QL NF1 Module-Adult 
X 
 
X 
Pain 
 
Age of Subject (years) 
 
16+** 
Subject: NRS-11 Pain Intensity 
X 
    and    BPI-Pain Interference 
X 
 
 
 
Background Information Forms to be Completed by the Subject 
 
 
 
 
*If subjects are 21 years old at study entry, they should be administered the Adult PedsQL NF1 Module. If 
subjects are 16 to 20 years old at study entry, they should be administered the Teen PedsQL NF1 Module.  
However, if subjects turn 21 years old during the study, they should continue to be administered the Teen 
version of this scale that they started at study entry. 
**All subjects should complete the same self-report pain intensity and pain interference measures and 
background form.  
 
To allow for more meaningful analysis of the QOL data, the subject (>16 years) also will complete 
a self-report background information form at study entry and each QOL assessment.  This form 
will collect general information such as their level of education, work status, psychiatric diagnoses, 
and pain medications, as well as the visibility of NF1 tumors and severity of NF1 symptoms. 
 
These forms should be completed pre-treatment, after course 4 +2 weeks, 8 +2 weeks, 12 +2 
weeks, 18 +2 weeks, and 24 +2 weeks.  In addition, at the end of treatment +2 weeks if this is not 
encompassed in the times above. When administering these forms, review the instructions with 
the subjects and check to make sure they answered all the items.  If subjects have difficulty 
reading, it is permissible to read the items to them, but the subjects should answer the items 
themselves.  Completed forms should be sent (fax or mail copies) to the NF Consortium 
Operations Center within 2 weeks of completion.  For any questions regarding the QOL/pain 
assessment please contact: Pam Wolters at woltersp@mail.nih.gov.  See Appendix VII for a 
description of the QOL and pain measures. 
 
The QOL documents will be reviewed centrally by Dr. Pam Wolters.  If any responses 
are noted that suggest serious emotional distress, the PI at the subject’s site will be 
Questionnaire 
Age of Subject (years) 
 
16+** 
Background Information 
All subjects 
QOL Background Form 
X 


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notified.  The site PI will be responsible for acknowledging to Dr. Wolters receipt of 
these concerns and for initiating appropriate action as deemed clinically necessary. 
 
 
10.0 
ADVERSE REPORTING REQUIREMENTS 
 
10.1 
Definitions 
 
• Adverse Events: An adverse event is any new, undesirable medical occurrence or change 
(worsening) of an existing condition in a subject that occurs during treatment, whether or not 
considered to be product related. Therefore, adverse events are treatment emergent signs or 
symptoms. Elective hospitalizations for pretreatment conditions (e.g., elective cosmetic 
procedures) are not adverse events. Non-clinically significant abnormal laboratory values 
should not be reported as adverse events; however, any clinical consequences of the 
abnormality should be reported as adverse events.  All adverse events must be noted on the 
case report forms and submitted to the operations center within 2 weeks of completion of every 
treatment course. 
 
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 (within 24 hours) to 
the site PI and clinical coordinator, as well as the NF Operations Center.  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. 
 
• Serious Adverse Events: A serious adverse event is defined by regulatory agencies as one that 
suggests a significant hazard or side effect, regardless of the investigator’s or sponsor’s opinion 
on the relationship to investigational product. 
 
This includes, but may not be limited to, any event that (at any dose): 
is FATAL 
is LIFE THREATENING (places the subject at immediate risk of death); 
requires HOSPITALIZATION or prolongation of existing hospitalization; 
is a persistent or significant DISABILITY/INCAPACITY; or 
is a CONGENITAL ANOMALY/BIRTH DEFECT 
 
Important medical events that may not be immediately life threatening or result in death or 
hospitalization, but may jeopardize the subject or require intervention to prevent one of the 
outcomes listed above, or result in urgent investigation, may be considered serious. Examples 
include allergic bronchospasm, convulsions, and blood dyscrasias. A planned medical or 
surgical procedure is not, in itself, an SAE. 
 
10.2 
Common Terminology Criteria for Adverse Events (CTCAE) 
 


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This study will utilize the CTCAE of the National Cancer Institute for reporting and grading of 
adverse events.  A copy of the current version of the CTCAE version 4.0 can be downloaded 
from the CTEP home page: http://ctep.cancer.gov/reporting/ctc.html  
 
 
10.3 
Attribution: Definitions of relationship to study medication are as follows: 
 
• UNRELATED: bears no relation to timing of medication, similar to symptoms or signs expected 
in the disease process, does not recur on rechallenge. 
• UNLIKELY: does not have temporal relationship to intervention, could readily have been 
produced by the subject’s clinical state, environmental, or other interventions, does not 
reappear or worsen with reintroduction of intervention. 
• POSSIBLY: bears relation to timing of medication, similar to symptoms or signs expected in the 
disease process, does not recur on rechallenge. 
• PROBABLY: bears clear relation to timing of medication, distinct from symptoms or signs 
expected in the disease process, does not recur on rechallenge. 
• DEFINITELY: bears clear relation to timing of medication, distinct from symptoms or signs 
expected in the disease process, occurs on rechallenge. 
 
The expected adverse events related to administration of PD-0325901 are listed in Section 
6.1.5.  All other adverse events not attributed to study drug will be considered unexpected. 
Adverse events attributable to study drug will be reported if the adverse events are at an 
intensity that is more severe than previously documented or considered significant by the 
investigator. 
 
10.4 
Reporting Procedures for All Adverse Events 
 
All observed or volunteered adverse events, regardless of suspected causal relationship to study 
drug, will be recorded as Adverse Events in the case report forms and submitted to the Operations 
Center within 2 weeks of completion of each treatment course. 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., abnormal laboratory test results) should also be recorded.  
 
It will be left to the investigator’s clinical judgment whether or not an adverse event is of 
sufficient severity to require that the subject should be removed from treatment. A subject may 
also voluntarily withdraw from treatment due to what he or she perceives as an intolerable 
adverse event. If either of these occurs, the subject will be given appropriate care under medical 
supervision until symptoms cease or until the condition becomes stable. 
 
Adverse events will be assessed by the treating investigator for relationship to the study drug 
(unrelated, unlikely, possible, probable, or definitely related).  
 
10.5 
Expedited Reporting Guidelines 
 
The following adverse events require expedited reporting: 
 
• 
All adverse events that are both serious and unexpected per section 6.1.5 
• 
Adverse events that, in the opinion of the treating physician, might influence the benefit-risk 


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assessment of administration of PD-0325901 as outlined in the protocol 
• 
All grade 5 adverse events 
• 
A serious adverse event that occurs within 30 days of the last dose of the investigational agent 
• 
Expedited AE reporting timelines defined: 
“24 hours; 24 hours – The investigator must initially report the AE within 24 hours (or 
immediately if the event is fatal or life-threatening) of learning of the event to the Study 
Chair (brian.weiss@cchmc.org) and NF Operations Center followed by a complete written 
report within 24 hours of the initial 24-hour report.  
 
Adverse events requiring expedited reporting will be reported and documented on Form FDA 
3500A MedWatch Form http://www.fda.gov/medwatch/getforms.htm) and forwarded to: 
 
NF Consortium Operations Center 
Clinical Research Manager:  Vivien Phillips, RN                      205-934-5376 
Program Director:  Karen Cole – Plourde, BS                               205-934-5140 
Research Compliance Manager:  Roy McDonald, MPH               205-975-4075 
Direct Email:  nfconsortium@uab.edu  
 
The clinical research manager from the NF Consortium Operations Center will forward all related 
adverse events that are both serious and unexpected to the FDA on Form FDA 3500A 
MedWatch Form http://www.fda.gov/medwatch/getforms.htm to: 
  
MedWatch 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 
 
10.5.1 Pfizer Expedited Reporting Guidelines 
• 
Even though there may not be an associated SAE, exposure to the Pfizer Product during 
pregnancy and exposure to the Pfizer Product during lactation are reportable. 
• 
The SAEs that are subject to this reporting provision are those that occur from after the first 
dose of the Pfizer Product through 28 calendar days after the last administration of the Pfizer 
Product or longer if so specified in the Protocol. In addition, investigators should submit 
SAEs to Pfizer any time after the administration of the last dose of the Pfizer Product, if the 
Investigator suspects a causal relationship between the Pfizer Product and the SAE. 
• 
Investigators will assist Pfizer in investigating any SAE and will provide any follow-up 
information reasonably requested by Pfizer. 
• 
The NF Operations Center will forward any SAE report within 24 hours (or immediately if 
the event is fatal or life-threatening) of learning of the event to Pfizer followed by a complete 
written report within 24 hours of the initial 24-hour report. 
10.6 
Reporting of Protocol Violations/Deviations and Unanticipated Problems 
 
Site reporting to NF Operations Center 
Sites will report unanticipated problems and/or protocol deviations that impact subject safety or 
the scientific integrity of the study to the Operations Center promptly at NFConsortium@uab.edu.  
Other protocol violations and deviations should be reported to the NF Operations Center 
annually.   
 


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NF Operations Center reporting requirements 
The Operations Center will report unanticipated problems that impact subject safety or the 
scientific integrity of the study to the USAMRMC ORP HRPO promptly.  Unanticipated 
problems will also be reported to the protocol team, Medical Monitor, and DSMB. 
 
All unanticipated problems involving risk to subjects or others must be promptly reported by the 
NF Operations Center via phone (301-619-2165), email (usarmy.detrick.medcom-
usamrmc.other.hrpo@mail.mil), or facsimile (301-619-7803) to the HRPO.  A complete written 
report will follow the initial notification.  In addition to the methods above, the complete report 
can be sent to the US Army Medical Research and Materiel Command, ATTN: MCMR-RP, 810 
Schreider Street, Fort Detrick, Maryland 21702-5000.   
 
Suspensions, clinical holds (voluntary or involuntary), or terminations of this research by the 
IRB, the institution, the Sponsor, or regulatory agencies will be promptly reported to the 
USAMRMC ORP HRPO. 
 
Other protocol violations and deviations that do not impact subject safety or affect scientific 
integrity of the study will be provided annually to the Sponsor. 
 
 
11.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
11.1 
Criteria for Removal from Protocol Therapy  
 
a. Progressive disease (See Section 13) 
b. Completion of course 24 of therapy 
c. <15% reduction in target tumor volume after course 8 of therapy 
d. <20% reduction in target tumor volume after course 12 of therapy 
e. Refusal of further protocol therapy by subject/parent/guardian 
f. Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
g. Physician determines it is not in the subject’s best interest. 
h. Patient becomes pregnant 
i. 
Participant is prescribed a non-allowed concomitant medicine during study. 
j. 
Withdrawal of protocol consent 
k. Any surgical procedure on a target PN. 
l. 
PD-0325901-related toxicity requiring removal (see Section 8). 
 
Subjects who are off protocol therapy are to be followed until they meet the criteria for Off Study 
(see below).  
  
 
11.2 
Off Study Criteria 
 
For subjects who did not have a response (<20% shrinkage of target tumor) or have tumor 
progression (≥ 20%) at any time: 
a) 
Thirty days after the last dose of PD-0325901 (but note that subjects with ongoing toxicity 


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should be followed until the toxicity resolves or 30 days, whichever is longer) 
 
For subjects who had a response (≥20% target tumor shrinkage by 12 cycles) and never 
experience tumor progression: 
b) 
Completion of their one year follow-up MRI scan 
 
For all subjects (supercedes “a” or “b”): 
c) 
Death 
d) 
Lost to follow-up 
e) 
Withdrawal of consent for any further data submission. 
f) 
Initiation of subsequent other medical treatment directed towards the plexiform 
neurofibroma 
g) 
Initiation of medical treatment (e.g. chemotherapy, biologic therapy, radiation therapy) 
directed towards other NF1-related tumor such as an optic pathway glioma 
 
12.0 
STATISTICAL AND ETHICAL CONSIDERATIONS   
 
12.1 
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 4.0. 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. 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 subject 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. 
 
12.2 
Statistics and Feasibility 
 
The primary objective of this study is to determine if there is an adequate level of disease 
responsiveness to PD-0325901 in adolescents and adults with NF1 and inoperable plexiform 
neurofibromas. 
 
Sample Size 
 
Minimum: 9 evaluable subjects Maximum: 19 evaluable subjects Target: 17 evaluable subjects. 
To allow for 10% unevaluable subjects, a maximum of 19 subjects will be enrolled. We anticipate 
enrollment to be completed in 24 months with primary outcome measure defined in 30 months. 
 
The sample size for this trial is based on three primary factors:  safety based on risk versus 
benefit; efficacy of 25% response rate and power of 80% to achieve feasibility if this rate were 
true.   In order to balance these factors, we propose a two stage Simon Optimal Design32.  Two 
stage designs are designed to provide an overall Type I error that is based on the probability of 
stopping at the end of Stage 1 plus the conditional probability of rejecting the drug given one 
passed Stage 1 to get to Stage 2.  Thus, the overall Type I error was set at 5% and power at 80%.   
We assume a null hypothesis success rate of 5% versus a treatment with a 25% response rate.   


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Stage 1 will consist of 9 subjects to provide evidence of effectiveness and safety.   If at least 1 of 
the 9 subjects achieves a radiographic response (> 20% reduction in tumor volume) the study will 
be allowed to recruit the total sample size of 17 evaluable subjects.  The Stage I boundary is the 
same 0 of 9.  The second stage of the design requires only 3 or more of the 17 subjects to have a 
positive response. If the null hypothesis is true, there is a 63% chance of terminating after Stage 
1.  If the probability of success is actually 0.25, there is a 92% chance that 1 or more subjects s 
will exhibit a 20% reduction in tumor volume at Stage 1.  Thus, it is expected that the trial will 
continue with continuous recruitment if the 25% success rate is correct.   
 
For safety reasons, subjects who do not achieve at least a 15% reduction in tumor volume will not 
be continued beyond 8 cycles, as the likelihood of achieving a response (20% reduction in tumor 
volume) by 12 months is minimal. These subjects will be discontinued from the trial and counted 
in an "Intent to Treat" analysis as evaluable and as failures.  If there are no subjects with a 
response (20% or more reduction in tumor volume) by the end of 8 cycles, but one or more with a 
15% or more tumor volume reduction, recruitment will be suspended until the decision on futility 
(0 of 9 with at least 20% or more reduction in tumor volume after 12 cycles) or successful 
continuation can be definitively recommended.   That is, if there are a number of subjects with 
15% up to but not achieving a 20% reduction in tumor volume, the study will follow those 
subjects up to their post cycle 12 visit to determine if the recruitment can be restarted.  If none of 
these 9 achieves a 20% tumor volume reduction by 1 year, the study will be terminated. 
 
12.3 
Statistical Analysis Plan 
 
The basic statistical analysis plan for this proof of concept study will describe the subject 
population by baseline characteristics:  clinical, PK/PD, Quality of Life and pain scores at 
baseline.  Following complete accrual, study logistics will be summarized as per a Consort 
Diagram with reasons for withdrawal or unable to complete the study tabulated.  Appropriate data 
analysis sets will be defined. The full-analysis set will include data from all subjects who receive 
≥1 dose of therapy on this study; a safety analysis set will comprise data from subjects in the full-
analysis set with any treatment doses. Other data sets (responding, evaluable, and 
pharmacodynamic/pharmacokinetic data sets) will be defined and will include data from subjects 
who have the necessary baseline and on-study measurements to provide interpretable results for 
specific parameters of interest. 
 
Descriptive summaries will be prepared to show sample size, mean, standard deviation, 95% 
confidence intervals (CIs) on the mean, median, minimum, and maximum for continuous 
variables and counts, percentages, and 95% CIs on the percentage for categorical variables.  For 
endpoints relating to tumor control, subject well-being, and biomarkers, analyses will be done 
based on the full-analysis, responding, evaluable, or pharmacodynamic data sets, as appropriate. 
Time-to-event analyses will be performed with reference to the date of first treatment on this 
study.  Analyses will focus on evaluation of outcomes within each treatment arm and will be 
largely descriptive in nature as per the sample size justification section.  Changes in tumor 
volumes, etc. will be summarized by medians, ranges, and the corresponding 95% CI.  
Continuous and categorical variables will also be summarized as appropriate.  
 
Based on the safety analysis set, information regarding study treatment administration, drug 
dosing and course compliance, safety variables, will be described and summarized. Using data 
from the pharmacokinetic analysis set plasma concentrations will also be described and 
summarized.  Peak, Trough, Area under the curve and mean serum levels will be compared to 


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tumor responsiveness.  Safety will be assessed via tabulations of AEs and SAEs as well as Diary 
recordings following treatment dose/course of therapy. 
 
All analyses for outcome results will be based on evaluable subjects, as defined in section 12.4. 
 
At the end of the trial, we will report poor performance if the treatment is rejected at Stage 1, not 
meeting the criteria of at least 1 success in 9 cases.  If there is no success at Stage II, we will 
report a failure to reject the null hypothesis using the conditional probability of the added 
subjects. If the null hypothesis is rejected, the probability of the estimated success rate will be 
reported and 95% confidence intervals as well as the distribution of changes in tumor size. 
 
An early stopping rule will be invoked to potentially prevent accrual of subjects onto the study in 
the event that PD-0325901 is associated with a higher than acceptable rate of dose-
limiting toxicity (DLT) requiring removal from study (set at 10% or higher) during the first 2 
courses. Toxicity will be continuously monitored.  As per the 2nd table below, if at any time >2 of 
the first 10 subjects or 4 or more of the first 15 total subjects are removed for toxicity as per 
Section 8.3, then accrual will be stopped until the DSMB reviews safety and efficacy data for the 
study and recommends termination or despite the DLT (because of the benefit:risk assessment or 
other reasoning) recommends reopening recruitment. 
 
Table 1:  Stopping Boundaries requiring DSMB to consider terminating trial  
Number of subjects 
Trial will be stopped if the number of subjects with severe 
toxicity is greater than or equal to the number below 
10 
3   
(equivalent to a p-value of 0.07 that the rate of severe toxicity is 
10% or less) 
15 
4 
(equivalent to a p-value of 0.055 that the rate of severe toxicity 
is 10% or less) 
 
 
Using these rules and the binomial distribution, the chance of putting the trial on hold and 
potentially stopping early within the first 10 subjects: 
 


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True probability of toxicity 
Chance of stopping early 
  
.10 
7% 
  
.20 
32% 
  
.25 
47% 
  
.30 
.35 
.40 
62% 
74% 
83% 
 
 
 
In addition, any episode of retinal vein occlusion will halt enrollment until the DSMB reviews the 
case and the study and recommends termination or despite the DLT recommends reopening 
recruitment. 
 
12.4 
Definitions of Evaluable 
 
12.4.1  Evaluable for Toxicity 
12.4.1.1 
Any subject who received ≥ one dose of PD-0325901 and had a ≥ Grade 3 
PD-0325901-associated toxicity is evaluable for toxicity. 
12.4.1.2 
In the absence of a ≥ Grade 3 toxicity, any subject who completed one full 
course of therapy is evaluable for toxicity. 
12.4.2  Evaluable For Response – Subjects who have completed at least two courses of therapy 
and have had their first follow-up MRI evaluation. Subjects who did not respond and are 
later found to have a target tumor other than a plexiform neurofibroma (e.g. malignant 
peripheral nerve sheath tumor) are not evaluable for response. 
 
12.4.3  Evaluable for Pharmacokinetics – Any subject who has at least 4 samples drawn for 
pharmacokinetics is evaluable for pharmacokinetics. 
 
12.4.4  Evaluable for Pharmacodynamics – Any subject who has a dermal neurofibroma biopsy 
for pharmacodynamics prior to starting therapy plus at least one other dermal 
neurofibroma biopsy is evaluable for pharmacodynamics. 
 
12.4.5 
Evaluable for Plasma Cytokines/Growth Factors – Any subject who has at least one 
sample drawn for plasma cytokines/growth factors prior to starting therapy plus at least 
one other sample drawn is evaluable for plasma cytokines/growth factors. 
 
 
13.0 
RESPONSE CRITERIA  
Response is assessed by the NCI-POB at the time that follow-up 3D-MRI scans are performed 
(after course 4, 8, 12, and then after completion of every 6 courses thereafter). For the purpose of 


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determining the level of response (complete, partial, etc.) measurements from the follow-up scans 
are compared to the target lesion size in the pretreatment MRI scan using 3D data analysis.  
Complete Response (CR): A complete resolution of the target plexiform neurofibroma for ≥ 4 
weeks 
Partial Response (PR): A ≥20% reduction in the volume of the target plexiform neurofibroma 
lesion for ≥4 weeks.  
Stable Disease (SD): A <20% increase, and < 20% decrease in the volume of the target plexiform 
neurofibroma lesion for ≥4 weeks.  
Progressive Disease (PD): A ≥ 20% increase in the volume (by 3D-MRI) of the target plexiform 
neurofibroma compared to the pretreatment volume. 
 
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.  Subjects 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. 
 
Subjects with other evidence of disease progression than outlined above should also be discussed 
with the Principal Investigator. 
 
 
14.0 
HUMAN SUBJECTS PROTECTION & DATA SAFETY MONITORING PLAN 
 
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 
subjects within each group to this trial.  Subject accrual in regards to gender, and racial and ethnic 
groups is described in Section 4.0.  None of these groups are 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 risks that PD-0325901 could pose to the fetus or newborn.  This trial is 
designed to determine the activity of PD-0325901 in adolescents and adults with NF1 and 
inoperable PN and therefore, subjects <18 years old will be entered onto this research trial.  
Individuals will be enrolled at one of the sites that participate in the NF consortium.  Subjects 
may also be referred from outside centers but treatment will be directed at an NF consortium site. 
  
Participation of Subjects < 18 years of age 
The primary endpoint of this trial is to determine whether PD-0325901can result in tumor 
shrinkage in adolescents and adults with PN.  Therefore adolescents who meet eligibility criteria 
for this trial will be entered in the study.  
 
Evaluation of benefits and risks/discomforts  
The potential benefit from participation in this trial is the stabilization or reduction in the size of 
the PN, relief of symptoms caused by the PN, and prolongation of life. The primary risk to the 
subjects from participation in this trial is from PD-0325901 toxicity (Section 6.1.5).  Toxicities 
from PD-0325901 are outlined in Section 6.1.5 and are typically reversible when they occur.  


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Subjects enrolled on this trial will be carefully monitored for the development of toxicities, and 
guidelines for discontinuation of drug, and a toxicity stopping rule are in place. Blood samples 
will be obtained on this trial for required pharmacokinetic and optional pharmacodynamics 
studies. Samples will be identified by a code number that can be traced to the subject only by 
contacting the trial coordinating center.  However, as the blood samples are linked to the subject’s 
name, a small risk persists that unauthorized persons could gain access to information. Some 
testing may eventually reveal information that could result in discrimination with health or life 
insurance or employment.  We believe that these risks are minimal since it is already known that 
subjects enrolled on the study have neurofibromatosis. All research results will be kept 
confidential. Results from the pharmacodynamic studies will be considered preliminary and will 
require further analysis for verification. Therefore, results will not be communicated with the 
research subjects. Subjects also have the right to withdraw the blood specimens obtained for 
research purposes at any time.  
 
Depending on the age of the subject MRI studies may require sedation or anesthesia, which is 
associated with additional risks. Separate informed consent will be obtained from research 
subjects for sedation or anesthesia for MRI scans. 
 
Risk/benefit analysis 
The primary objective of this phase II trial is to define the objective response rate of PN treated 
with PD-0325901, and thus subjects entered on the trial will be treated with therapeutic intent and 
response to the therapy will be closely monitored. Therefore, this protocol involves greater than 
minimal risk, but presents the potential for direct benefit to individual subjects. The potential 
benefit of this treatment with PD-0325901 is that it may stop or slow down the growth of PN, or 
shrink PN. In addition PD-0325901 may lessen the symptoms, such as pain, that are caused by 
the tumor. 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. The volumetric MRI 
approach will provide more precise measurement of the size of PN, 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. 
 
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 subject and the subject’s parents or guardian if he/she is a child, and a 
signed informed consent document will be obtained. Consent will be obtained by the site PI or an 
associate investigator on the trial according to state and institutional guidelines.  Age appropriate 
assent forms for adolescents from 16 through 17 years have been developed for use in this trial.  
This is a multi-institutional trial, and the NF Operations Center will require evidence of local IRB 
approval and of USAMRMC ORP HRPO approval of the protocol prior to allowing for accrual of 
subjects at that institution. This trial will be conducted in compliance with the protocol, Good 
Clinical Practice (GCP) and the applicable regulatory requirements.  
 
Medical Monitor and Data Safety Monitoring Plan 
The trial PI and clinical coordinator will review the study progress regularly. Subjects entered on 
the trial and adverse events will be reviewed to ensure that the study is implemented as outlined 
in the protocol. Monthly reports will be generated by the NF Consortium to assess completeness 
of data. There will be monthly phone conferences between the NF Consortium and the Principal 
Investigator to address QA issues.  A Data Safety Monitoring Board has been established for the 
purpose of ensuring data compliance and regular monitoring of this trial.  
 


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Julia Glade Bender, MD will be medical monitor for this study. She is a qualified physician and is 
not associated with this particular protocol.  She will work closely with the Principal Investigator 
to monitor the participants’ treatment while on this study.   
 
 
 For research determined to be greater than minimal risk, DODI 3216.02 requires that the IRB 
approve, by name, an independent medical monitor with expertise consonant with the 
nature of risk(s) identified within the research protocol.  The IRB must approve a written 
summary of the research/medical monitors’ duties, authorities, and responsibilities.  
 
The medical monitor’s duties should be based on specific risks or concerns about the research. 
The medical monitor may perform oversight functions and report their observations and findings 
to the IRB or a designated official. The medical monitor may be identified from within or outside 
the PI’s institution.  
 
Medical monitor functions may include:  
• 
observing recruitment and enrollment procedures and the consent process for 
individuals, groups or units,  
• 
overseeing study interventions and interactions,  
• 
reviewing monitoring plans and UPIRTSO reports;  
• 
overseeing data matching, data collection, and analysis  
 
There may be more than one medical monitor (e.g., if different skills or experiences are 
necessary). The monitor may be an ombudsman or a member of the data safety monitoring board.  
At a minimum, the medical monitor:  
• 
may discuss the research protocol with the investigators, interview human subjects, 
and consult with others outside of the study about the research;  
• 
shall have authority to stop a research protocol in progress, remove individual 
human subjects from a research protocol, and take whatever steps are necessary to 
protect the safety and well-being of human subjects until the IRB can assess the 
monitor’s report;  
• 
shall have the responsibility to promptly report their observations and findings to 
the IRB or other designated official and the HRPO.  
 
  
 
In addition, on this study, the medical monitor is specifically 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 should comment on the outcomes of the event or problem, and in the case of 
a serious adverse event or death, comment on the relationship to participation in the study.  The 
medical monitor should also indicate whether he/she concurs with the details of the report 
provided by the study investigator.   
 
 
 


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15.0 
REFERENCES 
 
 
1. 
Wu, J., et al. Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 
loss in desert hedgehog-expressing cells. Cancer Cell 13, 105-116 (2008). 
2. 
Korf, B.R. Malignancy in neurofibromatosis type 1. Oncologist 5, 477-485 (2000). 
3. 
Korf, B.R. Plexiform neurofibromas. Am J Med Genet 89, 31-37 (1999). 
4. 
Evans, D.G., et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J 
Med Genet 39, 311-314 (2002). 
5. 
Needle, M.N., et al. Prognostic signs in the surgical management of plexiform 
neurofibroma: the Children's Hospital of Philadelphia experience, 1974-1994. J Pediatr 131, 678-
682 (1997). 
6. 
Huson, S.M., Harper, P.S. & Compston, D.A. Von Recklinghausen neurofibromatosis. A 
clinical and population study in south-east Wales. Brain 111 ( Pt 6), 1355-1381 (1988). 
7. 
Riccardi, V.M. & Eichner, J.E. Neurofibromatosis, (Johns Hopkins University Press, 
Baltimore, USA, 1986). 
8. 
Rasmussen, S.A., Yang, Q. & Friedman, J.M. Mortality in neurofibromatosis 1: an 
analysis using U.S. death certificates. Am J Hum Genet 68, 1110-1118 (2001). 
9. 
Gupta, A., Cohen, B.H., Ruggieri, P., Packer, R.J. & Phillips, P.C. Phase I study of 
thalidomide for the treatment of plexiform neurofibroma in neurofibromatosis 1. Neurology 60, 
130-132 (2003). 
10. 
Kebudi, R., Cakir, F.B. & Gorgun, O. Interferon-alpha for Unresectable Progressive and 
Symptomatic Plexiform Neurofibromas. Journal of pediatric hematology/oncology (2012). 
11. 
Citak, E.C., et al. Management of plexiform neurofibroma with interferon alpha. 
Pediatric hematology and oncology 25, 673-678 (2008). 
12. 
Jakacki, R.I., et al. Phase I trial of pegylated interferon-alpha-2b in young patients with 
plexiform neurofibromas. Neurology 76, 265-272 (2011). 
13. 
Widemann, B.C., et al. Phase 1 trial and pharmacokinetic study of the farnesyl 
transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: a report 
from the Children's Oncology Group. Pediatric blood & cancer 56, 226-233 (2011). 
14. 
Widemann, B.C., et al. Phase I trial and pharmacokinetic study of the farnesyltransferase 
inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and 
plexiform neurofibromas. J Clin Oncol 24, 507-516 (2006). 
15. 
Babovic-Vuksanovic, D., et al. Phase I trial of pirfenidone in children with 
neurofibromatosis 1 and plexiform neurofibromas. Pediatric neurology 36, 293-300 (2007). 
16. 
Babovic-Vuksanovic, D., et al. Phase II trial of pirfenidone in adults with 
neurofibromatosis type 1. Neurology 67, 1860-1862 (2006). 
17. 
Kim, A., et al. Phase I trial and pharmacokinetic study of sorafenib in children with 
neurofibromatosis type I and plexiform neurofibromas. Pediatric blood & cancer (2012). 
18. 
Lasater, E.A., et al. Nf1+/- mice have increased neointima formation via hyperactivation 
of a Gleevec sensitive molecular pathway. Hum Mol Genet 17, 2336-2344 (2008). 
19. 
Therasse, P., et al. New guidelines to evaluate the response to treatment 
in solid tumors. J Natl Cancer Inst 92, 205-216 (2000). 
20. 
Estey, E., et al. Therapeutic response in phase I trials of antineoplastic agents. Cancer 
Treat Rep 70, 1105-1115 (1986). 
21. 
Santarpia, L., Lippman, S.M. & El-Naggar, A.K. Targeting the MAPK-RAS-RAF 
signaling pathway in cancer therapy. Expert Opin Ther Targets 16, 103-119 (2012). 
22. 
De Luca, A., Maiello, M.R., D'Alessio, A., Pergameno, M. & Normanno, N. The 
RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and 
implications for therapeutic approaches. Expert Opin Ther Targets 16 Suppl 2, S17-27 (2012). 


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23. 
Ambrosini, G., et al. Sorafenib inhibits growth and mitogen-activated protein kinase 
signaling in malignant peripheral nerve sheath cells. Molecular cancer therapeutics 7, 890-896 
(2008). 
24. 
Sebolt-Leopold, J.S. Advances in the development of cancer therapeutics directed against 
the RAS-mitogen-activated protein kinase pathway. Clinical cancer research : an official journal 
of the American Association for Cancer Research 14, 3651-3656 (2008). 
25. 
Jessen, W.J., et al. MEK inhibition exhibits efficacy in human and mouse 
neurofibromatosis tumors. J Clin Invest 123, 340-347 (2013). 
26. 
Boasberg, P.D., et al. Pilot study of PD-0325901 in previously treated patients with 
advanced melanoma, breast cancer, and colon cancer. Cancer chemotherapy and pharmacology 
68, 547-552 (2011). 
27. 
LoRusso, P.M., et al. Phase I pharmacokinetic and pharmacodynamic study of the oral 
MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clinical cancer 
research : an official journal of the American Association for Cancer Research 16, 1924-1937 
(2010). 
28. 
Haura, E.B., et al. A phase II study of PD-0325901, an oral MEK inhibitor, in previously 
treated patients with advanced non-small cell lung cancer. Clinical cancer research : an official 
journal of the American Association for Cancer Research 16, 2450-2457 (2010). 
29. 
Wolkenstein, P., Zeller, J., Revuz, J., Ecosse, E. & Leplege, A. Quality-of-life 
impairment in neurofibromatosis type 1: a cross-sectional study of 128 cases. Arch Dermatol 137, 
1421-1425 (2001). 
30. 
Cleeland, C.S. & Ryan, K.M. Pain assessment: global use of the Brief Pain Inventory. 
Annals of the Academy of Medicine, Singapore 23, 129-138 (1994). 
31. 
Dworkin, R.H., et al. Core outcome measures for chronic pain clinical trials: IMMPACT 
recommendations. Pain 113, 9-19 (2005). 
32. 
Thall, P.F., Simon, R., Ellenberg, S.S. & Shrager, R. Optimal two-stage designs for 
clinical trials with binary response. Stat Med 7, 571-579 (1988). 
33. 
Hawker, G.A., Mian, S., Kendzerska, T. & French, M. Measures of adult pain: Visual 
Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain 
Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade 
Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and 
Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken) 63 Suppl 11, S240-252 
(2011). 
 
 


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56
 
APPENDIX I:  SCHEDULE OF EVALUATIONS 
† See section 9 for definitions of end of course. 
1. All studies to determine eligibility must be performed within 2 weeks prior to enrollment unless otherwise indicated below (See 
section 9.0). Consent must be obtained prior to enrollment but does not expire at 2 weeks. 
2. Height only required at baseline 
3. Slit lamp examination with binocular indirect ophthalmoscopy 
4. For females of childbearing age 
5. Subjects who had a response (>20% target lesion shrinkage by 12 cycles) are requested but not required to have an MRI performed 
at 4 months and 12 months after stopping drug if they are still on study. 
6. Subjects will have multiple blood draws at this time  
 
 
STUDIES TO BE OBTAINED 
Pre-Study1 
Course 1 
Subsequent courses 
Completion of 
Rx 
Informed Consent Assent 
X 
 
 
 
Eligibility Checklist 
X 
 
 
 
History 
X 
End† 
Post course 2, 3, 4, 8, 12, 18, and 24 † 
X 
Physical Exam with vital signs 
(including T, P, RR, BP) 
X 
End† 
Post course 2, 3, 4, 8, 12, 18, and 24 † 
X 
Height2, weight, BSA 
X 
End† 
Post course 2, 3, 4, 8, 12, 18, and 24 † 
X 
Performance Status (see Appendix 
II) 
X 
End† 
Post course 2, 3, 4, 8, 12, 18, and 24 † 
X 
Retinal Exam3 
X 
End† 
Post course 2,4,6,8,10,12,15,18, 21, 24† 
X 
PD-0325901 Diary Review 
 
End† 
Post course 2, 3, 4, 8, 12, 18, and 24 † 
X 
CBC, differential, platelets 
X 
 End† 
Post course 2, 3, 4, 8, 12, 18, and 24 † 
X 
Electrolytes including BUN, 
Creatinine, glucose, blood 
chemistry including albumin, total 
protein, alkaline phosphatase, 
SGOT, SGPT, bilirubin, CPK 
X 
 
 
End† 
 
Post course 2, 3, 4, 8, 12, 18, and 24 † 
 
X 
 
Urine/Serum Pregnancy4 
 
X  
(within 7 
days prior) 
 
Post course 4, 8, 12, 18, and 24 † 
X 
MRI including volumetric analysis 
X 
(within 4 
weeks prior) 
 
Post course 4, 8, 12, 18, 24 †  
X5 
Health-related quality of life and 
pain assessments 
X 
 
Post course 4, 8, 12, 18, 24 † 
X 
PD-0325901Pharmacokinetics6 
X 
Day 1  
 
 
Pharmacodynamic studies 
X 
Week 3 
 
 
Plasma Cytokines 
X 
Week 3 
Week 3 of course 4 
 


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APPENDIX II: PERFORMANCE STATUS SCALES/SCORES 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky performance scores are intended to be multiples of 10 
Score 
Description 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity, minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or do active work. 
60 
Required occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated.  Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
 


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APPENDIX III:  NIH CONSENSUS CLINICAL DEFINTION OF NEUROFIBROMATOSIS 
 
 
• 
Six or more café-au-lait spots (≥0.5 cm in prepubertal subjects or ≥1.5 cm in 
postpubertal subjects) 
• 
Two or more neurofibromas of any type or one plexiform neurofibroma  
• 
Freckling in the axilla or groin 
• 
Optic glioma 
• 
Two or more Lisch nodules 
• 
A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning 
of long bone cortex) 
• 
A first-degree relative with NF1 
 
 
 


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APPENDIX IV:  PROTOCOL FOR REQUIRED PRE-STUDY AND ON-STUDY MRI STUDIES 
Prior to starting treatment a measurable target plexiform neurofibroma must be identified.  In 
addition, up to two non-target plexiform neurofibromas may be identified as well.  
The goal will therefore be to use 3-D MRI only to follow the target and non-target plexiform 
neurofibroma(s) (a maximum of three lesions), which will be defined as index lesion(s).  
Pre-study imaging evaluation: 
1. Identify and select the index 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 should be followed by 3-D MRI analysis. 
2. Perform 3-D MRI sequences on the selected index lesions as outlined in the MRI 
acquisition protocols below.  
 
On study imaging evaluation: 
 
Unless clinically indicated otherwise obtain MRI of the index lesion(s) (target and non-target) 
only as outlined in the MRI acquisition protocol below after course 4, 8, 12, 18, and 24 while on 
study. 
 
MRI protocols: 
 
Images intended for volumetric analysis need to be performed without gaps between slices. Every 
attempt should be made to image the entire PN. The target tumor should be positioned close to 
the center of the imaging field and the outer edge of the tumor should be within the field of view. 
Peripheral nerve sheath tumors can be well visualized without the use of contrast agents on short 
TI inversion recovery (STIR) sequences because they have high signal intensity relative to 
normal tissues. The imaging protocol in the table below should be used for the imaging of the 
target and non target PN.  
 
If necessary, participating institutions may modify the MRI sequences to optimize differentiation 
of tumor and surrounding tissue.  Modifications should be noted, such that the same imaging 
protocol, and, if possible, the same MRI scanner, can be used for all subsequent MRI studies.   
 
All MRI studies requested per protocol will be submitted to the NCI POB within 1 week of 
acquisition for volume analysis.  
 
 
Volumetric sequence for PN** 
Axial STIR 
Recommended 
Range 
Head-Neck or 
Small## Trunk-
Extremity PN 
Large## Trunk-
Extremity PN 
Echo Train Length 
5 - 15 
7 
15 
TR 
3000 - 6000 
6000 
4000 


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60
TE 
30 - 50 
34 
30 
TI 
150-180 
150 
150 
Slice Thickness 
3 - 10 mm 
3 mm 
10 mm 
Skip 
0 
0 
0 
Matrix 
256x256 -  
512x512 
256x256 
320 x256 - 
512x512 
FOV 
18 - 50 cm 
22 cm 
45 cm 
Phase FOV 
0.8 
0.8 
0.8 
NEX 
2 - 4 
3 
2 
Frequency Direction 
A→P 
A→P 
A→P 
**Spinal/paraspinal PN should be imaged with the appropriate protocol based on tumor size. 
Tumors that include the neck and trunk, for which the majority of the tumor is in the trunk, 
should be imaged with the Large Trunk-Extremity PN protocol. 
##Tumors < 5 cm in longest diameter would be considered small.  Tumors > 10 cm longest 
diameter would be considered large.  Tumors between 5-10 cm in longest diameter should be 
imaged with the appropriate protocol based on best FOV coverage.   
Please contact Dr. Dombi if there are questions regarding the appropriate coverage or imaging 
protocol. 


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 Data Analysis:  
• 
All MRI data will be analyzed at the Pediatric Oncology Branch of the NCI.  The MRI data 
from each scan will be processed to assess the volume of the index plexiform neurofibroma. 
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 subject’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 Section 13.  Drs. Dombi and Widemann 
will inform Participating Investigators, the Principal Investigator, and the NF Consortium 
Operations Center about the results of the MRI study by written report.  
 
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 1 week of acquisition for volume analysis. 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.  Dr. Dombi will confirm for each 
patient in screening that the MRI imaging is adequate and that the target PN is measurable and 
amenable to volumetric MRI analysis. 
• 
Address for shipment of imaging studies: 
Dr. Eva Dombi, MDNCI, POB 
10 Center Drive, Building 10, room 1-5750 
Bethesda, MD 20892-1101 
Phone : 301-451-7023  
e-mail: dombie@mail.nih.gov 
 
 


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APPENDIX IVa:  MRI ELIGIBILITY FORM 
 
This form must accompany all MRI studies sent to the NCI POB for review of target plexiform 
neurofibroma eligibility (i.e. whether it is measurable and amenable to volumetric analysis).  
Please mail the MRI on a CD along with this form to: 
 
 
Eva Dombi, MD 
 
NCI, POB 
 
10 Center Drive, Building 10 CRC, Room 1-5750 
 
Bethesda, MD 20892 
 
Phone: 301-451-7023 
 
E-mail: dombie@mail.nih.gov 
 
 
PID#1:________ 
Date of MRI:  ___________ 
 
 
 
Location of target plexiform: 
_______________________________________________ 
 
 
 
 
From: 
Name of Investigator:  _______________________________________________ 
 
Study Center:   
_______________________________________________ 
 
Phone #: 
 
_______________________________________________ 
 
Email Address:   
_______________________________________________ 
 
 
 
 
 
_____________________________________________________________________________ 
From Eva Dombi, MD:  
 
The target PN is measurable and amenable to volumetric analysis:  
 
 
Yes:_____________ 
No: ____________ 
 
Comments: _______________________________________________ 
 
 


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APPENDIX V: SUBJECT DIARY ON PD-0325901 PROTOCOL 
 
 
 


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64
 
 
APPENDIX VI: PHARMACOKINETIC, PHARMACODYNAMIC AND CYOTKINE 
STUDIES 
Pharmacokinetic Worksheet  
 
Subject Consortium ID number: _____________ 
BSA (m2): 
 
PD-0325901dose (mg)  
 
mg given : 
 
 
Blood samples (3 ml) will be drawn for the pharmacokinetic profile during PD-0352901 therapy 
on Day 1 of Course 1 at the following times: before the morning dose of PD-0325901 (pre-dose), 
and at 30 min, 1 hr, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8 hrs, and 10-12 hrs after the Day 1 dose of PD-
0325901. For each pharmacokinetic profile there will be a total of 9 samples drawn.  
 
Procedure: Samples will be drawn as 3 mL whole blood into K2EDTA (lavender top) tubes 
• 
After collection, samples should be gently inverted 15 times to completely mix whole 
blood and anticoagulant 
• 
Blood samples should then be immediately placed into an ice bath so that they are kept at 
2-8 degrees Celsius 
• 
Whole blood samples should be centrifuged at 4 degrees Celsius for 10 minutes at 1,700 x 
g to separate the plasma from the red blood cells 
• 
Transfer plasma layer using a clean disposable pipette into the appropriately labeled 3.6mL 
cryovial 
• 
Immediately store plasma sample in a -70 degrees Celsius freezer until shipment. Once 
frozen, samples should not be allowed to thaw, including during shipment. 
• 
Time from blood collection to freezing of plasma should not exceed 30 minutes 
Samples will be shipped on dry ice Monday thru Thursday to Cincinnati Children’s 
Hospital Medical Center. 
Please ensure completion of all fields of PK worksheet and sample collection log prior 
to shipping, and include these documents in sample shipment.  
Samples with completed worksheet and sample log should be shipped using express 
next day priority delivery to the following address and to the attention of: 
 
Laboratory of Applied PK and Pharmacogenetics (Dr. Vinks) 
Cincinnati Children’s Hospital Medical Center 
3333 Burnet Ave.,  Rm R2469 
Attn. David Hahn, PhD 
Cincinnati, OH 45229 
Phone:  513-636-1905 
Fax:       513-636-1955 
David.Hahn@cchmc.org   
 
Please send email notification of shipment including tracking number on day 
samples are shipped.  
All Questions regarding sample shipment(s) may be addressed to David Hahn.  


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65
The Vinks laboratory will store the PK samples and ship in batches to Advion 
Laboratories for analysis. 
Pharmacokinetic modeling will be performed by Dr. Vinks’ Pharmacometrics 
Core. 
 
Sample Collection Log 
 
Subject ID #:_________________ 
 
Course 1, Day 1, Date: ___________ Day: ____________Time of dose: _________ 
 
 
Sample # 
Hours 
Scheduled Sample Time  
Actual Sample Time 
1 
pre dose 
 
 
2 
0.5 
 
 
3 
1.0 
 
 
4 
2.0 
 
 
5 
3.0 
 
 
6 
4.0 
 
 
7 
6.0 
 
 
8 
8.0 
 
 
9 
10.0-12.0 
 
 
* The next PD-0325901 dose will be administered after obtaining the 12 hour sample (Sample 9). 
 
Please include completed Appendix VI - PK worksheet and Sample Collection Log 
with your shipment 
 
 


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66
 
Pharmacodynamic Worksheet 
 
Pharmacodynamic Analysis of Dermal Neurofibromas 
 
Procedure: 
Three millimeter punch biopsies of 1-2 dermal neurofibromas (2 dermal neurofibromas per 
timepoint is preferred) will be made prior to initiating therapy with PD-0325901 and during week 
3 of course 1 at least 30 min but no more than 6 hours after taking the morning dose.  At each 
time point, one tumor will be fixed in 10% neutral buffered formalin (or its equivalent) for 
paraffin embedding, and shipped on wet ice.  At the same time, one tumor will be frozen in 
liquid nitrogen and stored at -80˚C and shipped separately, on dry ice.  If only one dermal 
fibroma is biopsied, it should be placed in formalin fixative as above. Time of tumor removal 
after drug dose will be noted.  
 
To Summarize: 
1. Place first punch biopsy sample in a 15ml conical tube and add 5ml of 10% neutral 
buffered formalin. Label tube with Subject ID, Course, course day, date of sample, and 
date and time of last PD dose. Ship sample with freezer ice packs. 
 
2. Place second punch biopsy in a cryovial (screw on the top), or aluminum foil, Subject ID, 
Course, course day, date of sample, and date and time of last PD dose, and drop into 
liquid nitrogen (Flash freezing the sample). Immediately store at -80 and ship separately 
on dry ice. 
 
 
Samples will be shipped as soon as possible to Cincinnati Children’s Hospital Medical. Samples 
should be shipped with express next day priority delivery to the following address and to the 
attention of: 
 
Ratner Laboratory 
Cincinnati Children’s Hospital Medical Center 
S Dock 
240 Albert Sabin Way 
Cincinnati, OH  45229 
c/o Nancy Ratner S7.250 
Phone:  513-636-3502 
Fax: 513-803-1083 
Email: lindsey.aschbacher-smith@cchmc.org 
 
 
Please include this completed worksheet with the sample shipment: 
Subject ID 
 
Course 
 
Course day 
 
Date of sample 
 
Date and time of last PD-0325901 dose: 
 
 


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67
Plasma Cytokines and Growth Factors 
CYTOKINE STUDIES Worksheet  
_____________ BSA (m2)     
PD-0325901dose (mg) ___, if 
given 
Date/time:  
 
Plasma Cytokines and Growth Factors  Procedure:  
10 ml blood will be drawn into EDTA tubes before treatment initiation, during week 3 of course 1 
and during week 3 of course 4. The sample will be collected at least 30 min but no more than 6 
hours after taking the morning dose. To summarize: 
• 
Pre-study measurement needed 
• 
Course 1, week 3: collection 30 minutes to 6 hours after taking the morning dose 
• 
Course 4, week 3: collection 30 minutes to 6 hours after taking the morning dose 
 
• After collection, samples should be gently inverted 15 times to completely mix whole blood and 
anticoagulant  
• Blood samples should then be immediately placed into an ice bath so that they are kept at 2-8 
degrees Celsius  
• Whole blood samples should be centrifuged at 4 degrees Celsius for 10 minutes at 1,700 x g to 
separate the plasma from the red blood cells  
• Transfer plasma layer using a clean disposable pipette into the appropriately labeled 3.6mL 
cryovial  
• Immediately store plasma sample in a -70 degrees Celsius freezer until shipment. Once frozen, 
samples should not be allowed to thaw, including during shipment.  
• Time from blood collection to freezing of plasma should not exceed 30 minutes  
 
Samples will be shipped on dry ice Monday thru Thursday.  
Samples will be shipped to Cincinnati Children’s Hospital Medical Center. Samples 
should be shipped with express next day priority delivery. Samples will be shipped to the 
following address: 
Cincinnati Children’s Hospital Medical Center  
S Dock, Ratner Laboratory S7.348 
240 Albert Sabin Way  
Cincinnati, OH 45229  
c/o Nancy Ratner S7.250     Phone: 513-636-3502 
Email: Lindsey.Aschbacher-Smith@cchmc.org 
Other email contacts in the lab: Nancy.Ratner@cchmc.org; Jianqiang.Wu@cchmc.org; 
Huiqing.Li@cchmc.org; Adam.Miller@cchmc.org; and Tilat.Rizvi@cchmc.org  
 
Please include this completed worksheet with the sample shipment: 
Subject ID 
 
Course 
 
Course day 
 
Date of sample 
 
Date and time of last PD-0325901 dose: 
 
 
 
 


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APPENDIX VII:  CONSORTIUM QOL AND PAIN MEASURES 
 
Below is a description of the QOL and pain measures to be administered in this protocol organized 
by the domain that the questionnaire assesses.   
 
NF1 Disease Specific QOL Measure 
 
The Adult PedsQL™ NF1 Module is a 74-item a self-report instrument to assesses NF1 disease-
specific quality of life (QOL) in adults, ages 21 years and older. It is comprised of 16 scales: 1) 
Physical functioning (8 items), 2) Emotional functioning (5 items), 3) Social functioning (3 items), 
4) Cognitive functioning (5 items), 5) Communication (3 items), 6) Worry (7 items), 7) Perceived 
physical appearance (3 items), 8) Pain and Hurt (3 items), 9) Paresthesias (2 items), 10) Skin 
irritation (5 items), 11) Sensation (4 items), 12) Movement and Balance (4 items), 13) Fatigue (3 
items), 14) Daily activities (12 items), 15) Treatment anxiety (4 items) and 16) Sexual functioning 
(3 items) (Nutakki et al., submitted; N. Swigonski, personal communication, September 26, 2012).   
 
The Teen PedsQL™ NF1 Module is a 75-item self-report for adolescents and young adults, ages 14 
to 20 years of age, which includes 16 scales: 1) Physical functioning (8 items), 2) Emotional 
functioning (5 items), 3) Social functioning (3 items), 4) Cognitive functioning (7 items), 5) 
Communication (3 items), 6) Worry (6 items), 7) Perceived physical appearance (3 items), 8) Pain 
& Hurt (3 items), 9) Paresthesias (2 items), 10) Skin irritation (5 items), 11) Sensation (4 items), 
12) Movement & Balance (4 items), 13) Fatigue (3 items), 14) Daily activities (12 items), 15) 
Treatment anxiety (4 items) and 16) School Activities (3 items). 
 
The PedsQL™ NF1 Module format, instructions, and Likert response scale are similar to the 
PedsQL™ 4.0 Generic Core Scales and other PedsQL™ Disease-Specific Modules. The 
instructions ask how much of a problem each item has been during the past one month.  A 5-point 
response scale is used for all items in the three versions of the instrument (0= never a problem, 1= 
almost never a problem, 2= sometimes a problem, 3= often a problem, 4= almost always a 
problem). Items are reverse scored and linearly transformed to a scale of 0-100 similar to PedsQL™ 
4.0 Generic Core Scales (0= 100, 1= 75, 2= 50, 3=25, 4=0).  Higher scores indicate better HRQOL 
and fewer symptoms or problems.  The total scale score is computed as the sum of all items on the 
PedsQL™ NF1 Module divided by the number of items answered (this accounts for missing data).  
Subscale scores are computed as the sum of the items divided by the number of items that were 
answered in that scale.  If more than 50% of the items in the scale are missing, the scale score is not 
computed. 
 
Feasibility, measured by the percentage of missing responses, was 4.8 % for all scales on the adult 
version of the PedsQL™ NF1 Module.  Internal consistency reliability for the Total Scale score 
(alpha =0.97) and Scale reliabilities ranging from 0.72 to 0.96 were acceptable for group 
comparisons. The PedsQL™ NF1 module distinguished between NF1 adults with excellent to very 
good, good, and fair to poor health status.  Thus, preliminary data demonstrates the initial 
feasibility, reliability and validity of the PedsQL™ NF1 module in adult patients (Nutakki et al., 
personal communication).  The preliminary data in a small sample of adolescents also looks 
promising with good feasibility (percentage of missing responses was 8.9%) and a total scale 
reliability of 0.96 (N. Swigonski, personal communication, October 10, 2012).   
 
Pain Measures 
 
1. Pain Intensity 


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The Numerical Rating Scale-11 (NRS-11) is a self-report segmented 11-point numeric scale that 
assesses pain intensity33.  It consists of a horizontal line with 0 representing “no pain” at the right end 
of the line and 10 representing “worst pain you can imagine” at the left end.  Subjects are asked to 
circle the one number from 0 to 10 that best describes 1) their “most important tumor pain” and 2) 
their “overall tumor pain” at its worst during the past week.  It takes less than 1 minute to complete.  
The NRS-11 is recommended as a core outcome measure of pain intensity for clinical trials31.   
 
2. Pain Interference 
The Brief Pain Inventory (BPI)—Pain Interference Scale is a 7-item self-report questionnaire that 
measures the extent to which pain interferes with daily functioning30.  Subjects are asked to indicate 
how much pain interfered with various activities (general activity, mood, walking, normal work, 
relations with other people, sleep, and enjoyment of life) in the past week, with scores ranging from 
0 (does not interfere) to 10 (completely interferes).  A total score is obtained by taking the mean of 
the scores for all 7 items; thus, the total pain interference score can range from 0 to 7. This scale takes 
less than 2 minutes to complete.  These items are recommended to assess pain interference in clinical 
trials31.  
 
Background Information 
 
To allow for more meaningful analysis of the QOL data, the participant (for subjects > 16 years) 
will complete a background information form at study entry and each subsequent QOL evaluation.  
This form will collect general information such as the subject’s level of education, work status, 
psychiatric diagnoses, and pain medications, as well as the perceived visibility of NF1 tumors and 
severity of NF1 symptoms.   
 
Administration Guidelines 
 
These QOL and pain measures should be completed pre-treatment, after course 4 +2 weeks, 8 +2 
weeks, 12 +2 weeks, 18 +2 weeks, and 24 +2 weeks.  When administering these forms, review the 
instructions with the subjects and check to make sure they answered all the items.  If subjects have 
difficulty reading, it is permissible to read the items to them, but the subjects should answer the 
items themselves.  Completed forms should be sent (fax or mail copies) to the NF Consortium 
Operations Center within 2 weeks of completion.  For any questions regarding the QOL/pain 
assessment please contact: Pam Wolters at woltersp@mail.nih.gov. 
 
If subjects are 21 years old at study entry, they should be administered the Adult PedsQL NF1 
Module.  If subjects are 16 to 20 years old at study entry, they should be administered the Teen 
PedsQL NF1 Module. However, if subjects turn 21 years old during the study, they should continue 
to be administered the Teen version of this scale that they started at study entry. 
All subjects should complete the same self-report pain intensity and pain interference measures and 
background form.  
 
Please see section 9 for a table listing the self-report QOL and pain measures to be completed by 
the subject. 
 
 
 


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PAIN QUESTIONNAIRE 
 
 
 


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71
NF1 QOL BACKGROUND INFORMATION SHEET 
 
 
 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
72
 
QOL INSTRUMENT (TEEN REPORT) 
For teens and young adults (16 to 20 years old) with NF-1 
 
 
 
                                                    DIRECTIONS 
Teens with neurofibromas sometimes have special problems. Please tell us how much of a problem each 
one has been for you during the past ONE month by choosing the appropriate options: 
 
0 if it is never a problem              
1 if it is almost never a problem 
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
 
There are no right or wrong answers. 
If you do not understand a question, take your best guess. 
Thank you for your help! 
                                                                                                                                                    
                                                                                                                                                    


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
73
Please select which of the following describes you the best:  
o I am a teen or young adult  (14 to 20 years old) with Neurofibromatosis Type 1 (NF-1) 
o Other, please specify _______________________________ 
 
How old are you? (in years)  ________________ 
 
Do you have plexiform neurofibromas?  
o Yes  
o No 
o Don’t know 
If yes, on a scale of 0 to 10 (where 0 is plexiform neurofibromas have no impact to 10 where 
plexiform neurofibromas have a huge impact), please rate the impact of your plexiform 
neurofibromas on your day-to-day life. ___________ 
 
In general, how would you rate your health? 
o Excellent  
o Very Good 
o Good 
o Fair 
o Poor 
 
 
How many times did you visit the doctor for your NF-1 in the past ONE year?  ____________ 
On average, how many different medications do you take for your NF-1 in a day? _________ 
 
 
 
 
 
 
 
 
 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
74
 
 
 
In the past ONE month, how much of a problem has this been for you... 
PHYSICAL FUNCTIONING (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Having headaches 
0 
1 
2 
3 
4 
2.  Feeling physically weak 
0 
1 
2 
3 
4 
3.  Walking more than one block 
0 
1 
2 
3 
4 
4.  Climbing stairs 
0 
1 
2 
3 
4 
5.  Running 
0 
1 
2 
3 
4 
6.  Doing a sports activity or exercise 
0 
1 
2 
3 
4 
7.  Lifting something heavy 
0 
1 
2 
3 
4 
8.  Doing chores around the house 
0 
1 
2 
3 
4 
 
EMOTIONAL FUNCTIONING (problems with...) Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Feeling anxious 
0 
1 
2 
3 
4 
2.  Feeling sad 
0 
1 
2 
3 
4 
3.  Feeling angry 
0 
1 
2 
3 
4 
4.  Feeling frustrated 
0 
1 
2 
3 
4 
5.  Feeling helpless or hopeless 
0 
1 
2 
3 
4 
 
SOCIAL FUNCTIONING (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Feeling isolated from others 
     0 
      1 
     2 
    3 
     4 
2.  Getting support from others 
     0 
      1 
     2 
    3 
     4 
3.  Having enough energy for social activities 
     0 
      1 
     2 
    3 
     4 
 
COGNITIVE FUNCTIONING (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Keeping attention on things 
     0 
      1 
     2 
    3 
     4 
2.  Remembering what people tell you 
     0 
      1 
     2 
    3 
     4 
3.  Remembering what you just heard or read 
     0 
      1 
     2 
    3 
     4 
4.  Thinking quickly 
     0 
      1 
     2 
    3 
     4 
5.  Solving math problems 
     0 
      1 
     2 
    3 
     4 
6.  Writing school papers or reports 
     0 
      1 
     2 
    3 
     4 
7.  Remembering what you were just thinking 
     0 
      1 
     2 
    3 
     4 
 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
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NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
76
 
COMMUNICATION (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Telling the doctors and nurses how you feel 
0 
1 
2 
3 
4 
2.  Asking the doctors and nurses questions 
0 
1 
2 
3 
4 
3.  Talking with others about your disorder 
0 
1 
2 
3 
4 
 
WORRY (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Worrying about neurofibromas 
0 
1 
2 
3 
4 
2.  Worrying about side effects from medical 
treatments 
0 
1 
2 
3 
4 
3.  Worrying about whether or not medical 
treatments are working 
0 
1 
2 
3 
4 
4.  Worrying that neurofibromas will grow bigger or 
reoccur 
0 
1 
2 
3 
4 
5.  Worrying about my future or the risk of having 
children  with Neurofibromatosis Type 1 
0 
1 
2 
3 
4 
6.  Worrying about the risk of other health related 
issues associated with Neurofibromatosis Type 1 
0 
1 
2 
3 
4 
 
PERCEIVED PHYSICAL APPEARANCE 
 (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Feeling that I am not good looking 
0 
1 
2 
3 
4 
2.  Not wanting other people to see my 
neurofibromas 
0 
1 
2 
3 
4 
3.  Being embarrassed about others seeing my body 
0 
1 
2 
3 
4 
 
PAIN AND HURT (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Aching or hurting 
0 
1 
2 
3 
4 
2.  Aching or hurting a lot 
0 
1 
2 
3 
4 
3.  Not sleeping because of pain 
0 
1 
2 
3 
4 
 
PARESTHESIAS (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  A burning sensation in some part of my body 
0 
1 
2 
3 
4 
2.  A tingling sensation in some part of my body 
0 
1 
2 
3 
4 
 
 
 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
77
 
 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
78
 
SKIN IRRITATION (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Itching  
0 
1 
2 
3 
4 
2.  Itching a lot 
0 
1 
2 
3 
4 
3.  Getting a skin rash when exposed to sun 
0 
1 
2 
3 
4 
4.  Tolerating temperature changes 
0 
1 
2 
3 
4 
5.  Rough skin 
0 
1 
2 
3 
4 
 
SENSATION (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Vision in one or both eyes 
0 
1 
2 
3 
4 
2.  Seeing well enough with glasses or contact  
lenses  
0 
1 
2 
3 
4 
3.  Hearing in one or both ears 
0 
1 
2 
3 
4 
4. Speech 
0 
1 
2 
3 
4 
 
MOVEMENT AND BALANCE (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Bending my body 
0 
1 
2 
3 
4 
2.  Moving one or both legs 
0 
1 
2 
3 
4 
3.  Using or moving one or both arms 
0 
1 
2 
3 
4 
4.  Keeping balance when sitting/standing 
0 
1 
2 
3 
4 
 
SCHOOL ACTVITIES (problems with...) 
Never 
Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Writing or drawing with a pen or pencil 
0 
1 
2 
3 
4 
2.  Carrying school books 
0 
1 
2 
3 
4 
3.  Using a mouse or keyboard on the computer 
0 
1 
2 
3 
4 
 
DAILY ACTVITIES (problems with...) 
Never 
Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Putting on shoes 
0 
1 
2 
3 
4 
2.  Buttoning my shirt 
0 
1 
2 
3 
4 
3.  Combing my hair 
0 
1 
2 
3 
4 
4.  Getting into the bathroom to use the toilet 
0 
1 
2 
3 
4 
5.  Undressing to use the toilet 
0 
1 
2 
3 
4 
6.  Getting in and out of bathtub or shower 
0 
1 
2 
3 
4 
7.  Brushing my teeth 
0 
1 
2 
3 
4 
8.  Eating with a fork and knife 
0 
1 
2 
3 
4 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
79
9.  Using a phone 
0 
1 
2 
3 
4 
10. Shopping 
0 
1 
2 
3 
4 
11. Managing money 
0 
1 
2 
3 
4 
12. Driving 
0 
1 
2 
3 
4 
 
 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
80
FATIGUE (problems with...) 
Never 
Almost  
Never 
Some- 
times 
Often 
Almost 
Always 
1.  Feeling tired 
0 
1 
2 
3 
4 
2.  Resting a lot 
0 
1 
2 
3 
4 
3.  Having enough energy to do things that I like to do 
0 
1 
2 
3 
4 
 
TREATMENT ANXIETY(problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Getting scared about going to the doctor 
0 
1 
2 
3 
4 
2.  Getting scared about going to the hospital 
0 
1 
2 
3 
4 
3.  Being responsible for my medicines or  therapy 
0 
1 
2 
3 
4 
4.  Managing my Neurofibromatosis Type 1 
0 
1 
2 
3 
4 
 
Please write any comments that you have about how NF-1 affects your health and well-being. 
Please write any comments about the survey and whether or not it captures how NF-1 affects 
people’s health and well-being. 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
78
QOL INSTRUMENT (ADULT SURVEY) 
For adults (> 21 years old) with NF-1 
 
 
                                                    DIRECTIONS 
This survey is for ADULTS with NF 1.  Neurofibromatosis type 1 sometimes causes special problems. 
Please tell us how much of a problem each one has been for you during the past ONE month by 
circling: 
 
0 if it is never a problem 
1 if it is almost never a problem 
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
There are no right or wrong answers. 
If you do not know an answer, take your best guess. 
Thank you for your help! 
                                                                                                                                                    
  
 
 
 
 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
79
 
Please select which of the following describes you the best (you can choose more than one):  
o I am an adult with Neurofibromatosis Type 1 (NF-1)  
o I am a professional who treats people with NF-1 
o I am a friend or family member of a person with NF-1 
o Other, please specify ___________________ 
 
How old are you? (in years)  ________________ 
 
Do you have plexiform neurofibromas?  
o Yes  
o No 
o Don’t know 
If yes, on a scale of 0 to 10 (where 0 is plexiform neurofibromas have no impact to 10 where 
plexiform neurofibromas have a huge impact), please rate the impact of your plexiform 
neurofibromas on your day-to-day life. ___________ 
 
In general, how would you rate your health? 
o Excellent 
o Very good 
o Good 
o Fair 
o Poor 
 
How many times did you visit the doctor for your NF-1 in the past ONE year? _____________ 
 
On average, how many different medications do you take for your NF-1 in a day? _________ 
 
 
 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
80
 
In the past ONE month, how much of a problem has this been for you... 
PHYSICAL FUNCTIONING (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Feeling physically weak 
0 
1 
2 
3 
4 
2.  Walking more than one block 
0 
1 
2 
3 
4 
3.  Climbing stairs 
0 
1 
2 
3 
4 
4.  Running 
0 
1 
2 
3 
4 
5.  Doing a sports activity or exercise 
0 
1 
2 
3 
4 
6.  Lifting something heavy 
0 
1 
2 
3 
4 
7.  Doing chores around the house 
0 
1 
2 
3 
4 
 
EMOTIONAL FUNCTIONING (problems with...) Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Feeling anxious 
     0 
      1 
     2 
    3 
     4 
2.  Feeling sad 
     0 
      1 
     2 
    3 
     4 
3.  Feeling angry 
     0 
      1 
     2 
    3 
     4 
4.  Feeling frustrated 
     0 
      1 
     2 
    3 
     4 
5.  Feeling helpless or hopeless 
     0 
      1 
     2 
    3 
     4 
 
SOCIAL FUNCTIONING (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Getting support from others 
     0 
      1 
     2 
    3 
     4 
2.  Having enough energy for social activities 
     0 
      1 
     2 
    3 
     4 
 
COGNITIVE FUNCTIONING (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Keeping attention on things 
     0 
      1 
     2 
    3 
     4 
2.  Remembering what people tell you 
     0 
      1 
     2 
    3 
     4 
3.  Remembering what you just heard/read 
     0 
      1 
     2 
    3 
     4 
4.  Thinking quickly 
     0 
      1 
     2 
    3 
     4 
5.  Remembering what you were just thinking 
     0 
      1 
     2 
    3 
     4 
 
COMMUNICATION (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Telling the doctors and nurses how you feel 
0 
1 
2 
3 
4 
2.  Asking the doctors and nurses questions 
0 
1 
2 
3 
4 
3.  Talking with others about your disorder 
0 
1 
2 
3 
4 
 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
81
 
 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
82
 
WORRY (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Worrying about my neurofibromas 
0 
1 
2 
3 
4 
2.  Worrying about side effects from medical 
treatments 
0 
1 
2 
3 
4 
3.  Worrying about whether or not medical 
treatments are working 
0 
1 
2 
3 
4 
4.  Worrying that neurofibromas will grow bigger or 
reoccur 
0 
1 
2 
3 
4 
5.  Worrying about my future or the risk of having 
children  with Neurofibromatosis Type 1 
0 
1 
2 
3 
4 
6.  Worrying about the risk of other health related 
issues associated with Neurofibromatosis Type 1 
0 
1 
2 
3 
4 
 
PERCEIVED PHYSICAL APPEARANCE 
                               (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Feeling that I am not good looking 
0 
1 
2 
3 
4 
2.  Not wanting other people to see my 
neurofibromas 
0 
1 
2 
3 
4 
3.  Being embarrassed about others seeing my body 
0 
1 
2 
3 
4 
 
PAIN AND HURT (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Aching or hurting 
0 
1 
2 
3 
4 
2.  Aching or hurting a lot 
0 
1 
2 
3 
4 
3.  Not sleeping because of pain 
0 
1 
2 
3 
4 
 
PARESTHESIAS (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  A burning sensation in some part of my body 
0 
1 
2 
3 
4 
2.  A tingling sensation in some part of my body 
0 
1 
2 
3 
4 
 
SKIN IRRITATION (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Itching  
0 
1 
2 
3 
4 
2.  Itching a lot 
0 
1 
2 
3 
4 
3.  Getting a skin rash when exposed to sun 
0 
1 
2 
3 
4 
4.  Tolerating temperature changes 
0 
1 
2 
3 
4 
5.  Rough skin 
0 
1 
2 
3 
4 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
83
 
 
 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
84
 
 
SENSATION (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Vision in one or both eyes 
0 
1 
2 
3 
4 
2.  Seeing well enough with glasses or contact  
lenses  
0 
1 
2 
3 
4 
3.  Hearing in one or both ears 
0 
1 
2 
3 
4 
4. Speech 
0 
1 
2 
3 
4 
 
MOVEMENT AND BALANCE (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Bending my body 
0 
1 
2 
3 
4 
2.  Moving one or both legs 
0 
1 
2 
3 
4 
3.  Using or moving one or both arms 
0 
1 
2 
3 
4 
4.  Keeping balance when sitting or standing 
0 
1 
2 
3 
4 
 
DAILY ACTVITIES (problems with...) 
Never 
Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Putting on shoes 
0 
1 
2 
3 
4 
2.  Buttoning my shirt 
0 
1 
2 
3 
4 
3.  Combing my hair 
0 
1 
2 
3 
4 
4.  Getting into the bathroom to use the toilet 
0 
1 
2 
3 
4 
5.  Undressing to use the toilet 
0 
1 
2 
3 
4 
6.  Getting in and out of bathtub or shower 
0 
1 
2 
3 
4 
7.  Brushing my teeth 
0 
1 
2 
3 
4 
8.  Eating with a fork and knife 
0 
1 
2 
3 
4 
9.  Using a phone 
0 
1 
2 
3 
4 
10. Shopping 
0 
1 
2 
3 
4 
11. Managing money 
0 
1 
2 
3 
4 
12. Driving 
0 
1 
2 
3 
4 
 
FATIGUE (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Feeling tired 
0 
1 
2 
3 
4 
2.  Resting a lot 
0 
1 
2 
3 
4 
3.  Having enough energy to do things that I like to 
do 
0 
1 
2 
3 
4 
 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
85
TREATMENT ANXIETY(problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Getting scared about going to the doctor 
0 
1 
2 
3 
4 
2.  Getting scared about going to the hospital 
0 
1 
2 
3 
4 
3.  Being responsible for my medicines or  therapy 
0 
1 
2 
3 
4 
 
 


NF Protocol #106 - Version 1.2  
 
     Participant’s Study ID: 
 
 
 
12/03/2014  
 
     Protocol: 
 
 
 
Course Number: 
 
 
 
Visit Date: ____________________________ 
 
86
SEXUAL FUNCTIONING (problems 
with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
Not 
Applicable 
1.  Fatigue or lack of energy affecting 
your satisfaction with your sex life 
0 
1 
2 
3 
4 
        5 
2.  Pain affecting your satisfaction with 
your sex life 
0 
1 
2 
3 
4 
5 
3.  Ability to have children with a 
fertile partner 
0 
1 
2 
3 
4 
5 
 
 
Please write any comments that you have about how NF-1 affects your health and well-being. 
Please write any comments about the survey and whether or not it captures how NF-1 affects 
people’s health and well-being.