Medical Treatment of "High-Risk" Neurofibromas in Patients With Type 1 Neurofibromatosis: A Clinical Trial of Sequential Medical Therapies
Phase: PHASE2
Conditions: Neurofibromatosis 1
Sponsor: Corewell Health West

Clinical Protocol and Supporting Clinical Documentation 
 
Protocol Title: 
 
 
Medical Treatment of “high-risk” Neurofibromas in Patients with Type 1 
Neurofibromatosis: A Clinical Trial of sequential medical therapies. 
 
Phase:  II 
 
Principle Investigator  
 
Albert S. Cornelius, MD 
Director of Education and Outreach  
Pediatric Hematology/Oncology 
Helen DeVos Children’s Hospital 
100 Michigan Ave NE, MC85 
Grand Rapids, MI  49503 
Office  
616 391-2086 
Fax 
616 391-9450 
E-mail 
Albert.Cornelius@devoschildrens.org 
 
Co-investigator  
 
 
David Dickens, MD 
Assistant Director of Clinical Services 
Pediatric Hematology/Oncology 
Helen DeVos Children’s Hospital  
Director Pediatric Hospice of Michigan 
 
 

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TABLE OF CONTENTS 
Section 
Page 
 
1 Abstract 
3 
 
 
2 Study Hypotheses 
3 
 
2.1 
Specific Aims 
3 
 
2.2 
Study Design and Treatment Plan 
4 
 
3 Background 
 
3.1 
Plexiform Tumors in Neurofibromatosis Type 1 Patients 
6 
 
3.2 
Previous Treatments for Plexiform Tumors in NF1 
6 
 
3.3 
Pathophysiology of Growth in Plexiform Tumors and Study Medications 
7 
 
3.4 
Use of Chemotherapy for NF1 
7 
 
3.5 
Preliminary Studies at Helen DeVos Children’s Hospital  
8 
 
3.6 
NF1 and Pre-existing Neuropsychological Conditions 
8 
 
4 Inclusion Criteria 
9 
 
5 Exclusion Criteria 
9 
 
5.1 
Criteria for Removal from Study Participation 
10 
 
5.2  Inclusion of Women and Minorities 
10 
 
6 Observations 
 
6.1 
Pre-treatment Evaluation 
10 
 
6.2 
Evaluations During Protocol Therapy 
11 
 
6.3 
End of Therapy Evaluations 
12 
 
6.4 
Off Therapy Follow-up of Responding Patients 
12 
 
6.5 
Response Criteria 
13 
 
7  Study Treatment 
 
7.1 
Duration of Study Treatment 
13 
 
7.2 
Treatment Arm 1 
13 
 
7.3 
Treatment Arm 2 
14 
 
7.4 
Dose Adjustments 
14 
 
7.5 
Adverse Events 
15 
 
 
7.5.A Definition of Adverse Events 
 
 
7.5.B Definition of Serious Adverse Events 
 
 
7.5.C Adverse Event Reporting 
 
 
7.5.D Data and Safety Monitoring 
 
8 Statistical Considerations 
16 
 
9 Drug Information 
 
9.1 
CELECOXIB 
16 
 
9.2 
PEG-INTERFERON ALPHA-2B 
17 
 
9.3 
TEMOLOZOLOMIDE 
19 
 
9.4 
VINCRISTINE SULFATE 
20 
 
9.4.1 
Dose Modification for Vincristine 
21 
 
9.4.2 
Grading of Sensory Neuropathy 
21 
 
 
9.4.3 
Grading of Motor Neuropathy 
22 
 
9.4.4 
Hyperbilirubinemia 
22 
 
9.4.5 
Drug Extravasation 
22 
 10 Subject Stipends or Payments 
22 
   11   Data Handling and Record Keeping 
23 
 
   12  References Cited 
24 
 13 Appendices 
 
13.1 
Appendix 1 – Performance Scales 
26 
 
13.2 
Appendix 2 – Dose Chart for Celecoxib by Weight 
27 
 
13.3 
Appendix 3 – NIH Diagnostic Criteria for NF1 
28 
              13.4    Appendix 4 – Psychological Evaluations                                                                                    29 
 

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1 
ABSTRACT 
 
Plexiform neurofibromas are commonly seen in patients with Neurofibromatosis type I.  A 
significant number of these plexiform neurofibromas can result in severe disability from 
neurologic impingement, chronic pain, skeletal dysplasia, vascular complications, and/or organ 
dysfunction due to displacement or infiltration. Occasionally, these lesions are life-threatening 
due to the size or location of the tumor.  Presently, there is no effective medical therapy to offer 
patients with “high-risk” plexiform neurofibromas. We have observed dramatic responses within 
the last two years in two patients with chronic “high-risk” plexiform neurofibromas. One patient, 
who had a large symptomatic pelvic “high-risk” plexiform neurofibroma, had complete 
resolution of symptoms along with approximately 50% tumor shrinkage with a treatment 
combination of naproxen and interferon alpha-2b. The second patient, who had a large cranio-
facial “high-risk” plexiform neurofibroma that had already caused an ischemic stroke by 
compression of the carotid artery, experienced a complete radiographic response (regression of 
the plexiform tumor) with a combination of celecoxib and interferon alpha-2b together with 
vincristine and temozolomide. These preliminary findings were conducted without grant funding. 
 
This clinical trial will further evaluate the effectiveness of these treatment combinations in 
patients with “high-risk” plexiform neurofibromas. Eligible patients will begin treatment with the 
combination of a cox-2 inhibitor (celecoxib) at a dose of 10 milligrams/kilogram/day (max 800 
mg/day) and pegylated interferon alpha-2b at a dose of 1 microgram/kilogram/given weekly 
(CI). If the patients have at least a partial response after six months they may continue on the 
same treatment for up to two years. However, if the patient experiences less than a partial 
response, or has stable or progressive disease after six months of CI therapy, then vincristine (at 
a dose of 0.75 mg/m2) and temozolomide (150 mg/m2/day given 5 consecutive days each month) 
will be added to the celecoxib and interferon alpha-2b backbone (CITV). Response to the CITV 
therapy will be assessed after six months of treatment. 
 
2 
STUDY HYPOTHESES 
 
 
The hypothesis to be tested is NF1 patients with “high-risk” plexiform neurofibromas that 
respond to treatment with celecoxib and pegylated interferon alpha-2b (CI) is significantly 
greater than 0—indicating an improved treatment response rate over traditional therapy. 
 
 
The additional hypothesis to be tested is that “high-risk” plexiform neurofibromas who have 
demonstrated resistance to treatment with celecoxib and pegylated interferon alpha-2b (CI) will 
respond to the addition of temozolomide and vincristine (CITV), and this response rate will be  
significantly greater than 0. 
 
2.1 Specific Aims 
A. To define an algorithm for the medical treatment of “high-risk” plexiform 
neurofibromas using a sequential application of commercially available medications. 
B. To evaluate tumor response based on objective evaluation of symptom assessment and 
tumor measurements.   

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C. To evaluate the toxicity of Celecoxib/Interferon alpha-2b and Celecoxib/Interferon 
alpha-2b/Temozolomide/Vincristine treatments in this selected population of young 
patients.  
D. To specifically evaluate psychological toxicity of Celecoxib/Interferon alpha-2b and  
Celecoxib/Interferon alpha-2b/Temozolomide/Vincristine in this selected population of 
patients with NF-1 
E. To improve the quality of life experienced by patients with “high-risk” plexiform 
neurofibromas by decreasing the pain and functional disability caused by these tumors. 
 
2.2 Study Design and Treatment Plan 
This is a phase II single arm study with sequential treatments available by response where all 
participants begin therapy with a combination of celecoxib and interferon alpha-2b (CI, 
treatment-1). Response to CI therapy will be assessed at six months by clinical and radiographic 
evaluations. Those patients who have achieved a partial response  (improvement in pain, 
improvement in functioning, or ≥50% reduction in tumor size) or complete response (resolution 
of pain, and normalization of functioning with a ≥ 90% reduction in tumor size) will continue 
with the same CI therapy for up-to two years on study.  
 
Patients who have rapidly progressive disease (≥50% growth in tumor size) within the first six 
months of CI treatment are required to undergo tumor biopsy to evaluate for malignancy. If this 
biopsy is negative for malignancy then these patients may begin treatment with 
celecoxib/interferon alpha-2b/temozolomide/vincristine (CITV, treatment-2).  
 
Patients who have not achieved at least a partial response to CI therapy after six months of 
treatment are also eligible to change to CITV treatment.  For these patients a biopsy of the tumor 
is recommended but not required to verify the pathology of the tumor before advancing to CITV 
therapy. 

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Study Entry
Off Study
Evaluate 
Responses at 
6 Months
Continue 
CITV for
18 Months
Start CITV
Biopsy 
Required
Biopsy of 
Tumor 
Recommended
Continue CI 
Therapy for
18 Months
Evaluate 
Responses at 
6 Months
Begin 
Treatment
With CI
Legend
CI - Celocoxib + interferon alpha 2b
CITV - Celocoxib/Interferon alpha-2b/Temozolomide/Vincristine
PD - Progressive disease 
SD - Stable disease
PR - Partial response (more than 50% shrinkage of the tumor)
CR - Complete response (more than 90% shrinkage of the tumor)
SD/PR/CR
PR/CR
PD > 50%
SD/PD
SD/PR/CR
Malignant
PD
Benign
PD
Study Design
 
 

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3 
BACKGROUND 
 
3.1 Plexiform Tumors in Neurofibromatosis Type 1 Patients 
Neurofibromatosis type 1 (NF1) is a progressive genetic disorder with diverse cutaneous, 
neurologic, skeletal and neoplastic manifestations that affects 1 in 4000 persons [1]. While most 
of these persons are only mildly affected, some patients may experience severe compromise such 
as disabling disfigurement, neurologic impairment, or life-threatening compressions of vital 
structures.  Three types of neurofibromas have been described in patients with NF1.  a) 
Dermal/cutaneous: Soft, non-painful raised cutaneous lesions. b) Subcutaneous/solitary 
neurofibromas: Firm round masses that occur along the course of peripheral nerves, which are 
often painful and can compromise local structures as they enlarge. A variant of solitary 
neurofibromas may occur along the spine, which can extend into the spinal foramina and cause 
scoliosis or spinal cord compression. c) Plexiform neurofibromas: Soft poorly defined masses 
that often have the feeling of a bag of wet ropes. Plexiform neurofibromas are the most common 
cause of disfigurement in patients with NF1, and may be associated with life-threatening 
occlusion of the airway.  In addition, plexiform neurofibromas are often associated with 
dysfunction of peripheral nerves with weakness, and painful neuropathy [2]. For the purposes of 
this study we consider any neurofibroma that is causing severe disfigurement (cosmetic or 
functional, i.e. spine), chronic pain, impairment of neurological function, or compression of vital 
structures to be “high-risk.”  Most of these “high-risk” neurofibromas are the plexiform type of 
neurofibroma.  
 
3.2 Previous Treatments for Plexiform Tumors in NF1 
Surgical resection is the only proven treatment for “high-risk” plexiform neurofibromas.  
Unfortunately, complete surgical resection is not possible for most patients with “high-risk” 
plexiform neurofibromas. Even when complete surgical resection is thought to be successful, 
half of the patients develop recurrent tumors after surgery.   Partial surgical resection is not 
effective, but is sometimes used in patients facing imminent loss of function from these tumors.  
These limitations make surgical treatment of symptomatic neurofibromas on the face, spine and 
pelvis particularly difficult [1, 3, 4]. Therefore, the search for effective adjuvant medical 
therapies is warranted. 
 
The medical treatment of “high-risk” plexiform neurofibromas has been disappointing. Ketotifen 
has been used to reduce the painful pruritis of solitary or plexiform neurofibromas, but they do 
not reduce the size of tumors [1]. Gupta and Cohen studied the use of thalidomide in patients 
with serious plexiform neurofibromas in patients with NF1.  Four of the 12 patients studied did 
show a minor response to thalidomide with 2 of these 4 patients demonstrating radiographic 
improvement. Seven of 12 patients reported an improvement in neurofibroma related symptoms. 
However, the widespread use of thalidomide was limited by an increased risk of neuropathy and 
somnolence and the authors did not recommend thalidomide for future trials [3].  Interferon 
alpha (IFNα) has been the subject of a previous phase II clinical trial which has yet to be 
published. According to a recent review, 96% of patients receiving IFNα therapy were 
considered at least stable, with a few patients showing radiographic or symptomatic 
improvement [5]. 
 
 
 

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others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this 
obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
3.3 Pathophysiology of Growth in Plexiform Tumors and Study Medications 
The pathophysiology responsible for the development of plexiform neurofibromas in NF-1 
patients is multi-factorial and only partially understood. It is known that plexiform 
neurofibromas are heterogeneous collections of cells including Schwann cells, fibroblasts, and 
mast cells [6]. While the Schwann cells are generally accepted as the neoplastic cell of origin, 
recent evidence suggests that the tumor stroma likely contributes to the proliferative state of 
these tumors. Stroma-derived elements including tumor growth factor beta (TGF- β) [7], matrix 
metalloproteinase(MMP)-9 [8] and vascular endothelial growth factor (VEGF) [9] are known to 
be elevated in plexiform neurofibromas, suggesting that they may serve as therapeutic targets. 
The initial agents selected for this trial were chosen in part for their known antagonism in these 
signaling pathways. Interferon has been shown to down-regulate both TGF-β mRNA production 
in fibroblasts derived from human hypertrophic scar tissue [10] and VEGF expression in human 
neuroendocrine tumor samples [11]. Cycloxygenase(COX)-2 inhibition (the inducible target 
enzyme of celecoxib) decreases both MMP and VEGF expression in animal models of breast, 
prostate, and colorectal cancers [12-15]. High-dose Celecoxib is now approved for use to reduce 
the incidence of adenomatous colorectal polyps in patients with Familial Adenomatous 
Polyposis. 
 
Additional intrinsic cellular aberrations that result from the NF-1 defect justify the therapeutic 
use of both interferon and celecoxib.  Neurofibromin normally inactivates the growth promoting 
pathway of RAS/mTOR [5]. NF-1 patients, being deficient in neurofibromin, have a functionally 
activated RAS/mTOR pathway. Interferon induced apoptosis has been shown to be mediated via 
the mTOR pathway, making neurofibromas the ideal target tumor type for interferon based 
therapies [16]. In addition to mTOR activation, oncogenic RAS mutations also up-regulate COX-
2 expression which would further promote tumor growth and angiogenesis [17, 18] again making 
COX-2 inhibitors an intriguing therapy. Very little information exists on the interplay between 
interferons and COX-2. In vitro evidence suggests that interferon alpha induces COX-2 
expression in vitro [19, 20], which may explain the partial benefit of single agent interferon 
therapy in NF-1 patients. A recent clinical trial of combination interferon alpha plus celecoxib 
therapy for metastatic renal cell carcinoma patients was completed and documented the safety of 
this combination [21].  
 
3.4 Use of Chemotherapy for NF1 
The use of conventional chemotherapy in NF-1 patients has been approached with much 
trepidation over concerns of mutagenesis.  While it is true that NF-1 patients have a relative risk 
of malignancy that is approximately 4-6 fold higher than the general population [22], the use of 
chemotherapy (carboplatin) in NF-1 patients has never been shown to increase that risk further 
[23]. Temozolomide has shown benefit in the treatment of unresectable gliomas, tumor of 
neuronal origin, and was therefore chosen as the cytotoxic agent on this protocol [24]. The 
design of this protocol reserves the use of chemotherapy only for patients with persistent high-
risk lesion despite the use of non-chemotherapeutic agents (celecoxib plus interferon). The 
combination of temozolomide and both interferon and celecoxib have been trialed separately in 
advanced melanoma patients and has shown some promise without discernable added toxicity 
[25, 26]. 
 
 
 

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others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this 
obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
3.5 Preliminary Studies: Helen DeVos Children’s Hospital Experience 
We have had the opportunity to treat many patients with “high-risk” plexiform neurofibromas at 
Helen DeVos Children’s Hospital (HDVCH), including patients who have participated in 
therapeutic clinical trials. While most of our experience using published therapy has been 
disappointing, there are two patients who within the last three years have had informative 
responses to treatment.  
 
The first patient was referred to HDVCH for treatment of a large plexiform neurofibroma of the 
pelvis and lumbar spine which had caused chronic pain, leg weakness, and bladder dysfunction 
which was unresponsive to a third attempt at surgical treatment.  This patient was started on a 
regimen of naproxen and Interferon alpha-2b and within six weeks this patient’s chronic pain had 
resolved.  Within 12 weeks the tumor was physically softer and measurably smaller on clinical 
examination. Along with these changes the patient’s chronic leg weakness resolved, and bladder 
function become normal. After six months of therapy the mass was dramatically smaller on 
examination and measurable shrinkage by CT scan was noted.  The patient was maintained on 
treatment with both medications for two years.  Because of difficulty concentrating in school, the 
treatment has been reduced to naproxen alone. On recent follow-up examination the high-risk 
plexiform neurofibroma remains smaller than at diagnosis while using normal-dose naproxen.  
 
The second patient is an infant that had a large disfiguring plexiform neurofibroma of the face 
and skull which was noted at birth. The growth of the tumor was controlled with interferon 
alpha-2b from 3 months of age but no tumor regression was noted on this therapy.  At three years 
of age the patient developed a symptomatic optic glioma and the interferon was interrupted for 
12 months while she received vincristine and carboplatin; (During this therapy the patients 
plexiform tumor was stable in size). Following this, the interferon was restarted but at five years 
of age the interferon alpha-2b was discontinued in order to participate in a therapeutic trial of 
thalidomide (Cleveland Clinic, Cleveland Ohio). After three months of treatment this patient’s 
plexiform tumor was markedly larger, and the patient withdrew from the study medication. The 
patient continued to have slow growth of the tumor after re-starting interferon and so celecoxib 
was added. The patient showed a minor response to this therapy but had no further progression 
of her cranial-facial plexiform neurofibroma. Three years later (while continuing on treatment 
with celecoxib and interferon alpha-2b) the patient developed a progressive optic glioma and a 
symptomatic intrinsic brainstem tumor (never biopsied) which required additional therapy.  
Since the patient had previously shown rapid tumor growth when the interferon alpha-2b was 
discontinued for participation in the thalidomide trial, the celecoxib/interferon alpha-2b was 
continued while the patient received a combination of vincristine and temozolomide for 
treatment of these new tumors. The patient showed rapid shrinkage of her plexiform 
neurofibroma after the first treatment of celecoxcib/interferon alpha-
2b/vincristine/temozolomide, and after three months of treatment had complete resolution of the 
cranial-facial plexiform neurofibroma.  This patients’ plexiform tumor continues to be in a 
clinical and radiographic remission after 24 months of treatment with celecoxib/interferon alpha-
2b/vincristine/temozolomide. 
 
 
3.6 NF1 and Pre-existing Neuropsychological Conditions 
Children with NF1 most commonly demonstrate impairments in language, visual-spatial testing, 
attention and concentration [29].  Recently published studies find that between 52%  and 60% of 
children with NF1 have significant learning impairments [27, 28].  Up to 81% of children with 

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NF1 can have moderate to severe impairment in one or more areas of cognitive functioning [29]. 
This information emphasizes the importance of obtaining a baseline evaluation of all children 
(and young adults) who participate in this study. It will be impossible to determine the true 
cognitive toxicity of interferon alpha 2b in this population without establishing a baseline for 
cognitive functioning for each patient. 
 
4 
INCLUSION CRITERIA 
A. Patients must “high-risk” plexiform neurofibromas associated with a diagnosis of NF1 
(see appendix III for diagnostic criteria for NF1).  For the purposes of this study these 
tumors need to be disfiguring, causing chronic disability due to organ dysfunction or 
pain, or be in a life threatening location. 
B. Patients must be 2-30 years old with a minimum bodyweight of 10 kilograms due to 
dosing restrictions associated with celecoxib.  10 adults (ages 18-30) and 10 pediatrics 
(ages 2-17) will be enrolled.  
C. Patients and/or patient’s guardian must voluntarily agree to provide informed consent 
for study participation. 
D. Adequate renal function is required as measured by the serum creatinine. If the serum 
creatinine is higher than laboratory norms (indicating impaired renal function) a 24 
hour urinary creatinine clearance will be ordered. If the creatinine clearance is less than 
40ml/min/1.73 m2, these patients are excluded from study participation.  
E. Volunteer Screening Procedures:  At the direction of the study investigators, patients 
will be screened by the Research Coordinator for potential participation in the study 
following all inclusion/exclusion criteria. 
 
5 
EXCLUSION CRITERIA  
A. Patients who have a previously untreated active optic glioma are not considered eligible 
for this study since other medically accepted therapy is available for first-line treatment 
of this tumor. 
B. Patients who have a history of any previous allergy to study medications (Celecoxib, 
Interferon alpha-2b, Temozolomide, Vincristine) are excluded from study participation.  
C. Patients with a known history of ischemic vascular disease will be excluded from study 
participation. Both interferon and celecoxib can aggravate ischemic vascular disease. 
Study participation by an individual with known peripheral vascular disease may place 
the participant at undue risk of renal insufficiency, cardiovascular disease, and/or 
stroke. 
D. Female patients who are pregnant are excluded from study participation, these study 
medications may be damaging to a developing fetus and should not be used in women 
who are pregnant.  
E. Women who are breast feeding are excluded from this study. 
F. Patients who are identified to have significant depression or other psychological 
disturbance that require medical intervention are excluded from this study. 

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5.1 Criteria for Removal from Study Participation 
A. Patients who experience a rapid growth of their tumor during the first six months of 
treatment are eligible to remain on study if they have a tumor biopsy that pathologically 
confirms a plexiform neurofibroma and excludes a malignant tumor phenotype.   
B. Pathologic diagnosis of malignancy will result in removal from study participation. 
C. Patients who are identified to have significant depression or other psychological 
disturbance that require medical intervention will be removed from study and 
discontinue all study medications. These patients will then be referred to their primary 
care physician for further treatment. 
D. Patients will be asked to bring any unused study medications with them to each visit. 
Patients who consistently have less than an 80% compliance rate with study 
medications (by direct counting of injections and or pills) will be removed from study. 
However, patients who receive less than 80% of the specified dose of study 
medications due to toxicity mandated dose reductions will remain study eligible. 
E. Women who become pregnant during study therapy will be removed from study 
participation, and therapy will be discontinued since any of the study prescribed 
medications may be dangerous to a developing fetus.  
 
5.2 Inclusion of Women and Minorities:  Women and minorities who fit all inclusion/exclusion 
criteria will be included in this study. 
 
6       OBSERVATIONS 
 
Along with the following, additional tests/procedures/evaluations may be performed as deemed 
necessary for patient care by the study investigator. 
 
6.1 Pre-Treatment Evaluation 
A. Initial physical examination with measurement of weight, blood pressure, clinical 
tumor measurements, and evaluation of activity using the Karnofsky Performance Scale 
(for patients >16 years old) or the Lansky Play Performance Scale (for patients ≤16 
years old) scale assessment 
B. Photographic documentation of tumor appearance will be requested and included in the 
study record following patient/guardian consent.  These images will be available only 
to study personnel.  
Photographic records of tumors at diagnosis and throughout the study will be kept on a 
separate electronic recording device organized by unique study number (not by name).  
These records will be retained for an indefinite length of time.  This information will 
not be released to other institutions or physicians without the expressed written consent 
of the patient or patient guardian. Written consent will be obtained from the patient or 
patient guardian prior to submission of these images for later publication. 
C. Complete blood count with differential and chemistry profile that includes electrolytes, 
Ca, PO4, BUN, Cr, Bilirubin, ALT, and AST. 

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D. Urine pregnancy test for all female patients of childbearing potential must be negative 
at study entry. 
E. Psychological evaluation by a licensed psychologist.  See Appendix 4 for detailed 
information regarding evaluation.  
F. MRI studies will be ordered locally and must be completed within 8 weeks of study 
participation.  All MRI images for this study will be sent via data storage device to Dr. 
Brigitte Widemann at the National Institutes of Health (a collaborating physician at the 
NIH) for 3-dimensional volumetric measurements after de-identification by Spectrum 
Health radiological services. 
 
6.2 Evaluations During Protocol Therapy 
A. Monthly physical exams (+/- 7 days) for the first 3 months to monitor toxicity, and 
every three months (+/- 14 days) for the duration of study participation.  Attention to 
psychological side effects will be a part of each physical examination. 
B. Photographic documentation of tumor appearance will be requested every three months 
(+/- 14 days) of treatment, and included in the study record following patient/guardian 
consent. 
C. Monthly (+/- 7 days) CBC and chemistry profile that includes electrolytes, Ca, PO4, 
BUN, Cr, Bilirubin, ALT, and AST for the first six months. If the patient continues 
Treatment Arm 1, then these laboratory studies can be evaluated every 3 months (+/- 14 
days) at the discretion of the study physician.  
D. For patients who proceed on to Treatment Arm 2, monthly (+/- 7 days) CBC and 
chemistry profile that includes electrolytes, Ca, PO4, BUN, Cr, Bilirubin, ALT, and 
AST will be evaluated for the duration of trial therapy. 
E. Psychological evaluation by a licensed psychologist will occur at 3 months, 12 months, 
and 24 months, (+/- 30 days), of study participation with more frequent evaluations as 
clinically indicated (see Appendix 4 for detailed information regarding evaluation).  
Study participants and family members will be encouraged to call study personnel with 
concerns about psychological functioning. 
F. MRI studies will be ordered locally after 6, 12, and 24 months, (+/- 30 days), of study 
participation to evaluate tumor response, these images will then be sent to Dr. Brigitte 
Widemann at the National Institutes of Health (a collaborating physician at the NIH) 
for 3-dimensional volumetric measurements.  Additional studies can be ordered as 
deemed necessary for patient care by the study physician. Any studies done for other 
purposes will also be evaluated for tumor response information. 
G. Female patients of childbearing age must have a negative urine pregnancy test before 
participating and participants must agree to disclose potential pregnancy as soon as 
suspected to the study physician or nurse. 
H. Female participants of childbearing potential who proceed to treatment arm 2 will 
require a urine pregnancy screening test with each monthly visit to avoid fetal injury 
from chemotherapy. If a pregnancy is confirmed then the patient will be removed from 
study participation. 

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obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
I. Patients who are found to have active psychosis or depression that may be worsened by 
the use of interferon are excluded from study participation. 
 
6.3 End of Therapy Evaluations   
A. Patients will undergo detailed physical examination with measurement of weight, blood 
pressure, clinical tumor measurements, and evaluation of activity using the Karnofsky 
Performance Scale (for patients >16 years old) or the Lansky Play Performance Scale 
(for patients ≤16 years old) scale assessment.  
B. Photographic documentation of tumor appearance will be requested and included in the 
study record following patient/guardian consent. 
C. Complete blood count with differential and chemistry profile that includes electrolytes, 
Ca, PO4, BUN, Cr, Bilirubin, ALT, and AST. 
D. Psychological evaluation by a licensed psychologist. See Appendix 4 for detailed 
information regarding evaluation.  
E. MRI studies will be ordered locally, these images will then be sent to Dr. Brigitte 
Widemann at the National Institutes of Health (a collaborating physician at the NIH) 
for 3-dimensional volumetric measurements. 
 
6.4 Off Therapy Follow-up of Responding Patients 
Patients who respond to this therapy will be asked to return for follow-up evaluations every 
three months (+/- 14 days) for the first year off therapy and every six months (+/- 30 days) 
for the next three years off therapy to determine the duration of response.  Evaluations will 
include: 
A. Patients will undergo detailed physical examination with measurement of weight, blood 
pressure, clinical tumor measurements, and evaluation of activity using the Karnofsky 
Performance Scale (for patients >16 years old) or the Lansky Play Performance Scale 
(for patients ≤16 years old) scale assessment.  
B. Photographic documentation of tumor appearance will be requested and included in the 
study record following patient/guardian consent. 
C. MRI studies may be ordered to evaluate tumor response, these images will then be sent 
to Dr. Brigitte Widemann at the National Institutes of Health (a collaborating physician 
at the NIH) for 3-dimensional volumetric measurements.  Any studies done for other 
purposes will also be evaluated for tumor response information. 
D. Psychological evaluation by a licensed psychologist, if the end of therapy evaluation 
showed detrimental changes for the on-study evaluation.  See Appendix 4 for detailed 
information regarding evaluation.  
 
 
 
 
 
 

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obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
6.5 Response Criteria 
A. PD     - Progressive disease, with an increase of at least 20% over previous tumor 
evaluations 
B. SD     - Stable disease, tumors that measure between 20% larger and 50% smaller than 
previous measurement with no improvement in tumor related symptoms and 
daily functioning. 
C. PR     - Partial response, 50-90% shrinkage of the tumor,  
D. PR-S - 
Less than 50% shrinkage of the tumor with marked improvement in tumor 
related symptoms and daily functioning 
E. CR     - Complete response, more than 90% shrinkage of the tumor with associated 
resolution of tumor associated symptoms and disability not caused by 
abnormal bone growth.  Patients with persistent symptoms resulting from 
preceding orthopedic or neurologic damage will not be considered as 
persisting tumor-related symptoms and may qualify at complete responders. 
 
7 
STUDY TREATMENT 
 
7.1 Treatment Duration:  
 
Each treatment arm will be given for a minimum of six months, presuming the patient has 
not experienced progressive disease, before advancing to the next arm. Total duration of 
therapy on study is two years for any individual treatment plan (i.e. treatment-1 or 
treatment-2).  
 
7.2 Treatment  Arm 1  
A. Celecoxib 10 mg/kg/day given by mouth (once or twice daily). See Appendix 2 for 
dosage table by weight. 
B. Pegylated interferon alpha-2b at a dose of 1 microgram(mcg)/kg of body weight given 
as a subcutaneous injection weekly. This dose was well tolerated by 26/28 patients in a 
previous trial [30].  To reduce the toxic side effects associated with beginning 
interferon therapy, the patients will begin with a dose of 0.3 mcg/kg, then escalate to 
0.6 mcg/kg at week two, and 1 mcg/kg at week 3.  Diphenhydramine at 1 mg/kg orally 
is recommended one time before and tid for 24 hours after the first interferon dose.  
Pre-medication with diphenhydramine at 1 mg/kg orally is recommended before each 
dose of interferon until drug tolerance is established.  
1. If a patient experiences fever >40oC, rigors, or appetite suppression with weight     
loss, then the dose of interferon will be reduced to the previous dosage until the 
identified symptoms improve before resuming dosage escalation. 
2. Warning:  Interferons, including interferon alfa-2b, can cause or aggravate fatal or 
life-threatening neuropsychiatric (including suicidal ideation and attempts), 
autoimmune, ischemic, and infectious disorders. Patients will be monitored 
closely with monthly clinical and laboratory evaluations. Patients with 
persistently severe or worsening signs or symptoms of these conditions will be 

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obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
withdrawn from therapy. In many but not all cases these disorders resolve after 
stopping interferon alfa-2b therapy. 
C. If a study patient has progressive disease or no response to treatment 1 after six months, 
he/she will proceed to treatment 2.  Patients who experience a rapid growth of tumor on 
treatment 1 must first undergo a biopsy of this tumor to determine the pathologic 
phenotype of this tumor. Patients with a malignant phenotype will be removed from 
study participation and will be referred for appropriate medical treatment. 
 
7.3 Treatment  Arm 2  
A. Continue treatment arm 1 medications and add: 
B. Vincristine (Oncovin®) 0.75 mg/m2/dose or 0.025 mg/kg/dose if the patient weighs 
<15kg (maximum dose 2mg) to be given intravenously weekly x 4 doses then every 
month with temozolomide [vincristine dose is 50% of normal because of concurrent 
interferon].  The dose of vincristine will be adjusted for grade 3 or 4 toxicity. See page 
20 (section 9.4). 
C. Temozolomide (Temodar®) (150 mg/m2/day) for 5 consecutive days given by mouth 
every month.  Fractionate Temodar® into 2-3 daily doses with appropriate antiemetic 
coverage before each dose.  
 
7.4 Dose Adjustments  
A. Hepatic impairment: discontinue therapy if serum glutamic oxaloacetic transaminase 
exceeds 5 times the upper limit of normal.  
B. Hematologic: WBC count less than 1.5 x 10(9) /L; granulocyte count less than 0.75 x 
10(9) /L; platelet count less than 50 x 10(9) /L) reduce dose of temozolomide by 50% 
and escalate to full dose as tolerated.  Peg- interferon alpha 2a can also cause 
hematologic toxicity, if the patient is not receiving temozolomide, the peg- interferon 
alpha 2a dose will be reduced by 50% and escalate to full dose as tolerated. 
C. Hematologic: WBC count less than 1 x 10(9) /L; granulocyte count less than 0.5 x 
10(9) /L; platelet count less than 25 x 10(9) /L) hold and restart temozolomide (or peg-
interferon alpha 2a) at less than 50% of previous dose after hematologic recovery and 
escalate to full dose as tolerated. 
Special Circumstances: In the event that a patient with a pre-existing hematologic 
condition that is associated with cytopenias (neutropenia, anemia or thrombocytopenia) 
qualifies for study participation, then the interpretation of these hematologic toxicity 
guidelines may be cautiously adjusted. Specifically, patients who are receiving 
celocoxib/interferon (CI) may receive supportive care utilizing growth factors (g-CSF 
[Neupogen], erythropoietin), prophylactic antibiotics, or immunoglobulin (ie IVIG for 
immune thrombocytopenia Purpura) to reduce the complications associated with these 
cytopenias while continuing to receive full doses of study medications. Steroids should 
not be used in that they may also affect tumor response. However, should additional 
complications from these cytopenias occur (fever with neutropenia, clinical infections, 
or bleeding with thrombocytopenia), then adjustment of study medications to assure 
patient safety must take place.  

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others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this 
obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
Patients who are receiving celocoxib/interferon/temozolomide/vincristine (CITV) do 
not qualify for this ‘exception’ and must follow the listed dose adjustment guidelines 
for cytopenias. 
D. Renal impairment: discontinue therapy if the serum creatinine exceeds 2 mg/dL  
E. Severe adverse reactions: temporarily discontinue therapy if severe adverse reactions 
develop. When the patient has recovered, interferon may be restarted at 50% of the 
previous dosage and escalated to full dose as tolerated at the discretion of the study 
physician. 
F. Psychological: Interferons, including interferon alfa-2b, can cause or aggravate life-
threatening neuropsychiatric disorders. Patients will be monitored closely with monthly 
clinical evaluations. Patients with persistently severe or worsening signs or symptoms 
of these conditions will be withdrawn from therapy. In many but not all cases these 
disorders resolve after stopping interferon alfa-2b therapy.  Patients with milder 
exacerbations of psychological dysfunction will be referred to a psychiatrist for 
consideration of treatments to control the symptoms without completely discontinuing 
study medications. 
 
7.5 Adverse Events 
A. Definition of an adverse event: For the purposes of this study, an adverse event is 
defined as any inter-current illness which produces an adverse change from 
pretreatment baseline during the course of the study, whether the adverse event is 
considered related to the study treatment or not.  Adverse events that are graded as 
grade 3 or 4 by the common Terminology Criteria Version 3.0 for adverse events as 
published by the U.S. Department of Health and Human Services will be recorded.  
 
B. Definition of a serious adverse event: Serious adverse events (SAE) include any event 
resulting in death, any life-threatening experience, an event that causes or prolongs 
hospitalization, any event that causes persistent or significant disability or incapacity, or 
events that require medical or surgical intervention to prevent the above. 
C. Adverse event reporting: At each contact with the subject, the investigator will seek 
information on adverse events by specific questioning and as needed examination. 
Information on adverse events including onset date, duration, severity, relationship to 
the investigational agent, action taken with respect to the investigational agent and 
outcome will be recorded in the source document and also in the appropriate case report 
form (CRF).  
The clinical course of each event will be followed until resolution, stabilization, or until 
it is determined that the study treatment is not the cause of the adverse event. Serious 
adverse events at the end of the study period will be followed to determine the final 
outcome. Any serious adverse event that occurs after the study period that is considered 
to be possibly related to the study treatment will be recorded and reported immediately.   
 
All unexpected and related adverse events will be reported to the Spectrum Health IRB 
(Institutional Review Board), per Spectrum Health IRB policies. 
 

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others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this 
obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
D. Data and safety monitoring: A multidisciplinary committee (composed of principal 
investigator and/or sub-investiators, pharmacist, nurses, and research study staff) will 
evaluate this study for the purpose of data and safety monitoring. The committee will 
evaluate the need for amendments, revisions, and/or study discontinuation at least 
quarterly during the time of active patient participation.  More frequent meetings will 
be arranged as needed for toxicity monitoring. 
 
8 
STATISTICAL CONSIDERATIONS 
 
The endpoint of this study is response to therapy which will be established clinically as defined 
elsewhere in this proposal.  As long as patients show measurable response based on performance 
criteria (using Lansky or Karnofsky Performance Status Scales, see Appendix 1) or tumor 
evaluation they are considered a responder.  The simple design of this study allows for a binary 
statistical evaluation of response, where a response is considered anything more than 0 (which is 
considered to be stable or progressive disease). 
 
The unknown factor in determining sample size is the number of patients who will respond to 
treatment arm 1 with celecoxib/interferon alpha-2b(“CI”).  If most study participants show a 
response to treatment arm 1, then treatment arm 2 may not have an adequate number of 
participants to determine response rates (even given this simple design).  We anticipate a 
response rate approaching 50% to treatment arm 1.  This estimate a total study size of 20 patients 
is required to provide up to 10 patients eligibility to proceed to celecoxib/interferon alph-
2b/temozolomide/vincristine (CITV) treatment (i.e., Treatment Arm 2). However, a significant 
number of patients may withdraw from study participation due to toxicity.  Thus we recommend 
accruing 10 patients in each treatment arm with a total sample size of 20 patients so that a 
minimum of 10 patients will be available for evaluation in treatment arm 2. 
 
This phase II clinical trial aims to establish the efficacy of a novel treatment for NF1.  Patients 
receiving this treatment will be in treatment arm 2, having already failed non-chemotherapy 
based therapy in treatment arm I.  Therefore, the alternative hypothesis to be tested is that 
response to treatment arm 2 is significantly greater than 0—indicating improvement in this group 
of patients over non-chemotherapy based therapy.  The corresponding null hypothesis being that 
the response rate in treatment arm 2 is 0.  Under the assumption of independence, only a handful 
of patients should be necessary to reject the null hypothesis (approximately 5 if a response rate of 
20% is expected in arm 2).  However, since the samples are not independent, this sample size 
must be increased somewhat.  Since a response rate of approximately 50% is expected in arm 1, 
approximately 10 patients will be available for arm 2, which should be adequate to demonstrate a 
response rate > 0 in arm 2 even after adjustment for the non-independence of the samples.   
 
9 
DRUG INFORMATION 
  
9.1 
Celecoxib (Celebrex)  revised Aug 2002 
 
Source and Pharmacology: Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that is 
a selective inhibitor of COX-2 (cyclooxygenase-2). Cyclooxygenases 1 and 2 are enzymes that 
are involved with conversion of arachidonic acid to prostaglandins. COX-1 is present normally 
in much of the body and is particularly involved in platelet aggregation and protective 

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obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
mechanisms of the gut and kidney. COX-2 is formed in higher concentrations in response to 
inflammation and injury. Selective inhibitors of COX-2 have analgesic, anti-inflammatory, and 
antipyretic effects, with less frequent toxicity to the gut and kidneys, and little-to-no inhibition of 
platelet function. Prostaglandins that are produced by COX 1 and 2 appear to be involved with 
angiogenesis, and celecoxib has been shown to have anti-angiogenic effects. At high doses, it has 
been shown to reduce the formation of polyps in patients with familial adenomatous polyposis. 
Celecoxib is metabolized to inactive metabolites primarily by P-450 2C9. It appears that some 
drugs that stimulate or inhibit P-450 2C9 enzymes can increase or decrease the clearance of 
celecoxib. Celecoxib may inhibit P-450 2D6 and reduce the clearance of drugs metabolized 
primarily by that route. Celecoxib is approximately 97% bound to plasma proteins. The 
elimination half-life of celecoxib is approximately 11 hours.  
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children out 
of every 100 
Immediate: 
Within 1-2 
days of 
receiving drug 
Dyspepsia, may mask fever 
in neutropenic patients (L) 
 
Hypersensitivity reactions 
(especially with history of 
sulfa or aspirin 
hypersensitivity, or asthma 
triad) 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
 
 
Fluid retention (L), edema, 
acute renal failure (L), liver 
dysfunction 
Delayed: 
Any time later 
during therapy, 
excluding the 
above 
conditions 
 
 
GI bleeds, peptic ulcer 
disease 
Cardiovascular disease, 
known or risk factors for; 
increased risk of serious 
cardiovascular thrombotic 
events, myocardial 
infarction, and stroke 
 
Late: 
Any time after 
completion of 
treatment 
 
 
 
(L) Toxicity may also occur later. 
Supplier: Commercially available.  See package insert for more detailed information. 
 
9.2 Peg-Interferon alpha-2b (PEG-Intron™)  Revised May 2007  
 
 
 
 
 
  
Source and Pharmacology:  Interferon alpha is a protein produced by recombinant DNA 
techniques. Intron A and Roferon A are obtained from strains of E. Coli bearing a genetically-
engineered plasmid containing either interferon alpha 2b or interferon alpha 2a gene, respectively, 
from human leukocytes. Their structures differ by one amino acid at the 26 position.  Alpha-IFN 

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obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
has been shown to have antiviral, immunomodulatory, and antiproliferative effects both in vitro 
and in vivo.  Interferons bind to specific membrane receptors on the cell surface and induce several 
enzymes which result in decreased protein synthesis and DNA synthesis by acting on 
transcriptional and translational processes.  Other enzymes are induced by IFN and contribute to a) 
the inhibition of virus replication in virus-infected cells, b) suppression of cell proliferation, and c) 
such immunomodulation activities as enhancement of phagocytic activity of macrophages and 
augmentation of the specific cytotoxicity of lymphocytes for target cells. 
Following a single subcutaneous (SC) dose of PEG-Intron, the mean absorption half-life (t ½ ka) 
was 4.6 hours. Maximal serum concentrations (Cmax) occur between 15-44 hours post-dose, and 
are sustained for up to 48-72 hours. The Cmax and AUC measurements of PEG-Intron increase in 
a dose-related manner. After multiple dosing, there is an increase in bioavailability of PEG-
Intron. Week 48 mean trough concentrations (320 pg/mL; range 0, 2960) are approximately 3-
fold higher than Week 4 mean trough concentrations (94 pg/mL; range 0, 416). The mean PEG-
Intron elimination half-life is approximately 40 hours (range 22 to 60 hours) in patients with 
HCV infection. The apparent clearance of PEG-Intron is estimated to be approximately 22.0 
mL/hr·kg. Renal elimination accounts for 30% of the clearance. Single dose peginterferon alfa-
2b pharmacokinetics following a subcutaneous 1.0 µg/kg dose suggest the clearance of 
peginterferon alfa-2b is reduced by approximately half in patients with impaired renal function 
(creatinine clearance <50 mL/minute). Pegylation of interferon alfa-2b produces a product (PEG-
Intron) whose clearance is lower than that of non-pegylated interferon alfa-2b. When compared 
to INTRON A, PEG-Intron (1.0 µg/kg) has approximately a seven-fold lower mean apparent 
clearance and a five-fold greater mean half-life permitting a reduced dosing frequency. At 
effective therapeutic doses, PEG-Intron has approximately ten-fold greater Cmax and 50-fold 
greater AUC than interferon alfa-2b.  
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Fever, fatigue, 
headache, site reaction, 
rigors, myalgia, 
myelosuppression 
 anorexia, nausea,  
arthralgia, diarrhea 
(L) 
Vomiting, chills, stomatitis, somnolence (L), 
psychosis (L), elevated transaminases,  peripheral 
neuropathy (L), sinus tachyrhythmias, 
hypocalcemia, pancreatitis, hyperkalemia, 
anaphylaxis, dyspnea, hypotension 
Prompt: 
Within 2-3 weeks, prior 
to the next course 
 
 depression 
Rash, dizziness, impotence, thyroid function 
changes, cardiovascular events 
Delayed: 
Any time later during 
therapy, excluding the 
above conditions 
 
 
Alopecia, menstrual disorder, colitis, 
ophthalmologic disorders 
Late: 
Any time after 
completion of 
treatment 
 
 
 
 (L) Toxicity may also occur later. 
 
Supplier:  Commercially available.  See package insert for more detailed information. 
Warning: Interferons, including interferon alfa-2b, can cause or aggravate fatal or life-
threatening neuropsychiatric (including suicidal ideation and attempts), autoimmune, ischemic, 

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others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this 
obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
and infectious disorders. Patients will be monitored closely with monthly clinical and laboratory 
evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions 
will be withdrawn from therapy. In many but not all cases these disorders resolve after stopping 
interferon alfa-2b therapy. 
9.3 
Temozolomide (Temodar) NSC # 362856 Revised: Aug 2001 
 
Source and Pharmacology:  An orally administered alkylating agent, a second generation 
imadazotetrazine.  A prodrug of MTIC, temozolamide spontaneously decomposes to MTIC at 
physiologic pH. Exerts its effect by cross-linking DNA. This is likely a site specific alkylation at 
the O6-position of guanine with some effect at the N7 position. Temozolamide reaches its peak 
concentration in 1 hour.  Food reduces the rate and extent of absorption.  It has an elimination half-
life of 1.13hr (intraperitoneally) and 1.29hxr (orally) with an oral bioavailability of 0.98. Total 
apparent body clearance is 100ml/min/m2 and plasma elimination half-life is ~100 minutes.  
 
 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to <5 children out 
of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Anorexia, nausea, vomiting, 
abdominal pain, diarrhea, 
constipation, headache, rash, 
itching, urinary frequency 
and/or infection 
Convulsions, hemiparesis, 
dizziness, ataxia, 
confusion, dysphagia, 
anxiety, thrombo-
embolism (L) 
Prompt: 
Within 2-3 weeks, 
prior to next course 
Myelosuppression 
Mucositis, lethargy, 
peripheral edema 
Amnesia, insomnia, 
depression, myalgia, 
diplopia, visual changes 
Delayed: 
Anytime later 
during therapy, 
excluding the 
above conditions 
 
Alopecia, hepatotoxicity 
 
Late: 
Anytime after 
completion of 
therapy 
 
 
Secondary tumors or 
cancer 
 (L) Toxicity may also occur later. 
 
Supplier:  Commercially available.  See package insert for more detailed information.  
 
 

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others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this 
obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
9.4 Vincristine Sulfate (VCR, Oncovin ) NSC #067574 
Revised: Nov. 2003 
 
Approved roadmap abbreviation: VCR 
 
Source and Pharmacology:  Vincristine is an alkaloid isolated from Vinca rosea (periwinkle). It 
binds to tubulin, disrupting mircotubules and inducing metaphase arrest. Its serum decay pattern is 
triphasic, with initial, middle and terminal half-lives of 5 minutes, 1.3 hours, and greater than 24 
hours , respectively.  It is excreted in the bile and feces. There is poor CSF penetration. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children out 
of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Local ulceration if 
extravasated 
Jaw pain 
 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Alopecia 
Weakness, constipation, 
abdominal pain 
Paralytic ileus, ptosis, 
diplopia, night blindness, 
vocal cord paralysis, 
myelosuppression, SIADH, 
seizure 
Delayed: 
Any time later 
during therapy, 
excluding the 
above conditions 
Loss of deep tendon 
reflexes 
Numbness, tingling and 
clumsiness 
Veno-occlusive disease, 
blindness, optic atrophy 
Late: 
Any time after the 
completion of 
treatment 
 
 
 
Unknown Frequency and Timing:  **Fetal and teratogenic toxicities 
 
**Fetal toxicities and teratogenic effects of vincristine (either alone or in combination with other antineoplastic 
agents) have been noted in humans.  The toxicities include:  chromosome abnormalities, malformation, 
pancytopenia, and low birth weight. It is unknown whether the drug is excreted in breast milk. 
 
Formulation and Stability:  Available in solutions of 1mg/1ml in 1, 2, or 5ml vials.  Refrigerate 
and protect from light.  Once opened, it should be refrigerated and used within 10 days.  Note:  The 
drug is light-sensitive. 
 
Guidelines for Administration: IV push over <1 minute.  Special Precautions:  Avoid 
extravasation.  Decrease dose for infants (e.g., less than 10 kg, divide m2 dose by 30, multiply by 
weight in kg.  Alternatively, give 50% of calculated dose).  Precaution:  Concomitant radiation 
therapy to the liver may enhance toxicity.  Precaution: When dispensing vincristine in other than 
the original container, it is imperative that it be packaged in the provided overwrap which bears the 
following statement: “Do not remove covering until moment of injection.  Fatal if given 
intrathecally.  For intravenous use only.” 
 

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Supplier:  Commercially available.  See package insert for further information. 
 
9.4.1 Dose Modification Guidelines for Vincristine: 
 
 
Definition of Neuropathy 
A. Severe neuropathic pain (grade 3 or greater):  Hold dose(s). When symptoms subside, 
resume at 50% previous dose, then escalate to full dose as tolerated. 
NOTE: neuropathic pain can be not only severe but difficult to treat. However, because 
vincristine is an important component of curative therapy and the majority of neuropathies 
are ultimately reversible, vincristinetherapy may be given at full dose at investigator 
discretion. Severe peripheral neuropathies, with or without a positive family history might 
suggest the need for a molecular diagnostic evaluation to rule out Charcot Marie Tooth 
Disease (CMT), Type 1A or Hereditary neuropathy with liability to pressure palsies. Drugs 
such as gabapentin may be of value. 
B. Vocal Cord paralysis:  Hold dose(s). When symptoms subside, resume at 50% previous 
dose, then escalate to full dose as tolerated. 
C. Foot Drop, paresis:  Should be grade 3 to consider holding or decreasing dose. These 
toxicities are largely reversible but over months to years. Accordingly, holding doses of 
vincristine and/or lowering the dose may not result in rapid resolution of symptoms and 
may compromise cure. See above for comment on CMT. Physical therapy may be 
beneficial to maintain range of motion and provide AFO’s and other forms of support. 
Drugs such as gabapentin may be of value. 
D. Jaw pain: Treat with analgesics; do not modify vincristine dose. 
E. Constipation or ileus (> Grade 3) or typhlitis:  Hold dose(s); institute aggressive 
regimen to treat constipation if present. When symptoms abate resume at 50% dose and 
escalate to full dose as tolerated. 
9.4.2 Grading of Sensory Neuropathy (from Balis): 
Grade 1:  Paresthesias, pain, or numbness that do not require treatment or interfere with 
extremity function. 
Grade 2:  Paresthesias, pain, or numbness that are controlled by non-narcotic medications 
(without causing loss of function), or alteration of fine motor skills (buttoning 
shirt, writing or drawing, using eating utensils) or gait, without abrogating ability 
to perform these tasks. 
Grade 3:  Paresthesias or pain that are controlled by narcotics, or interfere with extremity 
function (gait, fine motor skills as outlined above), or quality of life (loss of sleep, 
ability to perform normal activities severely impaired). 
Grade 4:  Complete loss of sensation, or pain that is not controlled by narcotics. 
 
 
 
 
 

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others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this 
obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
9.4.3 Grading of Motor Neuropathy (from Balis): 
Grade 1:  Subjective weakness, but no deficits detected on neurological exam, other than 
abnormal deep- tendon reflexes. 
Grade 2:  Weakness that alters fine motor skills (buttoning shirt, coloring, writing or 
drawing, using eating utensils) or gait without abrogating ability to perform these 
tasks. 
Grade 3:  Unable to perform fine motor tasks (buttoning shirt, coloring, writing or drawing, 
using eating utensils) or unable to ambulate without assistance. 
Grade 4:  Paralysis. 
 
9.4.4 Hyperbilirubinemia 
Direct Bili Dose reduction 
< 3.1 mg/dl  Full dose 
3.1- 5.0 mg/dl  50% 
5.1-6.0 mg/dl  75% 
6.0 mg/dl   Withhold dose and administer next scheduled dose if toxicity has 
resolved. Do not make up missed doses. 
 
9.4.5 Extravasations: 
In the event of an extravasation, discontinue the IV administration of the drug and institute 
appropriate measures to prevent further extravasation and damage according to institutional 
guidelines. Suggestions below may be helpful but none are considered definitive: 
A. Stop infusion, aspirate drug and blood if possible, remove needle 
B. Apply warm compress immediately for 1 hour then rotate on/off every 15 minutes for 
24 hours. 
C. Hyaluronidase 150 units/ml reconstituted with NS-inject 1ml for each 1 ml of drug 
extravagated or 
D. Treat with cold compresses, dilute thru infiltration of 5 mL of an 8.4% solution of 
sodium bicarbonate and/or local injection of hydrocortisone. 
 
 
10 
SUBJECT STIPENDS OR PAYMENTS 
 
Study subjects will receive a gift card following the completion of study visits to reimburse for  
expenses that are a result of study participation.  Subjects will be compensated as follows: 
 
Subject lives less than 75 miles from the hospital:  $25 gift card 
Subject lives more than 75 miles from the hospital:  $50 gift card 
Subject lives more than 300 miles from the hospital:  $100 gift card 
 
As multiple tests or evaluations may be required for a particular study visit, subjects will receive 
a maximum of one gift card per month.
 

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agreed to in writing, by accepting or reviewing this document, you agree to hold this information in confidence and not copy or disclose it to 
others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this 
obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
11 
DATA HANDLING AND RECORD KEEPING 
 
11.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Signed informed consent for study participation will include a HIPAA authorization.   
 
In the event that a subject revokes authorization to collect or use protected health 
information (PHI), the investigator will retain the ability to use all information collected 
prior to the revocation of subject authorization. For subjects that have revoked 
authorization to collect or use PHI, attempts will be made to obtain permission to collect 
vital status at the end of their scheduled study period. Any study information sent out of 
Spectrum Health will be de-identified.  
 
11.2 Source Documentation and Case Report Forms 
Source data is all information, original records of clinical finding, observations, or other 
activities in a clinical trial, necessary for the reconstruction and evaluation of the trial.  
Source data are contained in the source documents, and will be recorded within 24 hours of 
patient encounter. 
 
A study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded. All missing data must be explained. If a space 
on the CRF is left blank because the procedure was not done or the question was not asked, 
write “N/D”. If the item is not applicable to the individual case, write “N/A”.  If any entry 
error has been made, to correct such an error, draw a single straight line through the 
incorrect entry and enter the correct data above it. All such changes must be initialed and 
dated. Do not erase or ‘white-out’ errors. For clarification of illegible or uncertain entries, 
print the clarification above the item, then initial and date the entry.  
 
11.3 Data Storage 
All study records will be kept in a restricted access facility.  Hard copy records will be 
stored in a locked room or filing cabinet. Data will be retained within a Spectrum Health 
facility for a duration according to Spectrum Health policy requirements and applicable 
regulations.  
 
11.4 Data Monitoring 
The investigators will permit study-related monitoring, audits, and inspections by the 
Spectrum Health IRB, appropriate government regulatory bodies, and Spectrum Health 
research compliance and quality assurance groups of all study related documents. 

Medical Treatment of “high-risk” Plexiform Neurofibromas version 2010-Jun.-08 
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agreed to in writing, by accepting or reviewing this document, you agree to hold this information in confidence and not copy or disclose it to 
others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this 
obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
12 
REFERENCES CITED: 
 
1. 
Eichenfield, L.F., et al., Guidelines of care for neurofibromatosis type 1. American 
Academy of Dermatology Guidelines/Outcomes Committee. J Am Acad Dermatol., 1997. 
37(4): p. 625-30. 
2. 
Roos, K.L. and D.W. Dunn, Neurofibromatoses. CA Cancer J Clin., 1992. 42(4): p. 241-
54. 
3. 
Gupta, A., et al., Phase I study of thalidomide for the treatment of plexiform 
neurofibroma in neurofibromatosis 1. Neurology., 2003. 60(1): p. 130-2. 
4. 
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., 
1997. 131(5): p. 678-82. 
5. 
Packer, R.J., et al., Plexiform neurofibromas in NF1: toward biologic-based therapy. 
Neurology., 2002. 58(10): p. 1461-70. 
6. 
Le, L.Q. and L.F. Parada, Tumor microenvironment and neurofibromatosis type I: 
connecting the GAPs. Oncogene, 2007. 12: p. 12. 
7. 
Yang, F.C., et al., Nf1+/- mast cells induce neurofibroma like phenotypes through 
secreted TGF-beta signaling. Hum Mol Genet., 2006. 15(16): p. 2421-37. Epub 2006 Jul 
11. 
8. 
Levy, P., et al., Molecular profiles of neurofibromatosis type 1-associated plexiform 
neurofibromas: identification of a gene expression signature of poor prognosis. Clin 
Cancer Res., 2004. 10(11): p. 3763-71. 
9. 
Kawachi, Y., et al., Expression of angiogenic factors in neurofibromas. Exp Dermatol., 
2003. 12(4): p. 412-7. 
10. 
Tredget, E.E., et al., Transforming growth factor-beta mRNA and protein in hypertrophic 
scar tissues and fibroblasts: antagonism by IFN-alpha and IFN-gamma in vitro and in 
vivo. J Interferon Cytokine Res., 2000. 20(2): p. 143-51. 
11. 
Rosewicz, S., et al., Interferon-alpha: regulatory effects on cell cycle and angiogenesis. 
Neuroendocrinology., 2004. 80(Suppl 1): p. 85-93. 
12. 
Yoshida, S., et al., COX-2/VEGF-dependent facilitation of tumor-associated 
angiogenesis and tumor growth in vivo. Lab Invest., 2003. 83(10): p. 1385-94. 
13. 
Larkins, T.L., et al., Inhibition of cyclooxygenase-2 decreases breast cancer cell motility, 
invasion and matrix metalloproteinase expression. BMC Cancer., 2006. 6: p. 181. 
14. 
Yao, M., et al., Cyclooxygenase-2 selective inhibition with NS-398 suppresses 
proliferation and invasiveness and delays liver metastasis in colorectal cancer. Br J 
Cancer., 2004. 90(3): p. 712-9. 
15. 
Attiga, F.A., et al., Inhibitors of prostaglandin synthesis inhibit human prostate tumor 
cell invasiveness and reduce the release of matrix metalloproteinases. Cancer Res., 2000. 
60(16): p. 4629-37. 
16. 
Thyrell, L., et al., Interferon alpha-induced apoptosis in tumor cells is mediated through 
the phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway. J Biol 
Chem., 2004. 279(23): p. 24152-62. Epub 2004 Mar 31. 
17. 
Hoang, B., et al., Oncogenic RAS mutations in myeloma cells selectively induce cox-2 
expression, which participates in enhanced adhesion to fibronectin and chemoresistance. 
Blood., 2006. 107(11): p. 4484-90. Epub 2006 Feb 23. 

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25 
This document contains confidential information belonging to Albert S. Cornelius, David Dickens and Spectrum Health. Except as otherwise 
agreed to in writing, by accepting or reviewing this document, you agree to hold this information in confidence and not copy or disclose it to 
others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this 
obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
18. 
Sheng, H., J. Shao, and R.N. Dubois, K-Ras-mediated increase in cyclooxygenase 2 
mRNA stability involves activation of the protein kinase B1. Cancer Res., 2001. 61(6): p. 
2670-5. 
19. 
Lee, J., et al., Interferon-alpha resistance can be reversed by inhibition of IFN-alpha-
induced COX-2 expression potentially via STAT1 activation in A549 cells. Oncol Rep., 
2006. 15(6): p. 1541-9. 
20. 
Bostrom, P.J., et al., Interferon-alpha inhibits cyclooxygenase-1 and stimulates 
cyclooxygenase-2 expression in bladder cancer cells in vitro. Urol Res., 2001. 29(1): p. 
20-4. 
21. 
Rini, B.I., et al., Maximal COX-2 immunostaining and clinical response to celecoxib and 
interferon alpha therapy in metastatic renal cell carcinoma. Cancer., 2006. 106(3): p. 
566-75. 
22. 
Korf, B.R., Malignancy in neurofibromatosis type 1. Oncologist., 2000. 5(6): p. 477-85. 
23. 
Listernick, R., et al., Carboplatin therapy for optic pathway tumors in children with 
neurofibromatosis type-1. J Neurooncol., 1999. 45(2): p. 185-90. 
24. 
Gururangan, S., et al., Temozolomide in children with progressive low-grade glioma. 
Neuro-oncol., 2007. 9(2): p. 161-8. Epub 2007 Mar 8. 
25. 
Garcia, M., et al., Phase II multicentre study of temozolomide in combination with 
interferon alpha-2b in metastatic malignant melanoma. Melanoma Res., 2006. 16(4): p. 
365-70. 
26. 
Gogas, H., et al., Temozolomide in combination with celecoxib in patients with advanced 
melanoma. A phase II study of the Hellenic Cooperative Oncology Group. Ann Oncol., 
2006. 17(12): p. 1835-41. Epub 2006 Sep 15. 
27. 
Hyman, S.L., E. Arthur Shores, and K.N. North, Learning disabilities in children with 
neurofibromatosis type 1: subtypes, cognitive profile, and attention-deficit-hyperactivity 
disorder. Dev Med Child Neurol., 2006. 48(12): p. 973-7. 
28. 
Coude, F.X., et al., Academic impairment is the most frequent complication of 
neurofibromatosis type-1 (NF1) in children. Behav Genet., 2006. 36(5): p. 660-4. 
29. 
Hyman, S.L., A. Shores, and K.N. North, The nature and frequency of cognitive deficits 
in children with neurofibromatosis type 1. Neurology., 2005. 65(7): p. 1037-44. 
30. 
Sood, A., et al., Pegylated interferon alfa 2b and oral ribavirin in patients with HCV-
related cirrhosis. Indian J Gastroenterol., 2006. 25(6): p. 283-5. 
 

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others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this 
obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
13 
APPENDICES 
 
13.1 Appendix 1: Performance Status Scales 
 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
 
Karnofsky 
Score 
Lansky 
Normal, no complaints, no 
evidence of disease 
100 
Fully active, normal 
Able to carry on normal 
activity, minor signs or 
symptoms of disease 
90 
Minor restrictions in physically 
strenuous activity 
Normal activity with effort; 
some signs or symptoms of 
disease 
80 
Active, but tires more quickly 
Cares for self, unable to carry 
on normal activity or do active 
work 
70 
Both greater restriction of and les 
time spent in play activity 
Required occasional assistance 
but is able to care for most of 
his/her needs 
60 
Up and around, but minimal active 
play; keeps busy with quieter 
activities 
Requires considerable 
assistance and frequent 
medical care 
50 
Gets dressed, but lies around much 
of the day; no active play, able to 
participate in all quiet play and 
activities 
Disabled, requires special care 
and assistance. 
40 
Mostly in bed’ participates in quiet 
activities 
Severely disabled, 
hospitalization indicated. 
Death not imminent 
30 
In bed; needs assistance even for 
quiet play 
Very sick, hospitalization 
indicated. Death not imminent 
20 
Often sleeping; play entirely 
limited to very passive activities 
Moribund, fatal processes 
progressing rapidly 
10 
No play; does not get out of bed 
 

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others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this 
obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
13.2 
Appendix 2:  Dosage chart for celecoxib by weight.  
Target dose = 10mg/kg/day 
 
Weight 
AM dose 
 
PM dose 
 
10-15kg 
100mg 
 
-0- 
 
15-20kg 
100mg 
 
50mg 
100mg on odd numbered 
calendar days only 
20-25kg 
100mg 
 
100mg 
 
25-30kg 
150mg  
100mg on even # days and 
200mg on odd # days 
100mg 
 
30-35kg 
200mg 
 
100mg 
 
35-40kg 
200mg 
 
150mg 
100mg on even # days and 
200mg on odd # days 
40-45kg 
200mg 
 
200mg 
 
45-55kg 
300mg 
 
200mg 
 
55-65kg 
300mg 
 
300mg 
 
65-75kg 
400mg 
 
300mg 
 
>75kg 
400mg 
 
400mg 
 
 
 

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others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this 
obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
13.3 Appendix 3 
The National Institute of Health (NIH) has created specific criteria for the diagnosis of NF-1. 
Two of these seven "Cardinal Clinical Features" are required for positive diagnosis (Huson, 
1994). 
• 
6 or more café-au-lait macules over 5 mm in greatest diameter in pre-pubertal individuals 
and over 15 mm in greatest diameter in post-pubertal individuals  
• 
2 or more neurofibromas of any type or 1 plexiform neurofibroma  
• 
Freckling in the axillary or inguinal regions  
• 
Optic glioma  
• 
2 or more Lisch nodules (iris harmartomas)  
• 
A distinctive osseous lesion such as sphenoid dysplasia or thinning of the long bone 
cortex with or without pseudarthrosis  
• 
A first degree relative (parent, sibling, or offspring) with NF1 by the above criteria 
 

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others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this 
obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
13.4  Appendix 4:  Psychological Evaluations 
Evaluation will include a measure of cognitive abilities (WPPSI-III, WISC-IV or WAIS-IV), 
visual-spatial abilities (Beery VMI or D-KEFS Tower Test), attention and impulsivity (Conner’s 
CPT), academic achievement (WJ-III), depression (Children’s Depression Inventory or Beck 
Depression Inventory), executive function (BRIEF) and behavior (CBCL).  Test selection is 
dependent upon age (see chart below). 
 
      * Completed annually 
Description of Psychological Testing Battery 
 
Wechsler Intelligence Scale for Children- Fourth Edition (WISC-IV) 
The WISC-IV consists of nine subtests used to measure verbal intelligence, perceptual 
intelligence, full scale intelligence, working memory and processing speed. 
 
Wechsler Preschool and Primary Scale of Intelligence- Third Edition (WPPSI-III) 
The WPPSI-III consists of ten subtests used to measure verbal intelligence, perceptual 
intelligence, processing speed and general language. 
 
Beery Test of Visual Motor Integration (Beery VMI) 
The Beery VMI is a developmental sequence of geometric forms to be copied with paper and 
pencil. It is designed to assess the extent to which individuals can integrate their visual and 
motor abilities. 
 
2 years to 5 years 
6 years to 16 years 
17 years and older 
WPPSI-III* 
WISC-IV* 
WAIS-IV* 
Beery VMI 
Beery VMI (up to 8 years, then D-
KEFS Tower Test) 
D-KEFS Tower Test 
 
Conner’s CPT 
Conner’s CPT 
BRIEF (age 5 and up) BRIEF 
 
CBCL 
CBCL 
 
 
Children’s Depression Inventory 
Beck Depression Inventory 
 
WJ-III 
Letter-Word Identification, 
Calculation, Passage Comprehension 
& Applied Problems 
WJ-III 
Letter-Word Identification, 
Calculation, Passage Comprehension 
& Applied Problems 

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obligation, Albert S. Cornelius, David Dickens and Spectrum Health must be promptly notified. 
Delis-Kaplan Executive Function System (D-KEFS) Tower Test 
A means of assessing several key executive functions, including spatial planning, rule learning, 
inhibition of impulsive and preservative responding and the ability to establish and maintain the 
instructional set, by constructing target towers. 
 
Conner’s Continuous Performance Test (Conner’s CPT) 
The Conner’s CPT is a vigilance or attention test that requires respondents to press a button 
when a specified letter is presented, or not press a button when a specified letter is presented. 
The CPT measures attentiveness and impulsivity. 
 
Woodcock-Johnson Tests of Achievement- Third Edition (WJ-III) 
The WJ-III standard achievement measures take an inventory of academic skills including 
reading and math. 
 
Children’s Depression Inventory (CDI) 
The Children’s depression inventory is a self-report measure that measures the extent and 
severity of depressive symptoms in children aged 7 to 17 years of age. 
 
Beck Depression Inventory 
The BDI is a 21-item self-report instrument measuring the severity of depression in adults and 
adolescents aged 13 years and older.