Clinical trial NCT02343224
Conditions: Juvenile Pilocytic Astrocytomas Optic Pathway Gliomas
Sponsor: Emory University
Start date: 2014-11-01; Completion date: 2020-11-11
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase II study of the drug, pegylated interferon alfa-2b (PEG-Intron), used to treat brain tumors in a pediatric population. Researchers want to see if treatment with PEG-Intron will stop tumor growth for patients with juvenile pilocytic astrocytomas or optic pathway gliomas.

The purposes of this study are:

* To learn more about the response to pegylated interferon
* To learn more about the side effects of pegylated interferon
* To learn more about MRI images in patients with Juvenile Pilocytic Astrocytomas or Optic Pathway Gliomas.
* To learn more about quality of life in patients treated with pegylated interferon

Detailed description:
Low grade gliomas are the most common pediatric central nervous system malignancies and can occur in different parts of the brain. Patients who undergo gross total resection, usually those with hemispheric tumors, have an excellent prognosis with surgical resection alone. Patients for whom gross total resection is not achievable have a significant risk of disease progression. Therefore, these patients benefit from adjuvant therapy. Multiple chemotherapy regimens have shown some efficacy in residual tumor, but more than 50% of patients experience recurrences. Radiation has been shown to be an effective therapy in the treatment of these tumors. Because of concerns regarding radiation toxicity especially in young children, and progression despite chemotherapy, novel approaches are needed. This protocol represents an attempt to measure the efficacy and safety of use of pegylated interferon for patients with recurrent, refractory Juvenile Pilocytic Astrocytomas (JPA) or optic pathway gliomas. It provides a different approach to the commonly used treatment modalities. The objectives of this study are to determine the response of children with chemotherapy-refractory progressive JPA or optic pathway gliomas (OPG) to weekly pegylated interferon alpha-2b. The secondary objectives include to better identify the toxicities of weekly pegylated interferon alpha-2b (PEG-Intron™) in pediatric patients with unresectable, refractory, recurrent JPAs or optic pathway gliomas, to evaluate various magnetic resonance imaging techniques for noninvasive monitoring of metabolic and biologic changes in the tumors and to evaluate the quality of life for patients with recurrent, refractory JPAs who receive therapy with pegylated interferon alpha-2b (PEG-Intron™).

The primary end point is to determine the response rate. A two-stage design has been selected to evaluate the response rate. If the treatment demonstrates at least a 25% response rate, the researchers would consider it a promising regimen for further study. A response rate less than 5% is considered evidence of unpromising regimen. Seventeen evaluable pediatric patients with JPA or OPG will be accrued. If at least 3 responders are seen among the 17 patients, this will be considered evidence of a promising response rate for further evaluation.

Arms: arm 1: Subjects will receive PEG-Intron based on their weight (1 mcg/kg/dose) once a week
Interventions: intervention 1: Pegylated interferon alpha-2b
Intervention descriptions: intervention 1: PEG-Intron 1mcg/kg/dose weekly through an injection under the skin on the same day each week

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Vers   12-14-2018                           1 
 
 
Aflac Cancer and Blood Disorders Center 
Children's Health Care of Atlanta 
Emory University 
 
A Phase II Study Of Pegylated Interferon ALFA-2b  in 
Children with 
Recurrent  or Refractory and Radiographically  or 
Clinically Progressive  Juvenile Pilocytic  
Astrocytomas and Optic Pathway Gliomas 
 
 
NCT Number: NCT02343224 
 
 
Protocol Version Date: December 14, 2018 
 
 
 


Protocol Vers   12-14-2018                           2 
 
Principal Investigator: 
Dolly Aguilera MD 
 
 
Co-Principal Investigator: 
Tobey MacDonald MD. 
 
 
 
 


Protocol Vers   12-14-2018                           3 
 
Study Committee 
Claire Mazewski MD  
Anna Janss MD, PhD.  
Robert Craig Castellino MD.  
Radiology: Judith Gadde MD.  
Pathology: Matthew Schniederjan MD 
Neuro-Opthalmology: Jason Peragallo MD 
Neurology: David Wolf MD 
Statistics:  Zhengjia Chen PhD. 
Research Pharmacist: Jane Chen, Pharm D 
Coordinator Research Coordinator:   Karen Jacobs 
Clinical Trials Coordinator- Shelley Mays 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Vers   12-14-2018                           4 
 
Table of Contents 
Abstract ........................................................................................................................................................7 
Experimental Design Schema.......................................................................................................................8 
1.Objectives .................................................................................................................................................. 9 
1.1 Primary Objectives................................................................................................................................9 
1.2 Secondary Objectives............................................................................................................................9 
2. Background…………………….......................................................................................................................9 
2.1 Introduction and Rationale for development.......................................................................................9 
2.2 Chemotherapy for pediatric low grade gliomas...................................................................................10 
2.3 Interferon Alpha...................................................................................................................................12 
2.4 Pegylated interferon alfa-2b ........................................................................................................12 
2.5 Clinical Data of Pegylated interferon in Cancer.........................................................13 
2.6 Pegylated interferon and Clinical Studies and case series..............................................................14 
2.7 Dose and Schedule................................................................................................................................15 
2.8 Imaging.................................................................................................................................................16 
3.0 Study Enrollment Procedures and patient Eligibility…………................................................................. 17 
3.1 Study Enrollment ………………………………………………………………………………………………………………………..….17 
3.1.1 Patient Registration...........................................................................................................................17 
3.1.2 IRB approval.......................................................................................................................................17 
3.1.3 Reservations and Contact Requirements...........................................................................................17 
3.1.4 Timeline Summary............................................................................................................................17 
3.1.5 Informed Consent/Assent..................................................................................................................17 
3.1.6 Screening procedures........................................................................................................................18 
3.1.7 Eligibility Checklist.............................................................................................................................18 
3.2 Eligibility Criteria ................................................................................................................................. 18 
3.2. Inclusion Criteria................................................................................................................................. 18 
3.3 Exclusion Criteria .................................................................................................................................21 
4.0 Treatment Program   ............................................................................................................................22 


Protocol Vers   12-14-2018                           5 
 
4.1 Overview of treatment plan.................................................................................................................22 
4.2 Concomitant Therapy Restrictions........................................................................................................23 
4.3 Pegylated interferon Administration.......................................................................................24 
4.4 Criteria for starting subsequent course of treatment .........................................................................29 
5.0 Dose Modifications for Toxicity ...........................................................................................................29 
5.1 Non-hematologic Toxicity...................................................................................................................29 
5.2 Hematological Toxicity........................................................................................................................30 
6.0 Drug Information..................................................................................................................................30 
7.0 EVALUATION MATERIAL AND DATA TO BE ACCESIONED.....................................................................33 
7.1   Required Clinical, Laboratory and Disease Evaluations ………………………………………………………………....34 
7.2 Follow- Up............................................................................................................................................36 
8.0 Criteria for Removal from Protocol Therapy and OFF Study Criteria ...................................................37 
8.1 Criteria for Removal off Protocol.........................................................................................................37 
8.2 Off Study Criteria..................................................................................................................................37 
9.0 Statistical Considerations...................................................................................................................  37 
9.1 Sample Size and Study Duration ..........................................................................................................37 
9.2 Study Design ........................................................................................................................................37 
9.3 Methods of Analysis........................................................................................................................... 38 
9.3.1 End Points.........................................................................................................................................38 
9.4 Analysis of Efficacy  .............................................................................................................................38 
9.5 Monitoring of Efficacy......................................................................................................................... 38 
9.6 Monitoring for Toxicity....................................................................................................................... 39 
9.7 Interim Monitoring for Toxic Deaths....................................................................................................39 
9.8 Analysis of Toxicity...............................................................................................................................39 
9.9 Subject Accrual ....................................................................................................................................39 
9.10 Radiology Evaluation..........................................................................................................................40 
10.0 Evaluation Criteria............................................................................................................................. 41 
10.1Common terminology Criteria Adverse Events..................................................................................41 


Protocol Vers   12-14-2018                           6 
 
10.2 Methodology for Tumor Measurements...........................................................................................41 
10.3 Tumor Measurements.......................................................................................................................41 
10.4 Determination of Progression or Response........................................................................................42 
10.5 Overall Response Assesment.............................................................................................................43 
11.0 Adverse reporting Requirements.......................................................................................................46 
12.0 Study Reporting and Monitoring........................................................................................................47 
Appendix 1 Performance Score..................................................................................................................48 
Appendix 2 Quality of Life Questionnaires.................................................................................................49 
Appendix 3 Eligibility Checklist..................................................................................................................65 
Appendix 4 Patient Diary ...........................................................................................................................67 
13. References............................................................................................................................................69 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Vers   12-14-2018                           7 
 
ABSTRACT 
Low grade gliomas are the most common pediatric central nervous system malignancies and can occur 
in different parts of the brain. Patients who undergo gross total resection, usually those with 
hemispheric tumors, have an excellent prognosis with surgical resection alone. Patients for whom gross 
total resection is not achievable have a significant risk of disease progression. Therefore, these patients 
benefit from adjuvant therapy.  Multiple chemotherapy regimens have shown some efficacy in residual 
tumor, but more than 50% of patients experience recurrences. Radiation has been shown to be an 
effective therapy in the treatment of these tumors. Because of concerns regarding radiation toxicity 
especially in young children, and progression despite chemotherapy, novel approaches are needed. This 
protocol represents an attempt to measure the efficacy and safety of use of pegylated interferon for 
patients with recurrent, refractory Juvenile Pilocytic Astrocytomas (JPA) or optic pathway gliomas. It 
provides a different approach to the commonly used treatment modalities. Patients with progressive, 
refractory or symptomatic JPA who have received radiation and who have received at least one prior 
course of chemotherapy will be eligible for this study. All patients on the study will receive a course of 
pegylated interferon 1 mcg/kg/dose weekly lasting for up to 2 years.  Response will be evaluated with 
MRI every 12 weeks. The objectives of this study are to determine the response of children with 
chemotherapy-refractory progressive JPA or optic pathway gliomas (OPG) to weekly pegylated 
interferon alpha-2b.  The secondary objectives include to better identify the toxicities of weekly 
pegylated interferon alpha-2b in pediatric patients with unresectable, refractory, recurrent JPAs or optic 
pathway gliomas, to evaluate various magnetic resonance imaging techniques for noninvasive 
monitoring of metabolic and biologic changes in the tumors and to evaluate the quality of life for 
patients with recurrent, refractory JPAs who receive therapy with pegylated interferon alpha-2b The 
primary end point is to determine the response rate.  The secondary end point is to determine the Event 
Free survival. A two-stage design has been selected to evaluate the response rate. If the treatment 
demonstrates at least a 25% response rate, we would consider it a promising regimen for further study. 
A response rate less than 5% is considered evidence of unpromising regimen. Seventeen evaluable 
pediatric patients with JPA or OPG will be accrued. If at least 3 responders are seen among the 17 
patients, this will be considered evidence of a promising response rate for further evaluation. 
 
EXPERIMENTAL DESIGN SCHEMA:  
 
Cycle# 1  
Day0 
Day7 
Day 14 
Day 21 
Day28 
 
PEG-Interferon  
 (1 mcg/kg/week) 
X 
X 
X 
X 
X 
 
MRI imaging 
 
 
 
 
 
EVERY 12 
WEEKS. 
 
 
 
 
 
 


Protocol Vers   12-14-2018                           8 
 
EXPERIMENTAL DESIGN SCHEMA:  
 
 
 
 
 
 
 
 
Response Evaluation 
prior to 
Cycles 3, 5, 7, 9, 11  
 
 
 
 
 
 
 
 
Note: Each cycle is 28 days 
PD = Progressive Disease 
SD = Stable Disease 
PR = Partial Response 
CR = Complete Response 
 
 
 
 
 
 
Study Entry 
Cycles 1 to 3 Peg-Interferon  
1mcg/kg/dose weekly 
Response evaluation prior 
to cycles 4,7,10 and 13 
OFF THERAPY 
PD 
Response evaluation prior 
to cycles 16,19,22,25  
SD,PR,CR 
PD 
OFF THERAPY 


Protocol Vers   12-14-2018                           9 
 
1.0 OBJECTIVES 
1.1 PRIMARY STUDY OBJECTIVES  
To determine the objective response of children with recurrent or Refractory and radiographically or 
clinically progressive Juvenile Pilocytic Astrocytomas and Optic Pathway Gliomas who are treated with 
pegylated interferon alpha-2b Response will be determined as complete response or partial response.  
 
1.2 SECONDARY STUDY OBJECTIVES  
1.2.1  
To estimate event free survival (EFS) (based on standard two or three-dimensional tumor 
measurements) for children with recurrent, refractory or progressive Juvenile Pilocytic Astrocytomas 
and Optic Pathway Gliomas who are treated with Peginterferon. 
1.2.2  
To define the toxicities of long term weekly pegylated interferon alpha-2b in pediatric patients with 
refractory, recurrent and progressive Juvenile Pilocytic Astrocytomas and Optic Pathway Gliomas. 
1.2.3  
To compare response categories and EFS across the 3 MR sequences (T2-weighted, FLAIR, T1-weighted 
post-contrast). 
1.2.4  
To evaluate the quality of life for patients with recurrent, refractory and progressive Juvenile Pilocytic 
Astrocytomas and Optic Pathway Gliomas who receive therapy with pegylated interferon alpha-2b  
2.0 BACKGROUND 
2.1 Introduction/Rationale for Development 
Low-grade gliomas (LGGs) represent the most common pediatric central nervous system (CNS) 
malignancy, accounting for more than half of all such tumors. The most common locations are the 
cerebellum, followed by the cerebral hemispheres and by the deep midline structures such as the 
hypothalamus, thalamus, lateral and 3rd ventricles, and the corpus callosum. These tumors are also 
found along the visual pathways and in the brainstem and in the spinal cord. 
Pediatric LGGs include pilocytic, fibrillary, protoplasmic, gemistocytic, giant-cell astrocytomas, or 
pleomorphic xanthoastrocytoma, oligodendrogliomas and oligoastrocytomas. They belong to the WHO 
classification as grade I and II.  Juvenile Pilocytic Astrocytomas (JPAs) occur predominantly in young 
children and make up the majority of LGGs found along the optic pathway, as dorsally exophytic brain 
stem tumors, and in the cerebellum. Grossly, they appear well circumscribed, and in the cerebellum are 
often cystic, with a mural nodule. They typically, but not always, enhance on MR imaging. JPAs have 
been particularly associated with neurofibromatosis type 1 (NF-1), in this population lesions are mostly 
incidental findings and some of them can have indolent courses and close monitoring with imaging 
studies is  recommended. 


Protocol Vers   12-14-2018                           10 
 
Patients with JPA patients who have gross total resection, especially those with tumors located in the 
cerebellar and cerebral hemispheres, have excellent survival at 8 years 99% +/- 0.8% as well as excellent   
event free survival (EFS). From CCG9891 and POG9130, the results of 518 pediatric patients with low 
grade gliomas that only underwent surgical resection and no other treatment modality,   which had 
evidence of residual disease, the EFS at 5 years was 56%.  Patients younger than 5 years of age had 
worse EFS than the older counterpart; however this difference does not   translate into worse overall 
survival. [1]  JPAs that cannot be completely resected, mostly due to location in or near important 
structures, are likely to progress and will require additional therapy.  Effective treatment modalities 
include radiation and chemotherapy. 
Radiation therapy, while effective, has long term effects that can be minimized if the modality can be 
delayed or avoided. 
Merchant conducted a phase II study that included 78 pediatric patients with unresectable low grade 
gliomas who received radiation therapy. The 5 year EFS was 87% +/- 4.4 and 10 year EFS was 74.3% +/- 
15.4%.  The mean and standard error cumulative incidence of vasculopathy was 4.79% +/- 2.73 at 6 
years and it was higher for patients younger than 5 years of age at the time of radiation. The main 
reason to the delay in radiation in young patients with LGG is to reduce their risk of vasculopathy [2]. 
Additionally, patients with LGG after radiation treatment experienced some adverse endocrine events 
that were limited.  The 3 more common hormone replacements were:  growth hormone, thyroid and 
glucocorticoid.  The 5- and 10-year confident intervals for growth hormone replacement were 46.0% +/-
7.2% and 48.9% +/- 7.4%. The thyroid hormone replacement, 61.4% +/-7.5% and 64.0% +/-7.5%.  The 
glucocorticoid replacement was 19.2% +/-5.8% and 19.2% +/-5.8%. Additionally, in the CBCL activities 
scores, for patients with neurofibromatosis -1 who underwent treatment with radiation have a decrease 
in the score from 44.2 to 36.8 after 5 years of treatment, while the average score of a patient without 
NF-1 remained unchanged at 44.2806 despite radiation therapy. [2] 
 
 2.2 Chemotherapy for pediatric low grade gliomas:  
COG 9952 was the first randomized upfront clinical trial for low grade gliomas. It investigated two 
chemotherapy regimens for children less than 10 years with unresected LGGs. Regimen A included 
carboplatin and vincristine (CV). Regimen B included thioguanine, procarbazine, lomustine and 
vincristine (TPCV).  Only regimen A included patients with neurofibromatosis-1. Of 274 randomly 
assigned between both regimens, 137 received regimen A and 137 received regimen B. The 5-year EFS 
and overall survival (OS) rates were 45% ± 3.2% and 86% ± 2.2%, respectively. The 5-year EFS rates were 
39% ± 4% for CV and 52% ± 5% for TPCV ( P = 0.10). Independent factors by multivariate analysis that 
were predictive of worse EFS and OS are younger age and tumor size greater than 3 cm. Additionally, 
the location of the tumor  in the thalamic region was also associated with poor survival. [3]  
Boufet et al conducted a phase II trial with vinblastine for recurrent or refractory pediatric low grade 
glioma dose of 6mg/m2/dose. 36% of patients had complete, partial or minor response. 23/51 patients 
have not had progression. 5 year OS was 93.2% +/- 3/8% and 5 year PFS was 42.3% +/- 7.2%. Vinblastine 
as a weekly regimen was comparable to first line COG 9952. [4]   
The experience of bevacizumab for low grade gliomas is limited to case series. Ten children heavily 
treated for multiply recurrent LGG received the combination of bevacizumab and irinotecan for a 
median of 5.2 years of age, range 1.5-11.1 years. 70% patients had an objective radiographic response (1 
CR, 3 PR and 3 minor Responses). Other clinical improvements were: improved visual acuity, improved 


Protocol Vers   12-14-2018                           11 
 
motor function, weight gain in patients with a diencephalic syndrome, and reversal of psychomotor 
retardation.  Dose-limiting toxicities included transient leukoencephalopathy and grade 3 proteinuria. 
The majority of patients had durable responses.  Six patients remained on treatment for almost 2 years. 
Multiply recurrent low-grade gliomas in children demonstrated responses to the combination of 
bevacizumab and irinotecan.[5, 6]   
A second series reported 7 children who received bevacizumab with irinotecan. Tumor reduction could 
be observed in 6/7 (85%) patients with recurrent low-grade gliomas. Bevacizumab-related acute toxicity 
appears to be low in children, even in combination with irinotecan. [7] 
Finally, 14 pediatric patients with multiply recurrent low-grade gliomas were treated with bevacizumab 
and irinotecan for at least twelve months of follow-up after completion of initial therapy. Median 
treatment duration was 12 months (range, 1 - 24 months). 12/14 patients had an objective response; 
two had stable disease, and no progressions. 13/14 patients progressed after stopping bevacizumab at a 
median of four months. Four patients were retreated with bevacizumab alone and all responded or 
stabilized on treatment. Bevacizumab-based therapy is successful at inducing LGG regression and 
stabilization after initial therapy or with repeated treatment, although nearly all patients' tumors will 
progress off-therapy. Toxicities are not insignificant but usually reversible (6). A subsequent report, gave 
additional details of responses after progression of LGG when retreated with bevacizumab in   4/4 
patients, however alternative dose strategies such as bevacizumab as a single agent and interval does 
every 3 weeks were evaluated. [8] 
Therashima et al evaluated pediatric patients with centrally located LGG who received either chemo or 
radiation to better understanding the risk factors along with the effects of interventions on long-term 
outcome through a retrospective chart review. Forty-seven patients with a median follow-up of 79 
months were included in the analysis. The 5-year EFS and OS were 53% and 96%. The 5-year PFS for 
those that received radiation upfront was 76% vs. those who received chemotherapy as a first line 37%.  
p=0.02. The 5-year PFS after salvage RT was 55% for those who progressed after chemotherapy. [9]  
Pilocytic astrocytomas often have a solid and cystic component at presentation or recurrence. The 
management of the cystic component of the tumor can be difficult when gross total resection is not 
possible. Multiple treatment options are available, including additional resection, fenestration of the 
cyst, and placement of an Ommaya reservoir for intermittent aspiration, systemic chemotherapy, and 
radiation therapy. In a retrospective analysis, the cases of children with pathology confirmed WHO 
grade 1 astrocytomas and identified patients with complications arising from the cystic portion of the 
tumor were reported. 54 patients with tumors with a cystic component. In 31.4% there was progression 
of the cystic portion of the tumor.  The optic pathway/hypothalamus was the most common location for 
progressive tumor cysts.  Surgical resection was attempted in all cases at least once; a total of 39 
surgical procedures were performed. Cyst fenestration was attempted in 35.2%. Ommaya reservoir was 
placed in 47%. 9 patients got external beam radiation and 5/9 (56%) had stabilization of cyst growth 
with no additional therapies.  Intra-cystic administration of P32 was given to only one patient.  
Chemotherapy was used in 65% of cases.  7 of the 11 children who received chemotherapy required 
more than one regimen. This retrospective study shows that management of tumor-associated cysts in 
low grade gliomas remains challenging.  (Wolf D, Cohen KJ, Neuro-oncology  vol 14, 2012,  issue suppl 
i69-i81, abstract LG-35) 
 
 
 


Protocol Vers   12-14-2018                           12 
 
2.3 Interferon Alpha  
Mechanism of Action:  The interferons (IFN) are a family of glycoproteins with antiproliferative, antiviral, 
and immune-modulating capabilities. Studies have shown that they are involved in control of cell 
function and replication, but their mechanisms of action are not fully known. They bind to cell surface 
receptors, resulting in a signal transduction that induces or suppresses gene expression.  
The interferons induce protein synthesis, inhibit mitotic activity, modify cell membranes and regulate 
immune effector cells. They block cell transition from G0/G1 into the S phase of the cell cycle. They are 
known to suppress the expression of the c-myc and c-fos proto-oncogenes, and receptors for certain 
growth factors. Other  effects of peg interferon alpha-2b include inhibition of viral replication in virus-
infected cells, the suppression of cell cycle progression/cell proliferation, induction of apoptosis, anti-
angiogenic activities, and numerous immunomodulating activities, such as enhancement of the 
phagocytic activity of macrophages, activation of NK cells, stimulation of cytotoxic T-lymphocytes, and 
the upregulation of the Th1 T-helper cell subset.  
Peginterferon raises concentrations of effector proteins such as serum neopterin and 2’5’ 
oligoadenylate synthetase, raises body temperature, and causes reversible decrease in leukocyte and 
platelet counts. 
The type I interferons (IFN-alpha and IFN-beta) are also negative regulators of cell growth and can 
modify cell differentiation. Interferon-alpha can be induced by foreign cells, tumor cells, and virus-
infected cells that stimulate B- lymphocytes, null lymphocytes and macrophages.  
Numerous clinical trials have been performed investigating the utility of interferons for viral diseases 
and cancer. The interferons have been approved by the FDA for several clinical indications, including 
hairy cell leukemia, chronic myelogenous leukemia and melanoma. 
 Interferon therapy has been associated with a variety of side effects including an acute flu-like 
syndrome with malaise, fever and chills, irritability, fatigue and musculoskeletal pain. Longer-term 
effects include depression, anorexia, headache and cognitive impairment. At least some of these effects 
are felt to be dose-related.  
Clinical studies using alpha, beta and gamma interferons have been performed on patients with 
malignant brain tumors using different methods of administration, including intravenous, subcutaneous, 
intramuscular, intrathecal and intracavitary. The results have been mixed. 
 
2.4 Peg-interferon: 
There are 2  brand names of peginterferon alpha 2b on the market, both from the same manufacture.  
-PEG-Intron™(SCHERING-PLOUGH/MERCK) PEG-Intron™is a covalent conjugate of recombinant 
interferon alfa-2b with monomethoxy polyethylene glycol (PEG),  that was FDA-approved in January, 
2001 for use in patients with Hepatitis C.-Sylatron  (SCHERING-PLOUGH/MERCK) is a covalent conjugate 
of recombinant alfa-2b interferon with monomethoxy polyethylene glycol (PEG). The average molecular 
weight of the PEG portion of the molecule is 12,000 daltons. The average molecular weight of the 
SYLATRON molecule is approximately 31,000 daltons. The specific activity of pegylated interferon alfa-2b 
is approximately 0.7 x 108 international units/mg protein.  Initial approval   for the adjuvant treatment of 
melanoma. 


Protocol Vers   12-14-2018                           13 
 
Interferon alfa-2b is a water-soluble protein produced by recombinant DNA techniques from the 
bacterial fermentation of an E. Coli strain with a genetically engineered plasmid containing an interferon 
gene from human leukocytes. (package insert)  
Pegylation increases the biologic half-life of the compound, enabling it to be administered once weekly, 
and also reduces the peaks and troughs in blood levels.  Pegylated interferon uses a 12 kilodalton PEG 
that is attached to interferon in a linear fashion.  Maximal serum concentrations occur between 15-44 
hours after dosing, and are sustained for up to 72 hours. The mean elimination half-life is 22-60 hours in 
patients with Hepatitis C virus infection. Renal elimination accounts for 30% of the clearance. Although 
there is extensive data on the use of Pegylated interferon  in adults with hepatitis C and melanoma, 
there is limited data on its use in children or in patients with  other cancers. 
 
2.5 Clinical Data of Interferon in Cancer 
2.5.1 Interferon and Gliomas: In gliomas, Nagai et al  reported a partial response in 2 / 9 patients with 
glioblastoma treated with rIFN-alpha A, and 40% response rate (1 complete response, 7 partial 
responses) in 20 patients with glioblastoma treated with human fibroblast interferon-beta. [10] 
Two phase II trials of temozolomide with interferon alpha-2b (pegylated and non-pegylated) in patients 
with recurrent glioblastoma multiforme demonstrated PFS at 6months was 31% for 29 evaluable 
patients in the IFN study and 38% for 26 evaluable patients in the PEG group. In recurrent GBM patients, 
in combination with both studies of standard dose TMZ with either IFN or PEG showed improved 
efficacy when compared to reports using TMZ alone. The grade 3 or 4 toxicities more common were 
leucopenia and thrombocytopenia. Grade 3 or 4 fatigue occurred in 18% of patients on both studies. 
Lymphopenia was not seen frequently. [11]  
In a pediatric study involving children with recurrent malignant tumors treated with recombinant 
interferon-ß, 2 of 9 children with brainstem gliomas had a partial response (>50% reduction in tumor 
size) and 2 children had prolonged disease stabilization (1 child for 3.5 years).[12] 
 In a follow-up study of pediatric patients with brainstem gliomas treated with IV recombinant ß-
interferon during hyperfractionated radiation therapy, 13 of 32 patients required dose modifications 
due to hepatic or hematologic toxicity. [13] 
The optimal dosing for interferon alpha has not yet been established, although it has been used to treat 
a variety of neoplasms. It has traditionally been administered in high doses = 3,000,000 U/m2, 2-
3x/week. Significant side effects have limited its use.  
In one study in which interferon alpha-2a was administered to pediatric patients with recurrent or 
progressive craniopharyngiomas at a dose of 8,000,000 U/m2 daily for 16 weeks, followed by the same 
dose 3 times a week for an additional 32 weeks, the need for radiation therapy was significantly delayed 
in 6 of 15 patients, but more than 50% of the patients experienced significant toxicity requiring 
intervention or dose reduction within the first 8 weeks of therapy. [14] 
 
 


Protocol Vers   12-14-2018                           14 
 
2.6 Pegylated interferon in  Clinical Studies and Case Series  
-Pegylated interferon in Children with Diffuse Intrinsic Pontine Gliomas:  Warren et al conducted phase II 
trial of Pegylated interferon for children with diffuse intrinsic pontine glioma (DIPG). Pegylated 
interferon was administered as a low-dose of 0.3 μg/kg continuous exposure beginning 2 to 10 weeks 
after the completion of radiation therapy until they developed disease progression. Thirty-two patients 
(median age, 5.3 years; range, 1.8-14.8 years) received a median of 7 cycles of therapy. PEGylated 
interferon was well tolerated. The 2-year survival rate was not significantly improved compared with the 
historic cohort. The median time to progression was 7.8 months. DIPG compared with an historic control 
population, it did delay the time to progression. The scientific reason for the low dose of interferon was 
the anti-angiogenic affect seen in animal models. [15]  
-Pegylated interferon in Children with Cystic Craniopharyngiomas: 
In a different type of brain tumor, however it carries similarities to LGG since both can have cystic 
components, the use of Pegylated interferon has been described. Recently, a case series of 5 children 
with recurrent craniopharyngiomas treated with Pegylated interferon-alpha-2b was published. Their age 
ranged from 9 to 15 years treated for up to 2 years with subcutaneous injections of Pegylated interferon 
at a dose of 1-3 μg/kg/week. Tumor response was assessed using MRIs. All 5 patients had stable disease 
or responses to the Pegylater interferon. One patient experienced increase in the predominantly cystic 
tumor after 3 months of treatment, followed by a complete response with no recurrence for greater 
than 10 years.  Another patient had complete disappearance of the predominantly cystic component 
after 4 months of treatment, and a small residual calcified mass remains 5 years later. The third patient 
experienced a complete response after 7 months of treatment and remains without disease 19 months 
after starting treatment. The fourth patient experienced a 30% decrease in tumor size after 4 months of 
treatment, which was maintained for 12 months at which point the cyst began to increase in size. The 
final patient had stable disease 6 months after starting treatment. These case series are the basis for a 
clinical trial for recurrent craniopharyngiomas to evaluate the response to Pegylated interferon. Based 
on the responses, it could be possible to potentially delay or avoid the need for radiation therapy in the 
future. [16]  
 
-Pegylated interferon in Children with Progressive Neurofibromas:  The safety and tolerability of 
pegylated interferon was evaluated in a phase I trial in patients unresectable progressive or 
symptomatic plexiform neurofibromas (PN).Thirty patients (median age 9.3 years) were treated. All 5 
patients at the 4.5 μg/kg DL came off study or required dose reductions for behavioral toxicity or 
fatigue.  During the first 4 weeks, no dose-limiting toxicity (DLT) was seen in patients treated at the 3 
μg/kg dose level (DL), however similar DLT on the 3 μg/kg DL became apparent over time. At the 1.0 
μg/kg DL, there was 1 DLT (myoclonus) in 12 patients enrolled.  11/16 patients had pain improvement 
and 13/14 patients had a decrease in size of a palpable mass. Volumetric analysis had a 15%-22% 
decrease in volume in 5/ 17 patients (29%).  The dose recommended for phase II of pegylated interferon 
for pediatric patients is 1 μg/kg/wk.  This trial is currently ongoing.[17] (www.clinicaltrials.gov)  
 
 
 


Protocol Vers   12-14-2018                           15 
 
2.7 Dose and Schedule  
The type I interferons down-regulate the expression of pro-angiogenic molecules, including bFGF, IL-8, 
MMP-2 and MMP-9. Systemic chronic administration of IFN-a or IFN-ß has been shown to produce 
regression of vascular tumors by down-regulation of mRNA expression and protein production of the 
angiogenic factor, bFGF23.  
This effect requires long term exposure to IFNs, as has been demonstrated clinically and in vitro. 
Through in vitro and animal model, Slaton et.al have demonstrated that daily administration of 
interferon alpha-2a, at doses far below maximally tolerated doses, produced the most significant 
inhibition of tumor growth, tumor vascularization, and maximal inhibition of angiogenesis-regulating 
genes.   His experiments demonstrated that when human bladder cancer cell lines were implanted into 
the bladder of mice and the mice were injected subcutaneously daily, 1x/ week or 2x/ week for 4 weeks 
with interferon alfa-2a. Examination and evaluation after 4 weeks demonstrated that interferon alfa-2a 
administered daily produced superior anti-proliferative and anti-angiogenic activities compared to an 
equivalent weekly dose administered 1, 2 or 3 X/week.  
In a comparison of escalating daily doses of interferon alfa-2-a (2500-50,000 units/dose), maximal 
inhibition occurred at a dose of 5000 or 10,000 units/day. Administration of higher doses failed to 
produce significant anti-angiogenic effects. [18] 
 
2.7.1 Doses for Pegylated interferon  
-For patients with chronic hepatitis as a monotherapy the dose is 1 mcg/kg/Week SC x1 year. 
-For patients with melanoma with microscopic or gross nodal involvement within 84 days of definitive 
surgical resection including complete lymphadenectomy, the doses used are 6mcg/kg/week 
subcutaneous for 8 doses, then 3 mcg/kg/week SC for up to 5 yr.  Rotating the injection sites. 
-Phase I study in patients with neurofibromatosis related plexiform neurofibromas had a recommended 
dose for phase II of   1mcg/kg/week. [17] 
-The doses used for the patients treated in the series with recurrent craniopharyngioma ranged from 1 
to 3 mcg/kg/dose.  
-For this trial, the dose is 1 mcg/kg/dose. There are specific criteria for reduction of the dose based on 
toxicity. Two dose modifications have been permitted.  
 
 
 


Protocol Vers   12-14-2018                           16 
 
2.8 Imaging   
Imaging of the tumor will be assessed with MRI of brain and /or spine with and without contrast 
performed on a 1.5 or 3T scanner. Progressive disease will be defined on the basis of a comparison of 
the baseline scan to the scan demonstrating best response. All axial images should be obtained in a 
plane parallel to a line intersecting the bottom of the genu and of the splenium of the corpus callosum 
to assure consistency of imaging plane. Coronal images should be obtained in a plane perpendicular to 
the axial images. 
1) Axial diffusion tensor imaging whole brain 
2) Sagittal, volumetric T1-weighted, gradient echo whole head 
3) Axial T2-weighted fast spin echo (FSE) whole head 
4) 3D Coronal FLAIR. 
5) Coronal T2-weighted fast spin echo (FSE), fat saturated through the orbits and chiasm. 
6) Axial T2-weighted fast spin echo (FSE), fat saturated through the orbits and chiasm. 
7) Axial volumetric T1-weighted gradient echo post contrast whole brain. 
8) Axial Oblique T1-weighted Fat Suppressed gradient echo post contrast, optic nerves and chiasm. 
9) Coronal T1-weighted Fat suppressed gradient echo post contrast, optic nerves and chiasm. If imaging 
of the spine is needed, axial and sagittal T2 and post contrast T1 weighted images will be acquired. 
Diffusion images of the spine will be obtained if clinically indicated. Volumetric studies for MRI of the 
brain will be obtain to better evaluate the cystic component of the 
Low grade gliomas and be able to evaluate responses to the therapy.   
These sequences are the minimum required to evaluate the response to the treatment.  Additional 
sequences such as MR spectroscopy can be obtained if clinically indicated per institutional protocols.  
 
 
 
 


Protocol Vers   12-14-2018                           17 
 
3.0 STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
 
3.1 Study Enrollment 
 
3.1.1 Patient registration 
Patients may be enrolled on the study once all eligibility requirements for the study have been met. 
Patients who give informed consent for the protocol in order to undergo screening for eligibility are not 
considered enrolled and should not be enrolled until the screening is completed and they are 
determined to meet all eligibility criteria. A registration packet is available from the study coordinator to 
assist with registration requirements for this protocol. The Aflac Cancer Center CRO will provide 
electronic confirmation of registration and a study number will be assigned to the patient prior to begin 
treatment. 
The 
study 
number 
will 
be 
used 
to 
identify 
the 
patient 
in 
all 
future 
communications/interactions. An email confirming eligibility will be sent to the Study PI, and Co-PI. The 
date protocol therapy is projected to start must be no later than 14 calendar days after the date of study 
enrollment. Patients must not receive any protocol therapy prior to enrollment. 
 
3.1.2 IRB Approval 
Emory IRB approval of this study is to be provided to the Aflac CRO prior to any patient enrollment. 
 
3.1.3 Reservation and Contact Requirements 
Investigators should refer to the Emory IRB website to determine if the study is currently open for 
accrual and listed as active. Before enrolling a patient on study, a reservation must be made at the Aflac 
CRO. 
Patients must be enrolled within 14 calendar days of making a reservation. 
Eligible patients can make a reservation by contacting the Clinical Research Office, Monday through 
Friday, 8:00 am-4:30 pm Eastern Standard Time at (404) 824-2778 (phone) except holidays. Calls will be 
returned within one business day. The appropriate research coordinator will review preliminary 
eligibility by phone before forwarding a registration packet. The information requested in the 
registration packet must be completed. The signed informed consent statement along with the 
documentation confirming eligibility must be faxed to (404) 785-9248. Upon receipt of the completed 
registration packet, the research coordinator at Children's Healthcare of Atlanta will assign a unique 
study subject number.  
 
3.1.4 Timelines Summary 
All pre-treatment evaluations should be performed within 14 days prior to enrollment and 30 days for 
baseline MRI brain and/or spine. From the reservation to enrollment a maximum of 14 calendar days. 
From enrollment to start therapy maximum 14 calendar days. Patients must not receive any protocol 
therapy prior to enrollment. 
3.1.5 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 
patient or the patient’s parents or guardian if the patient is a child, and a signed informed consent and 
assent will be obtained according to institutional guidelines. 
 
 
 


Protocol Vers   12-14-2018                           18 
 
3.1.6 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 patient’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. 
 
3.1.7 Eligibility Checklist 
Before the patient can be enrolled, the responsible institutional investigator must sign and date the 
completed eligibility checklist. A signed copy of the checklist will be faxed immediately following 
enrollment to the Aflac Cancer Center CRO at 404-785-9248. 
 
3.2 Eligibility Criteria 
All clinical and laboratory studies to determine eligibility must be performed within 14 days prior to 
enrollment, except MRI brain and/or spine within 30 days prior to enrollment. If more than 14 calendar 
days elapse between the date eligibility studies were obtained and the start date of treatment, then the 
following studies must be repeated prior to treatment: CBC with differential, bilirubin, ALT (SGPT) and 
serum creatinine. If any of these repeat laboratory studies are outside the parameters required for 
eligibility (labs may again be repeated within 48-72 hours), then the patient is off protocol therapy. 
Imaging studies are required within 30 days prior to enrollment. 
Important note: The eligibility criteria listed below are interpreted literally and cannot be waived. All 
clinical and laboratory data required for determining eligibility of a patient enrolled on this trial must 
be available in the patient’s medical or research record which will serve as the source document for 
verification at the time of audit. 
 
 
3.2 INCLUSION CRITERIA  
3.2.1  Age 
Patients must be older than 3 years and   less than  or equal to 25 years of age at the time of enrollment  
3.2.2  Neurofibromatosis 
Patients with neurofibromatosis are eligible.  
3.2.3 Diagnosis   
Histologic confirmation is not required for this if the patient has NF-1 with MRI findings consistent with 
optic pathway glioma or JPA. Any other tumors will need histological confirmation, either at the time of 
diagnosis or at the time of recurrence. The histological diagnosis includes WHO grade I JPA. 
3.2.4    Measurable Disease 
Patients must have measurable residual disease, defined as tumor that is measurable in two or three 
perpendicular diameters on MRI. For a lesion to be considered measurable, it must be at least twice the 
slice thickness on MRI (i.e visible on more than one slice) 


Protocol Vers   12-14-2018                           19 
 
3.2.5  Brain and/or Spine MRI 
All patients must have a brain MRI with and without contrast (gadolinium) within 30 days prior to study 
enrollment. All patients with  history of spinal or leptomeningeal disease and those patients with  
symptoms suspicious of spinal disease, must have a spine MRI with  contrast ( gadollinium)  performed 
within 30 days prior to  study enrollment.   Lumbar Puncture is necessary if there is evidence of tumor  
dissemination on the MRI of spine. 
3.2.6 Performance status 
Performance Level: Karnofsky >or equal to 50% for patients > 10 years of age or Lansky > or equal to  50 
for patients < 10 years of age (Appendix I). Note: Patients 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. 
3.2.7 Prior therapy  
o 3.2.7.1 No limit in the number of previous surgical resections.  
o 3.2.7.2 No limit to number of prior anti-cancer regimens, including chemotherapy, biologic 
agents, immunotherapy, vaccines, monoclonal antibodies or radiation therapy. Patients who 
have received prior radiation therapy for this tumor are eligible.  There should be at least 2 
yearstime since the completion of radiation therapy.  
3.2.8  
Patients must have recovered (to CTC v.5.0 ≤ Grade 1 unless indicated below) from the acute toxic 
effects of all prior chemotherapy, immunotherapy prior to entering this study, with the exception of 
alopecia, weight changes and Grade I or II lymphopenia. 
 
a -Myelosuppressive chemotherapy: Must not have received within 3 weeks of enrollment onto 
this study (6 weeks if prior nitrosourea). 
B -Biologic (anti-neoplastic agent): At least 7 days must have elapsed since the completion of 
therapy with other biologic agents. For other biologic agents that have known adverse events 
occurring beyond 7 days after administration, this period must be extended beyond the time 
during which adverse events are known to occur. The duration of this interval must be 
discussed with the study chair. 
c-Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a monoclonal 
antibody.  Specifically for bevacizumab 36 days after the last dose.  
d -Resection: At least 3 weeks from the last surgical resection, prior to start study drug. 
              e- Immunotherapy: At least 42 days after the completion of any type of   
               immunotherapy, e.g. tumor vaccines.  
 g- Radiation therapy (RT): Patients must have had their last fraction of cranial or craniospinal 
Radiation ≥ 24 months prior to study entry.  
 
f. Study specific limitations on prior therapy: 
1) Patients who have received Poly-ICLC are eligible for this trial if all acute Poly-ICLC -related 
toxicity has resolved. 


Protocol Vers   12-14-2018                           20 
 
2) Patients must not have received Pegylated interferon previously. 
 
3.2.9 Concomitant Medications Restrictions   
 
a. Growth factor(s): Must not have received within 2 weeks of entry onto this study. 
b. Steroids: Patients who are receiving corticosteroids must be on a stable or decreasing dose   for at 
least 1 week prior enrollment in the study. 
 
 
3.2.10  Organ Function Requirements 
 
• 
Hepatic 
function: 
Patients 
must 
have 
adequate 
liver 
function, 
defined 
as 
 
o Total bilirubin <2.0x the upper limit of normal and 
o Direct bilirubin within normal limits and 
o SGPT (ALT) <2.5 x the upper limit of normal.  
o Patients with Gilbert syndrome are excluded from the requirement of a normal bilirubin but 
they must have an indirect bilirubin of <6mg/dl, and a direct bilirubin of <0.5mg/dl in order 
to be eligible. (Gilbert syndrome is found in 3-10% of the general population and is 
characterized by mild, chronic hyperbilirubinemia in the absence of liver disease or overt 
hemolysis).  
 
• 
Hematological function: Patients must have adequate bone marrow function defined as: 
 
o peripheral absolute granulocyte count of >1000/mm3,  
o hemoglobin >8 gm/dL, Patients may be transfused with RBC’s 
o platelet count >100,000/mm3.   Independent of transfusion. 
 
• 
Renal function: Patients must have an age-adjusted normal serum creatinine (see below) OR a 
creatinine clearance  or GFR >/= or more than 60 mL/min/1.73 m2.   
Age ( years) 
Maximum Serum Creatinine ( mg/dl) 
<5 
0.8 
5<age<10 
1.0 
10<age<15 
1.2 
>15 
1.5 
 
• 
Adequate Pulmonary function defined as: 
o no evidence of dyspnea at rest and pulse oxymetry >94% . 
 
3.2.11 If history of depression or psychiatric illness, has to be well controlled with antidepressants  
and/or  under psychiatrist/ psychologist care. 
 
 


Protocol Vers   12-14-2018                           21 
 
3.3 EXCLUSION CRITERIA  
3.3.1  
Patients who are receiving concurrent chemotherapy, or who are currently receiving other 
investigational chemotherapeutic agents or concurrently receiving radiation. 
3.3.2 
Patients with a known hypersensitivity to interferon-alpha.  
3.3.3 
Prior use of Pegylated interferon or interferon. 
3.3.4 
Less than 2 years since completion of radiation therapy. 
3.3.5 
Pregnant or breast-feeding females are excluded because the effects of pegylated interferon alfa-2b on 
the unborn fetus are unknown  
3.3.6 
Patients with clinically significant unrelated systemic illness (including autoimmune disease, serious 
infections or significant cardiac, pulmonary, hepatic or other organ dysfunction) which in the judgment 
of the Principal or Associate Investigators  would compromise the patient’s ability to tolerate this 
therapy or  are likely to interfere with the study procedures or results.  
3.3.7 
Dental braces or prosthesis that interferes with MR imaging. 
3.3.8 
History of noncompliance to medical regimens. 
3.3.9 
Patients unwilling to or unable to comply with the protocol. 
3.3.10 
Patients with a positive history of Hepatitis B or Hepatitis C. 
3.3.11  
Male patient whose sexual partner(s) are women of childbearing potential who are not willing to use 
adequate contraception, during the study and for 8 weeks after the end of treatment. 
3.3.12  


Protocol Vers   12-14-2018                           22 
 
Patients should not receive immunization with attenuated live vaccines within one week of study entry 
or during study period. Close contact with those who have received attenuated live vaccines should be 
avoided during treatment with pegylated interferon. Examples of live vaccines include intranasal 
influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines. 
3.3.13 
Patient with diagnosis of Diffuse Intrinsic Pontine Glioma. 
3.4 Regulatory 
 
3.4.1  
All patients and/or their parents or legal guardians must sign a written informed consent. 
The investigational nature and research objectives of this trial, the procedures and treatments involved 
and their attendant risks and discomforts and benefits, and potential alternative therapies will be 
carefully explained to the patient, the patient’s parents or guardian if he/she is a child, or previously 
assigned DPA and a signed informed consent document will be obtained prior to entry onto the study.  
The PI or an associate investigator on the trial will obtain consent. Where deemed appropriate by the 
clinician and the child’s parents or guardian, the child will also be included in all discussions about the 
trial and verbal assent will be obtained. The parent or guardian will sign the designated line on the 
informed consent attesting to the fact that the child has given assent.  
 
3.4.2  
All institutional, FDA, and NCI requirements for human studies must be met. 
 
4.0 TREATMENT PROGRAM 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care. Minor 
unavoidable departures (+/- up to 5 days) from protocol directed therapy (and up to 1 week for surgery) 
and/or disease evaluations for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable. If an unavoidable departure occurs, patients should 
continue to follow the roadmap and diary and get assessments within the 5 day  period, with the 
exception of course 1. 
 
4.1 Overview of the treatment plan 
Treatment with pegylated interferon alpha-2b must begin within 14 days of patient enrollment. Patients 
may be pre-medicated as needed with acetaminophen 10-15 mg/kg (maximum 650 mg per dose) or 
ibuprofen 10 mg/kg within 1 hour of receiving Pegylated interferon. The patients can continue on either 
acetaminophen or ibuprofen for up to 48 hours after Pegylated interferon injection. The maximum dose 
of ibuprofen in a 24-hour period will be 40 mg/kg.  Ibuprofen for Adolescents and Adults the maximum 
daily dose: 2.4 grams in 24 hours.  Premedication is optional. 
Each cycle of therapy will consist of pegylated interferon alfa-2b administered subcutaneously once 
weekly (+/- 5days) for 4 weeks for up to 2 years. Each dose should be administered on the same day 


Protocol Vers   12-14-2018                           23 
 
each week. There will be no breaks between cycles. Total number of cycles 26. Each dose is 1µg/kg 
subcutaneously. Nursing staff will instruct the patients or their caregivers regarding sites of injection and 
injection technique.  Teaching needs to be documented.  Rotating the sites of injection is strongly 
recommended.  
Patients and/or their caregivers will be asked to maintain a diary (Appendix 5) documenting the dose of 
pegylated interferon alpha-2b given, site of administration and any side effects. This diary will be 
reviewed at each clinic visit.  Patients will return to the Aflac clinic prior to start next cycles.  
Doses could be rounded up to the nearest upper 5mcg for easier administration. For patients whose 
weight is greater than 150kg the maximum dose of Pegylated interferon to be administered is 
150mcg/dose/ week. 
MRI brain and /or spine will be performed as a baseline within 30 days of enrollment and subsequently 
every 3 cycles.  
 
See section 7.1 for required observations prior to start therapy.  
 
4.2 Concomitant therapy restrictions 
 
4.2.1 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or biologic 
therapy   can NOT be administered to patients while on this study. The use of alternative or 
complementary therapies is discouraged. 
 
4.2.2 
Radiotherapy is not permitted. 
 
4.2.3 
Filgrastim (G-CSF) may be used at the treating physician’s discretion in patients with severe neutropenia 
(i.e. ANC <500/μL) to enhance neutrophil recovery when clinically indicated (for culture proven 
bacteremia or invasive fungal infections). Prophylactic or routine use of filgrastim in clinically well 
patients awaiting count recovery is not recommended. 
 
4.2.4 
Corticosteroid therapy is permissible only for the treatment of increased intracranial pressure or 
physiologic replacement. The lowest dose consistent with good medical management should be used. 
Corticosteroids should NOT be used as an antiemetic due to their effect on the blood brain barrier. 
Patients on steroids who require an increase in steroid dose for worsening neurologic symptoms should 
have an MRI performed within 5 days to rule out tumor progression. 
 
4.2.5 
Appropriate antibiotics, blood products, anti-emetics, fluids, electrolytes and general supportive care 
are to be used as necessary.  PCP prophylaxis is recommended following the institutional guidelines 
when absolute lymphocyte count is below 1200. 
 
 
 


Protocol Vers   12-14-2018                           24 
 
4.2.6 
 
Anticonvulsants may be administered as clinically indicated. However, it is recommended to avoid 
enzyme inducing anticonvulsants.  
 
For Supportive Care Guidelines  use Children's Oncology group  guidelines, see: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard Sections 
for Protocols. 
 
4.3 Pegylated interferon Administration 
 
Pegylated interferon will be administered weekly (+/- 5 days) at a dose of 1mcg/kg/dose via 
subcutaneous injection, approximately at the same time every week.   
It is important to rotate the injection sites.  Teaching will be done to the parents/guardian/patient   in 
the first and/or second injection so the family will learn the technique and can continue to do it at 
home. Family/guardian will be provided with diaries to document compliance and   side effects.  
Patients may be pre-medicated with acetaminophen or ibuprofen. Specifically, patients can receive 
acetaminophen 10-15 mg/kg (maximum 650 mg per dose, maximum dose 4 grams/24 hours) or 
ibuprofen 10 mg/kg within 1 hour prior to receiving PEPegylated interferon. The patients can continue 
on either acetaminophen or ibuprofen for up to 48 hours after the pegylated interferon injection as 
needed. The maximum dose of ibuprofen in a 24-hour period will be 40 mg/kg or patients with weight 
for more than 45 kg is 2.4 grams/24 hours. Premedication is optional. 
Pegylated interferon will begin a Cycle on Day 1 if ANC ≥ 1,000/μL, platelet count ≥ 100,000/μL 
(transfusion independent). 
Dose calculations should be based on actual weight and adjusted as necessary prior to each cycle.  
The maximum dose is 150 mcg. 
Note: The calculated dose should be rounded to the nearest highest 5mcg of the prescribed dose for 
convenience of administration. Each cycle is 28 days.  The total duration of the trial is 2 years a total of 
26 cycles.  
See Section 5.0 for   Dose Modifications Based on Toxicities. 
 
The therapy delivery maps (TDMs) for this cycle are on the next pages 
 
Following completion of the first cycle, the Pegylated interferon cycle is repeated weekly for up to a 
total of 26 cycles, as tolerated and in the absence of disease progression (see Section 10.4 for Response 
Evaluation).  If disease progression occurs, the patient will be taken off protocol therapy. 
Subsequent Pegylated interferon cycles should begin on Day 29 or when ANC ≥ 1,000/μL, platelet count 
≥ 100,000/μL (transfusion independent), whichever occurs later. 
 
 
 
 
 
 
 
 


Protocol Vers   12-14-2018                           25 
 
 
 
Therapy Delivery Plan  
Pegylated interferon Dose 1mcg/kg/dose 
4 consecutive weeks (28 days) will constitute one cycle. This 
therapy delivery map relates to all cycles of Pegylated 
interferon 
 
Patient Name:_______________ 
DOB_______________________ 
Criteria to start a cycle: ANC ≥ 1,000/μL and platelet count ≥ 100,000/μL (transfusion independent). This 
cycle lasts 28 days.   
DRUG 
ROUTE DOSAGE 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS  
 
Pegylated 
interferon 
SQ 
1 mcg/kg/dose 
Max dose  is 150 
mcg/dose 
weekly 
(+/-5 days)  
Premed 
with Tylenol 
or ibuprofen 
as needed. 
 
a. CBC with differential                                 
b. CMP, Magnesium, Phosphorous, 
Calcium, Uric Acid. 
c. PT/PTT                                                          
d.  Urinalysis 
e. Performance Score                                    
f.  Hx, PE, Neuro Exam, Wt, Ht, VS. 
g. pregnancy test  
h. Assessment of clinical toxicity/ 
adverse events      
i.  QOL questionnaire 
j. MRI of brain and/or spine                         
k.  Am Cortisol, Free T4, TSH. 
l. Ophthalmology Evaluation                       
m. Pegylated interferon Diary 
n. lumbar puncture (See section 7.1) 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
 
Cycle- 28 
Days (+/- 5) 
 
 
Date Due 
 
Date Given 
 
Chemotherapy 
Dose 
 
Studies 
1 
 
 
 
a-i, k, l, o 
 
 
 
 
 
 
 
 
 
a, b, e, f, h, m 
 
 
 
 
 
2 
 
 
 
a, b, e, f, h, m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Vers   12-14-2018                           26 
 
Cycle- 28 
Days (+/- 5) 
 
 
Date Due 
 
Date Given 
 
Chemotherapy 
Dose 
 
Studies 
3 
 
 
 
a, b, e, f, h, m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
a, b, d, e, f, h, i, j, m, n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
a, b, e, f, h, m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 
 
 
 
a, b, e, f, h, l, k, m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7 
 
 
 
a, b, d, e, f, h-j, m, n   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 
 
 
 
a, b, e, f, h, m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9 
 
 
 
a, b, d, e, f, h, m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 
 
 
 
a, b, d, e, f, h-j ,m, n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 
 
 
 
a, b, e, f, h, m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 
 
 
 
a, b, e, f, h, k, l, m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Vers   12-14-2018                           27 
 
Cycle- 28 
Days (+/- 5) 
 
 
Date Due 
 
Date Given 
 
Chemotherapy 
Dose 
 
Studies 
13 
 
 
 
a, b, d, e, f, i, j, m, n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14 
 
 
 
a, b, e, f, h, m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 
 
 
 
a, b, d ,e, f, h, m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16 
 
 
 
a, b, d, e, f, h-j,  m, n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17 
 
 
 
a, b, e, f, h, m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18 
 
 
 
a, b, e, f, h, l, k, m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19 
 
 
 
a, b, d, e, f, h-j, m, n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20 
 
 
 
a, b, e, f, h, m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
21 
 
 
 
a, b, d, e, f, h, m  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
22 
 
 
 
a, b, d, e, f, h-j, m, n   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Vers   12-14-2018                           28 
 
Cycle- 28 
Days (+/- 5) 
 
 
Date Due 
 
Date Given 
 
Chemotherapy 
Dose 
 
Studies 
23 
 
 
 
a, b, e, f, h, m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24 
 
 
 
a, b, d, e, f, h, i, k, l, m  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
25 
 
 
 
a, b, d e, f, h- j, m, n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
26 
 
 
 
a, b, e, f, h, m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
END of 
therapy 
 
 
 
 
 
a- Obtain weekly. If patient develops grade 4 neutropenia, CBCs should be checked every 3 to 4 days 
until recovery to grade 3.  
n-Obtain prior to starting cycle one only for females of childbearing potential.  For the rest of the 
protocol  follow institutional policies about pregnancy testing.  
j-Obtain after every third cycle and as clinically indicated.  MRI of spine obtain at same time points as 
brain MRI, for patients with known or suspected spinal disease.  
 
See Section 5.0 for Dose Modifications for Toxicities 
For supportive care guidelines see: 
 http://members.childrensoncologygroup.org/prot/reference_material.asp 
 
 
 
 
 
 
 
 


Protocol Vers   12-14-2018                           29 
 
4.4 Criteria for Starting Subsequent Courses of Treatment 
A course may be repeated every 28 days, up to a total of 2 years if the patient has at least stable disease 
and has again met laboratory parameters. 
Patients who complete a treatment cycle may receive another cycle if:  
• 
Disease Status: the patient has no evidence of progressive disease or in the opinion of the 
investigator, the patient is benefiting from the therapy with pegylated interferon alfa-2b ) as 
evidenced by a decrease in tumor-related symptoms.  
• 
Toxicity: the patient has not experienced any toxicity that meets off-study  criteria as described in 
Section 5.0 
• 
Patients will not be allowed to have a dose escalation after dose reduction due to toxicity. 
 
5.0 DOSE MODIFICATIONS FOR TOXICITY  
 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to keep the patient on study drug. If administration of Pegylated interferon must be 
interrupted because of unacceptable toxicity, drug dosing will be interrupted or modified according to 
rules described below. Toxicity will be assessed using the NIH-NCI Common Terminology Criteria for 
Adverse Events, version 5.0 
 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Referenc
e_5x7.pdf 
 
Pegylated interferon dose level modification guidelines 
 
Patients who experience significant toxicity as listed in section 5.0 will have the dose reduced by  25% of 
the dose on subsequent cycles.  Two dose reductions are allowed, as long as there is no evidence of 
progressive disease (see section 10.4) Patients who again experience dose modifying toxicity after 2 
dose reductions will be taken off protocol therapy.  
 
Dose Modification for Toxicity 
Dose and schedule 
 
Standard dose 
1mcg/kg/dose 
Dose Modifications 
First Dose Modification: reduction by 25% of dose 
 
Second Dose Modification: reduction by 50% of 
dose 
 
Permanently discontinue if unable to tolerate  
second dose modification 
*For patients whose weight is greater than 150kg, the maximum dose of Pegylated interferon to be 
administered is 150mcg/dose/week.   (See table above)  
5.1  Non-hematological  Toxicities 
The dose of Pegylated interferon will be reduced for any of the following toxicities at least possibly 
attributed to Pegylated interferon 
• Any Grade 4 non-hematological toxicity 
• Any Grade 3 non-hematological toxicity with the specific exclusion of: 


Protocol Vers   12-14-2018                           30 
 
- Grade 3 nausea and vomiting controlled by antiemetics 
- Grade 3 fever or infection 
- Grade 3 fever, myalgias, arthralgias, and rigors. 
- Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia responsive to 
oral supplementation. 
 
• Any Grade 2 non-hematologic toxicity that persists for > 3 days and is considered sufficiently medically 
significant or sufficiently intolerable by patients that it requires treatment interruption 
 
• Any other adverse event attributed to Pegylated interferon that requires treatment interruption for > 
3 days or which recurs upon drug re-challenge and requires treatment interruption. 
 
• Non-hematological toxicity that causes a delay of more than 14 days between treatment cycles. 
 
Patients who experience non-hematologic toxicity should have appropriate laboratory testing at least 
weekly until the toxicity has resolved. 
 
If the toxicity does not return to less or equal than Grade 1 within 14 days, the patient will no longer be 
eligible to receive treatment on this study.  
If the toxicity returns to less or equal to Grade 1 within 14 days, the patient may restart the study drug 
at initial dose modification once weekly and remain at that dose.  
If the same Grade 3 or 4 non-hematologic toxicity recurs, hold drug and wait until toxicity returns to less 
or equal to Grade 1. If toxicity returns to less or equal to grade 1 within 14 days, the patient may restart 
the study drug at second dose modification and remain at that dose. If the toxicity does not return to 
less than Grade 1 within 14 days, the patient will no longer be eligible to receive treatment on this 
study.  
If the same Grade 3 or 4 non-hematological toxicity recurs and it is felt to be due to the study drug, the 
patient will no longer be eligible to receive pegylated interferon alfa-2b. 
5.2 Hematologic Toxicity 
The dose of Pegylated interferon will be reduced for any of the following toxicities: 
• Grade 4 decreased neutrophil count (neutropenia) > 5 days duration 
• Grade 4 decreased platelet count (thrombocytopenia) > 5 days duration 
• ≥ 2 platelet transfusions per cycle for platelet counts < 30,000/μL 
• ≥ 14 day delay in starting subsequent cycles due to low ANC (< 1,000/μL or low platelet count (less 
than 100,000/μL.) 
Patients who experience hematologic toxicity should have appropriate laboratory testing at least weekly 
until the toxicity has resolved. 
 
6.0 DRUG INFORMATION 
6.1 Pegylated Interferon (Pharmaceutical Information PEG-Intron™ , Other Names: peg-interferon alfa-
2b ) 


Protocol Vers   12-14-2018                           31 
 
Chemical Structure: PEG-INTRON™is a covalent conjugate of recombinant interferon alfa-2b with 
polyethylene glycol (PEG). It is derived using recombinant DNA technology on a genetically engineered 
Escherichia coli bacterium that contains an interferon gene from human leukocytes.  
Molecular weight: 31,000 daltons  
Manufactured by: Schering-Plough/ MERCK  
How supplied: PEG-INTRON™is a lyophilized powder supplied in 2 ml vials for subcutaneous use. Each 
vial contains 74 µg, 118.4 µg, 177.6 µg, or 222 µg of PEG-INTRON™, and 1.11 mg dibasic sodium 
phosphate  anhydrous, 1.11 mg monobasic sodium phosphate dihydrate, 59.2 mg sucrose and 0.074 mg 
polysorbate  80. Following reconstitution with 0.7 ml of supplied diluent (Sterile water for injection, 
USP), each vial contains PEG-INTRON™at strengths of 100 µg/ml, 160 µg/ml, 240 µg/ml, or 300 µg/ml, 
respectively.  
SYLATRON: 
Manufactured by: Schering-Plough/MERCK  
Preparation and Administration  
Reconstitute SYLATRON with 0.7 mL of Sterile Water for Injection, USP.  
Reconstitution 
of SYLATRON 
Single-Use 
Vials 
SYLATRON  
Single-Use  
Vial  
Diluent (Sterile 
Water for 
Injection, USP)  
 Deliverable     
Product and         
Volume  
            Final  
   Concentration  
200 mcg*  add  
0.7 mL  
=  
200 mcg 
in 0.5 mL  
40 mcg/0.1 mL  
300 mcg†  add  
0.7 mL  
=  
300 mcg 
in 0.5 mL  
60 mcg/0.1 mL  
600 mcg‡  add  
0.7 mL  
=  
600 mcg 
in 0.5 mL  
120 mcg/0.1 mL  
 
*Total vial content of SYLATRON is 296 mcg.  
†Total vial content of SYLATRON is 444 mcg.  
‡Total vial content of SYLATRON is 888 mcg. 
Swirl gently to dissolve the lyophilized powder. DO NOT SHAKE.  
• Visually inspect the solution for particulate matter and discoloration prior to administration. Discard if 
solution is discolored, cloudy, or if particulates are present.  
• Do not withdraw more than 0.5 mL of reconstituted solution from each vial.  
• Administer SYLATRON subcutaneously. Rotate injection sites.  
• If reconstituted solution is not used immediately, store at 2°-8°C (36°-46°F) for no more than 24 hours. 
Discard reconstituted solution after 24 hours. DO NOT FREEZE.  
 
Storage and Stability:  


Protocol Vers   12-14-2018                           32 
 
The reconstituted solution should be used immediately and cannot be stored for more than 24 hours at 
2-8° C. The reconstituted solution contains no preservative, is clear and colorless. Do not freeze. 
Administration:  Pegylated interferon will be administered subcutaneously once weekly, on the same 
day each week. Rotating sites. Guidelines for administration: 
Education to the parents/patient and or caregivers will be provided on how to measure and draw the 
adequate amount of medication and subcutaneous administration will be taught to the family. Keep 
refrigerated. Procedures for proper handling and disposal of hazardous/anticancer drugs should be 
considered. 
 Adverse reactions reported with INTERFERON ALFA  (Package insert)  
CNS: neurologic deficits, headache, decreased mental status, dizziness, impaired memory, impaired 
concentration, paresthesia, confusion, change in taste or smell, irritability, insomnia, anxiety, change in 
behavior, visual disturbance, seizures, gait disturbances, hallucinations, encephalopathy, psychomotor 
retardation, coma, stroke, transient ischemic attacks  
Psychiatric: agitation, manic behavior, psychotic reactions, depression, suicidal ideationFlu-like 
symptoms: fatigue, myalgia, arthralgia, fever, chills, asthenia, sweating, leg cramps, malaise  
Gastrointestinal: nausea, vomiting, diarrhea, anorexia, abdominal pain, flatulence, impaired digestion, 
gingival bleeding, pancreatitis, colitis, gastrointestinal hemorrhage, stomatitis, abdominal fullness, 
hypermotility, hepatitis, dysphasia  
Skin: injection site reaction, alopecia, hair change, rash, dry skin, pruritus, hematoma, psoriasis, eczema, 
seborrhea, bruising  
Pulmonary: dryness or inflammation of the oropharynx, epistaxis, rhinitis, sinusitis, coughing, dyspnea, 
pneumonitis  
Cardiovascular: rhythm disturbances, chest pain, hypotension, hypertension 
Laboratory: neutropenia, thrombocytopenia, anemia, elevated liver function tests, proteinuria.  
Other: conjunctivitis, menstrual irregularity, syncope, sexual dysfunction, coagulopathy, weight loss, 
night sweats, thyroid dysfunction, diabetes 
Frequency of Side Effects of Pegylated Interferon 
Likely or Common  
Happens to   21 to  100  
children  out of every 100 
Less Likely or Occasional 
Happens to  5 to 20  
children out of every 100  
Rare but Serious,  
Happens to less than 5 children out 
of every 100. 
 
• 
Injection 
site 
inflammation 
and 
reaction  
( 
bruise, 
itchiness, 
irritation) 
• 
flu-like syndrome 
(headache, 
malaise, 
 
• 
dry skin 
• 
pharyngitis 
• 
impaired concentration 
• 
confusion 
• 
dizziness 
• 
decrease neutrophil  
• 
decrease 
in 
platelet 
 
• 
dry mouth   
• 
sweating excessively 
• 
blurred vision/conjunctivitis  
• 
neuropsychiatric 
events, 
including suicide, suicidal and 
homicidal ideation, depression, 
aggressive behavior  


Protocol Vers   12-14-2018                           33 
 
fatigue, myalgia) 
• 
fever  
• 
alopecia 
• 
depression 
• 
anxiety/emotional   
lability/irrritability  
• 
joint pain 
• 
nausea/vomiting 
• 
muscle pain 
• 
insomnia 
• 
rigors 
• 
irritation of the liver 
• 
anorexia/decrease in 
appetite 
• 
 
counts 
• 
hypothyroidism 
• 
hyperthyroidism 
• 
Hyperglycemia 
• 
abdominal pain 
• 
bloody diarrhea 
• 
chest pain 
• 
weight loss 
• 
gingival bleeding 
• 
proteinuria 
• 
flushing 
 
• 
psychotic reactions 
• 
agitation/nervousness 
• 
hypotension, 
arrhythmia, 
tachycardia, 
• 
cardiomyopathy, angina pectoris, 
myocardial infarction 
• 
Dyspnea, pulmonary infiltrates, 
pneumonia, 
bronchiolitis 
obliterans, 
interstitial 
pneumonitis and sarcoidosis 
• 
pancreatitis 
• 
Development or exacerbation of 
autoimmune 
disorders 
(e.g. 
thyroiditis, rheumatoid arthritis, 
interstitial 
nephritis, 
systemic 
lupus  erythematosus, psoriasis) 
• 
hypersensitivity 
reactions/ 
allergic reactions 
• 
rash 
• 
may impair human fertility 
• 
menstrual disorder 
• 
ischemic colitis 
 
 
 
Drug Interactions (Package Insert).  
Drugs Metabolized by Cytochrome P-450:  When administering Pegylated interferon with medications 
metabolized by CYP2C8/9 (e.g., warfarin and phenytoin) or CYP2D6 (e.g., ondansetron, flecainide), the 
therapeutic effect of these substrates may be decreased. 
Methadone:  Pegylated interferon may increase methadone concentrations.  The clinical significance of 
this finding is unknown; however, patients should be monitored for signs and symptoms of increased 
narcotic effect. 
7.0 EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care. Minor 
unavoidable departures (up to 96 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable.   
 
 
 


Protocol Vers   12-14-2018                           34 
 
 
7.1   Required Clinical, laboratory and Disease Evaluations  
All baseline studies must be performed within 14 days prior to enrollment and MRI of brain and/or spine 
within 30 days prior to enrollment. Obtain other studies prior to start of subsequent cycles and as 
otherwise indicated. 
STUDIES TO BE OBTAINED 
Pre-study 
1 
(Baseline) 
Prior 
to 
Each 
Cycle 
Q2 
weeks 
Cycle 1 
Prior 
to 
cycle 
4,7,10,13 
16,19,22,25  
Every 
six 
months 
When patient is 
removed 
from 
protocol Therapy  
** 
History 
X 
X 
X 
 
 
X 
Physical Exam with neurological 
exam (Wt,  Ht and VS) 
X 
X 
X 
 
 
X 
Performance Status 
X 
X 
 
 
 
X 
CBC, platelets and differential 
X 
X 
X5 
 
 
X 
CMP, 
magnesium 
phosphorous, 
calcium, Uric acid 
X 
X 
X5 
 
 
X 
PT, PTT 
X 
 
 
 
 
 
AM cortisol, Free T4, TSH,   
(growth 
hormone 
if 
clinically 
indicated)  
X 
 
 
 
X 
X 
Urinalysis / urine dipstick 
X 
 
 
X 
 
X 
Urine or serum pregnancy test 
X2 
 
 
 
 
 
MRI of brain w/wo contrast 
X3 
 
 
X 
 
X 
MRI spine 
X4 
 
 
X6 
 
X 
LP  for CSF cytology  
X9 
 
 
X10 
 
 
Opthalmology Evaluation 7 
X 
 
 
 
X 
X 
QOL questionnaire8 
X 
 
 
X 
 
X 
Pegylated interferon  Diary  
 
X 
X 
 
 
X 
Assessment 
of 
clinical 
toxicity/adverse events 
 
 
 
 
 
X 
 
1-Must be performed within 14 days prior to receiving the study drug with the exception of MRI of brain 
and spine.  MRI of the brain and or spine can be done in within 30 days prior to enrollment.  
2-Required for all females of childbearing potential as a baseline study, then continue to follow 
institutional guidelines regarding pregnancy testing.   
3- With and without contrast; within 30 days prior to enrollment. 
4-For patients with a known history of spinal disease, within 30 days  prior to enrollment on the study or 
when it is clinically indicated by the treating physician. 
5-If no > Grade I toxicity during the previous cycle, then every month in subsequent cycles through cycle 
27. 


Protocol Vers   12-14-2018                           35 
 
6-For patients with history of spinal disease; obtained at the same time points as MRI brain until no 
evidence of disease on 2 consecutive spine MRIs. Also when patient is removed from protocol therapy.  
7-Opthalmology evaluation only needed for patients with optic pathway gliomas. (Sooner than interval 
designated if indicated by neuro-opthalmologist/opthalmologist) 
8- Children   younger than 7 years and older will complete the parent survey only. For any child older 
than 7 years will complete also the patient questionnaire for Quality of life. QOL questionnaires are only 
available for English speaking patients. They have not been validated in other languages.  
9- LP only if there is evidence of tumor dissemination on spine MRI.  
10-Repeat only if cytology showed tumor cells at study entry, until you have 2 consecutive negative 
cytologies.  
** To be completed when patient comes off therapy unless it has been completed within the last 14 
days and no toxicity greater than grade 1 was found.   
This table only includes evaluations necessary to answer the primary and secondary aims. Obtain 
other studies as indicated for good clinical care. 
 
History and Physical Examination: This should include signs and symptoms caused by the tumor/cancer, 
and determination of performance status or Lanski score.  Patients must have a baseline neurological 
exam and neurological exam at the start of each new cycle. Weight, height and VS must be recorded.  
Laboratory Evaluation: 
-Hematology: Complete blood count, differential and platelet count every 2 weeks during the first cycle. 
If the patient does not experience any >Grade 1 hematologic toxicity during the first cycle, a CBC can be 
performed every 4 weeks on subsequent  cycles, and as clinically indicated. If a patient experiences 
>Grade 1 hematologic toxicity (except for lymphopenia), they will continue to have weekly lab work until 
they have a cycle with no >Grade 1 toxicity. Following that cycle the lab work will be performed every 4 
weeks (+/- 5 days) and as clinically indicated until completion of therapy. If the patient remains on-study 
beyond this and is hematologically stable, the patient will require lab work prior to every cycle as long as 
there is no >Grade 1 hematologic toxicity.  
-Chemistries: CMP, magnesium, phosphorous, calcium and uric acid every other week during the first 
cycle. If the patient does not experience any >Grade 1 laboratory toxicity on the first cycle which is 
possibly, probably, or definitely related to Pegylated interferon, these can be performed every month on 
subsequent cycles, and as clinically indicated. If a patient experiences >Grade 1 laboratory toxicity they 
will continue to have weekly lab work until they have a cycle with no >Grade 1 toxicity. Following that 
cycle the lab work will be performed every 4 weeks and as clinically indicated until end of therapy.  
If the patient remains on-study beyond this, the patient will require lab work prior to every cycle as long 
as there are no >Grade 1 laboratory toxicities.  
-Calcium, phosphorous, magnesium and uric acid will be performed prior to each cycle and as clinically 
indicated.  
-PT and PTT will be obtained at a baseline. Obtain later on only if clinically indicated.  


Protocol Vers   12-14-2018                           36 
 
-Endocrine Function Tests: First morning cortisol, free T4, TSH every six months or sooner if clinically 
indicated.   Growth hormone testing to be done if clinically indicated. 
-Urinalysis or urine dipstick is acceptable.  Urinalysis will be obtained if urine dipstick is abnormal. If 
urine evaluation is normal, then check at the same time points as the brain MRI. 
-Urine Pregnancy Test or Serum Pregnancy Test: required for females of childbearing potential.  
Additional pregnancy test per institutional guidelines.  At Aflac, monthly pregnancy test for females of 
childbearing potential. 
 
Radiology:  
MRI of the brain/and or spine will be performed every 3 cycles throughout the duration of the 
treatment. Initial evaluation will be performed at the end of the cycle #3.  Patients with a history of 
spinal disease will undergo a spine MRI at the same time points until there is no evidence of disease on 2 
consecutive spine MRI’s. All brain MRIs will include, if possible, diffusion-weighted, dynamic-enhanced, 
dynamic susceptibility, DT-MRI, and other MR sequences in addition to the standard MR sequences. All 
MRI's will be reviewed and interpreted with the neuroradiologist.  
Quality Of Life Questionnaire:  
• 
We have choosen the Peds-FACT-Br: Pediatric - For patients with Brain cancer, ages 7 to 12 year old 
or  greater than 12 years. Additionally, we will include the parent QOL questionnaire.  There are 2 
versions, for patients younger than 12 years and for patients 12 years or older. To be administered 
prior to start therapy and q3 months at the same interval as MRIs. See appendix 2A, 2B, 2C and 2D. 
• 
QOL questionnaires are not available for non -English speaking patients and they have not been 
validated in other languages.  QOL questionnaires are not required for non-english speaking patients 
 
Post-Therapy Evaluation  
The following tests and procedures should be performed, if possible, at the time a patient comes off 
therapy, regardless of the reason for coming off therapy, unless the test or procedure has been 
performed in the past 14 days.  
• 
History and physical examination.  
• 
Performance status.  
• 
Assessment of clinical toxicity/adverse events.  
• 
Laboratory Assessment:  
o Complete blood count, differential and platelet count  
o SGPT (ALT), bilirubin (total and direct), BUN, creatinine, electrolytes, calcium,  
o Magnesium, phosphorus, uric acid.  
o Urinalysis 
• 
MRI of Brain and/or spine.  
• 
QOL questionnaire 
• 
Ophthalmology evaluation  
 
7.2  Follow-up 


Protocol Vers   12-14-2018                           37 
 
• 
See COG Late Effects Guidelines for recommended post treatment follow-up: 
http://www.survivorshipguidelines.org/ 
 
 
8.0  CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
8.1 Criteria for Removal from Protocol Therapy 
a) Progressive disease (see definition in Section 10.4). 
b) Significant toxicity at least possibly attributed to Pegylated interferon despite two dose reductions (as 
statedin Section 5.0). 
c) Refusal of further protocol therapy by patient/parent/guardian. 
d) Completion of 26 cycles of protocol therapy. 
e) Physician determines it is in patient’s best interest. 
f) Development of a second malignancy. 
g) Patient becomes pregnant while on study. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see 
below).  Follow-up data will be required unless consent was withdrawn. 
 
8.2 Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another treatment study with tumor therapeutic intent. 
d) Withdrawal of consent for any further data submission. 
e) The fifth anniversary of the date the patient was enrolled on this study. 
 
 
 
9.0 STATISTICAL CONSIDERATIONS 
 
9.1  Sample Size and Study Duration 
This study will enroll patient without NF-1 and patients with NF-1. Based on the established accrual 
goals and incidence of pediatric low grade gliomas 17 patients can be accrued within 36 months of 
protocol activation, given an average of 1 patient per 2.1 months.  Assuming 15% of patients are not 
evaluable or eligible, 20 patients total will be required to be enrolled on this study.  
 
9.2 Study Design 
The study is designed using Simon’s two stage optimal design with a power of 80% and an alpha error of 
5%. We assume an uninterested response rate of 5% and the promising response rate is 25%.In the first 
stage of the study, 9 eligible patients will be enrolled. If none responder among the 9 patients, the study 
terminates and treatment will be determined to have no improvement in the response rate. Otherwise, 
the study will continue with the second stage in which 8 additional eligible patients will be enrolled for a 
total of 17 eligible patients. At the end of total patient accrual, at least 3 of 17 eligible patients must 


Protocol Vers   12-14-2018                           38 
 
achieve response in order to consider the treatment interesting for further evaluation. Response is 
considered as either CR or PR or SD.  
 
Optimal Two Stage Design 
Optimum Design  
First Stage Sample Size (n1) 
9 
 
Upper Limit For 1st Stage Rejection of Drug (r1) 
0 
 
Maximum Sample Size (n) 
17 
 
Upper Limit for 2nd Stage Rejection of Drug (r) 
2 
 
Expected Sample Size If Response Probability = P0 
11.96 
 
Probability of Early Termination at P0 
0.63 
 
 
9.3 Methods of Analysis: 
 
9.3.1 End Points 
9.3.1.1          Primary End points: 
• 
Objective response: best response determined from the sequence of objective status 
described in the section 10 as response criteria.  
 
9.3.1.2          Secondary End Points 
• 
Time to treatment failure (Event free Survival EFS) the time from study enrollment to 
tumor progression, tumor recurrence, death from any cause or occurrence of a second 
malignant neoplasm. 
• 
Time to death (Overall survival OS) the time from study enrollment to death from any  
cause.  
 
9.4   Analysis  of  Efficacy 
 
Each patient will be classified according to their ‘best response’ for the purposes of analysis of 
treatment effect. A responder is defined as a patient who achieves a best overall response of CR or PR at 
any time on the study. If a patient achieves a PR or CR and later has progressive disease or relapse, then 
the patient will be counted as a responder. The response rate will be calculated as the ratio of the 
number of patients who demonstrate response (CR or PR) divided by the number of patients evaluable 
for response. All patients eligible for study who receive any study drug will be considered evaluable for 
response. Any patient who goes off protocol therapy for any reason (patient/parent/physician choice, 
adverse event profile, etc.) prior to the first response evaluation will be considered a non-responder.  
Disease progression will be based on the results of institutional review. Standard survival methods will 
be used for analysis of EFS and OS. Analyses include log rank tests and the product-limit (Kaplan-Meier) 
estimate for estimation of EFS and OS probability. 
 
 
9.5  Monitoring for Efficacy 
Patients will be treated with Pegylated interferon on a single arm.  We will closely monitor the first 9 
patients enrolled. The early stopping criterion and the decision regarding ultimate further interest in this 


Protocol Vers   12-14-2018                           39 
 
agent will be based on the number of objective responses and disease progressions.  If the early 
stopping rule is met for no responses in the first 9 patients, the trial will be closed.   
A true response rate of 5% is considered inadequate, whereas a true response rate of 25% would be 
sufficient for further interest in this agent. 
The study will be a 2-stage design, with 9 evaluable patients in the first stage and 8 additional  evaluable 
patients in the second stage (17 patients total) with decisions made as follows: 
 
Number of Evaluable Patients  
Results 
Decision  
 
Stage One:  
9 evaluable patients  
zero responders  
Terminate enrollment with the  
conclusion the regimen does not  
demonstrate sufficient disease 
control 
 
Stage Two 
8 evaluable patients  
3 responders 
Complete  the trial  with the   
conclusion the regimen does  
demonstrate sufficient disease 
control to proceed with further 
development. 
 
9.6   Monitoring for Toxicity 
“Toxic events” will be defined as one in which a patient has two dose reductions and then experiences 
another significant toxicity as defined in Section 5.0, irrespective of attribution. A two-stage stopping 
rule will be used to monitor for an excessive number of these toxic events. All patients described below 
must be evaluable for toxicity. All patients who receive at least one dose of Pegylated interferon will be 
evaluable for toxicity. A review of treatment feasibility and patient safety will be undertaken if we 
observe at least 2/9 or 4/17 toxic events. The rule will be met about 4% of the time if the true incidence 
of toxic event is 10%, and 90% of the time if the true incidence is 30%. 
 
9.7   Interim Monitoring of Toxic Death 
Toxic death is death predominantly attributable to treatment-related causes. The occurrence of toxic 
death at any time will be a primary endpoint for safety monitoring. Any toxic death on study will be 
reviewed with DSMB prior to continuing enrollment on study. The study will be stopped if there is one 
toxic deaths on study. 
 
9.8  Analysis of Toxicity 
Estimates will be obtained using life-table methods, with an event defined as the first occurrence of a 
primary toxicity. Time scale used in the time to first occurrence of a key acute and subacute toxicity is 
time in days since the start of therapy. Patients who have progression or recurrence of disease will be 
censored in these analyses. The rates of individual toxicities in each course of treatment, the number of 
patients who require a dose reduction and number of patients who come off protocol therapy due to 
toxicity will be summarized using standard descriptive statistical methods. To evaluate hematologic 
toxicity of long term Pegylated interferon administration adverse event data will be collected using 
CTCAE version 5.0 toxicity coding. Grade 3 or greater hematologic toxicities will be recorded per 
reporting period. 
 
9.9 Subject Accrual  


Protocol Vers   12-14-2018                           40 
 
Subjects of both genders, from all racial and ethnic groups are eligible for this study if they meet the 
criteria outlined in Section 3.2. To date, there is no information that suggests differences in drug 
metabolism or disease response would be expected in one group compared to another. Efforts will be 
made to extend this accrual to a representative population, but in this study, a balance must be struck 
between patient safety considerations and limitations on the number of individuals exposed to 
potentially ineffective treatments on the one hand and the need to explore gender and ethnic aspects of 
clinical research on the other hand. If differences in outcome that correlates to gender or to ethnic 
identity are noted, accrual may be expanded or additional studies may be performed to investigate 
those differences more fully.  
 
9.10 Radiographic Evaluation 
MRI of brain with and without contrast must be performed within 30 days prior to enrollment on the 
study. Patients will undergo baseline and follow-up imaging in the same scanner if possible. All patients 
will receive a standard MRI, unless contraindicated, performed on either the 1.5T or 3T scanner. (If MRI 
is contraindicated, patient cannot be enrolled). Patients undergoing MRI may also undergo additional 
MR sequences such as dynamic contrast-enhanced (DCE) or MRI, dynamic susceptibility contrast (DSC) 
MRI as time permits. These sequences are part of standard brain tumor protocols. Percent agreement 
between the sequences will be estimated as the number of follow-up scans in which the corresponding 
sequence agreed divided by the total number of follow-up scans. Standard error will be estimated by 
use of the bootstrap method 26 to account for the correlated dependent response data, and these 
values will be used to estimate the 95% confidence intervals. The event-free survival distributions will be 
compared across the MR sequences, with a proportional hazards model developed for dependent 
survival data by Wei et al (1989). 
 
9.11 Ethical Issues  
Rationale for Subject Selection: Subject accrual for the study is available to both genders, racial and 
ethnic groups.  No groups are being excluded from participation in the trial. Some of the subjects could 
become cognitively impaired as a consequence of, for example, their brain tumor. Patients who are 18 
years old or older will be offered the opportunity to assign DPA prior to study entry. Adults who are 
cognitively impaired prior to study entry and who have not previously assigned DPA to a family member 
or friend will not be eligible for the trial, because they cannot give informed consent.  
9.12  Participation of Children   
Patients <21 years of age will be entered on this protocol. The primary objective of this trial is to 
determine if there is evidence of responses for patients receiving Pegylated interferon. The interferons 
have been extensively studied in both adults and children, and the side effects are well-described. 
Although pegylated interferon alpha-2b has not been extensively studied in children, we will use doses 
of interferon alpha-2b previously utilized in clinical trials, therefore we expect to see similar toxicity and 
similar side effects.  The trial will be conducted by pediatric oncologists who have extensive experience 
in performing investigational drug trials in children. Patients will be cared for in the Aflac Cancer and 
Blood Disorder Center. 
9.13  Risks and Benefits  


Protocol Vers   12-14-2018                           41 
 
Patients eligible for this trial are less than 21 years old. The primary risk to patients participating in this 
research study is from toxicity of pegylated interferon alfa-2b The protocol provides for detailed and 
careful monitoring of all patients to assess for toxicity. Patients will be treated with therapeutic intent 
and response to the therapy will be closely monitored. Patients will also be at risk from the MRI contrast 
agent, Gd-DTPA ( gadolinium). The risks of Gd-DTPA are well-defined and consist primarily of nausea. 
Allergic reactions are rare. The potential benefits from pegylated interferon alpha-2b are disease 
stabilization or shrinkage, a reduction in symptoms caused by the tumor/cancer, and prolonged survival 
and the potential to avoid and or delay radiation. Therefore, this protocol involves greater than minimal 
risk to children, but presents the potential for direct benefit to individual subjects.  
 
 
10.0 EVALUATION CRITERIA 
 
10.1 Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 5.0 of the CTCAE of the National Cancer Institute (NCI) for toxicity and 
performance reporting. A copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Referenc
e_5x7.pdf 
 
Please note: ‘CTCAE v5.0’ is understood to represent the most current version of CTCAE v5.0 as 
referenced on the CTEP website  
 
10.2 Methodology to Determine Tumor Measurement 
All axial images should be obtained in a plane parallel to a line intersecting the bottom of the genu and 
of the splenium of the corpus callosum (modified AC-PC line) - to assure consistency of imaging plane. 
Coronal images should be obtained perpendicular to the axial images. 
 
1) DAx TI, whole brain, 12 directions.2) Sagittal T1 weighted MP_RAGE (TR/TI 2300/900) 
3 Ax T2 weighted  (TR ~4500, TE ~75) 
4) 3D Coronal FLAIR (TR/TI 4800/1650) 
5 Coronal 2D, fat saturated TSE through the orbits and chiasm (TR ~3,500, Te ~80) 
6 Axial 2d, fat saturated TSE through the orbits and chiasm (TR ~3,500, Te ~80) 
Post-Contrast 
7) Axial, whole brain SPGR (TR/TE ~) 
8) Coronal 2d, fat saturated TSE through the orbits and chiasm (TR ~3,500, Te ~80) 
9) Axial 2d, fat saturated TSE through the orbits and chiasm (TR ~3,500, Te ~80) 
 
Series 5 and 8 should have the same slice locations. 
Series 6 and 9 should have the same slice locations. 
 
  
10.3   Tumor measurement 
Given the complexity of JPA/ OPG, the tumor size/response will be assessed in different segments: 
1. Optic nerve (right, left) 


Protocol Vers   12-14-2018                           42 
 
2. Chiasm /hypothalamus 
3. Brain parenchyma / retrochiasmatic visual pathways (optic tracts, optic radiations, internal capsule, 
posterior fossa) (right/left). 
 
Therefore, up to 5 measurements may be necessary. 
1. Longest diameter of target lesion(s) measured from the axial plane or the plane in which the aspect of 
the tumor is best seen or measured, provided the same plane is used in follow ups. 
 
2. The longest measurement of the tumor (or width, W) should be determined. 
 
3. The perpendicular measurements (transverse (T) measurement-perpendicular to the width in the 
selected plane. The length (L) – tumor extent in the plane perpendicular to the selected plane will not be 
used for measurement purpose. 
 
4. The lower limit of the target lesion(s) should be at least twice the thickness of the slices showing the 
tumor to decrease the partial volume effect (e.g. 8 mm lesion for a 4 mm slice). 
 
5. An automated tool (OncoTreat) will be employed to evaluate how the values obtained with this tool 
compare with the manually derived values. The manually derived values will be the measurements used 
for the study.  
 
 
10.4   Determination of tumor progression/response. 
 
Progressive disease 
 
Any patient with clinical or radiographic evidence of progressive disease following any treatment 
cycle will no longer receive pegylated interferon alfa-2b (see Section 5.1).  Radiographic progression 
is defined as appearance of new tumors or an increase in any previously measurable lesion by ≥25% 
in the product of the two longest perpendicular diameters or by 40% in the product of the three 
diameters. The preferred method for tumor measurement is to use the 3 diameters when available.   
If possible, tumor progression should be documented by the appropriate radiological study. For patients 
who develop worsening neurological symptoms, attempts should be made to distinguish progressive 
disease from other causes prior to removing the patient from the study 
Determination of tumor response or progression will be based on the pre-study baseline scan 
performed closest to time of study entry. Progressive disease will be defined based on the comparison 
of the baseline scan to the scan demonstrating best response. 
 
 
1. The amount of tumor enhancement is quite variable in LGGs from one scan to the next. 
Therefore, tumor response/progression will not solely be determined by change in the amount of 
enhancing disease on post contrast T1 images. Measurable change in size/extent must be present on 
FLAIR/T2 images, or on pre-contrast T1 images. 
 


Protocol Vers   12-14-2018                           43 
 
2. Development of new disease or progression in any established lesions is considered progressive 
disease, regardless of response in other lesions – e.g. when multiple lesions show opposite responses, 
the progressive disease takes precedence. 
 
Note: 
• 
CT scans should not be used to determine response. For MRI imaging, the longest diameter can be 
measured from the axial plane or the plane in which the tumor is best seen or measured, provided 
the same plane and MR sequence is used in follow ups. 
 
• 
The cystic components of a tumor are considered in separate tumor measurements.  See options 
below. 
 
Options: 
• 
If the cyst/necrosis is eccentric, the W, T and L of the solid portion should be measured, the 
cyst/necrosis excluded from measurement. 
• 
If the cyst/necrosis is central but represents a small portion of the tumor (<25%), disregard and 
measure the whole lesion. 
• 
If the cyst/necrosis is central but represents a large portion of the tumor, identify a solid aspect of 
the mass that can be reproducibly measured. 
• 
Leptomeningeal tumor spread is usually not a target lesion, and usually cannot be measured 
accurately. Presence and location of leptomeningeal tumor spread should be noted, change in 
extent/thickness assessed on follow up studies. 
• 
For patients with large cystic components (>25%): One cystic component should be identified in the 
baseline scan. It should be measured separately from the solid component.  It should be measured 
in 3 dimensions in the best sequence likely the T2 sequences.  (L x T x W).  
 
 
10.5   Overall Response Assessment 
The overall response assessment takes into account response in both target and non-target lesion, and 
the appearance of new lesions, where applicable, according to the criteria described in the table below. 
The overall response assessment is shown in the last column, and depends on the assessments of target, 
non-target, and new lesions in the preceding columns. 
 
Target 
Lesions 
 
Non-target 
Lesions 
 
New Lesions 
 
Overall 
Response 
 
CR 
CR 
NO 
CR 
CR 
IR/SD 
NO 
PR 
PR 
NON-PD 
NO 
PR 
CR OR PR 
NON-PD 
NO 
PR 
SD 
NON-PD 
NO 
SD 


Protocol Vers   12-14-2018                           44 
 
PD 
ANY 
YES OR NO 
PD 
ANY 
PD 
YES OR NO 
PD 
ANY 
ANY 
YES 
PD 
  
Abbreviations:  CR: complete response; IR: incomplete response, PD: progressive disease; PR: partial 
response; SD; stable disease. 
The section that follows will discuss the selection and evaluation of each of these types of lesions.  
 
 
10.6 Selection of Target and Non-Target Lesions 
 
1. For most CNS tumors, only one lesion/mass is present and therefore is considered a“target” for 
measurement/follow up to assess for tumor progression/response. 
 
2. If multiple measurable lesions are present, up to 5 should be selected as “target” lesions. Target 
lesions should be selected on the basis of size and suitability for accurate repeated measurements. All 
other lesions will be followed as non-target lesions (including CSF positive for tumor cells). 
 
3. The lower size limit of the target lesion(s) should be at least twice the thickness of the slices showing 
the tumor to decrease the partial volume effect (e.g. 8 mm lesion for a 4 mm slice). 
 
4. Any change in size of non-target lesions should be noted, though does not need to be measured. 
 
10.7 Response Criteria for Target Lesions: 
 
Response criteria are assessed in 3 dimensions – the product of L x W x T. An elliptical model volume 
(=0.5L x W x T) is used. 
To assess response/progression, the ratio is calculated:  
 
L x W x T (current scan) / L x W x T (reference scan) 
 
Development of new disease or progression in any established lesions is considered progressive disease, 
regardless of response in other lesions – e.g. when multiple lesions show opposite responses, the 
progressive disease takes precedence. Response Criteria for 3-dimensional target lesions: 
 
Complete Response (CR): Disappearance of all target lesions. 
 
Partial response (PR): ≥ 65% decrease in the sum of the products of the three perpendicular diameters 
of all target lesions (up to 5), taking as reference the initial baseline measurements. 
 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of the three perpendicular 
diameters of all target lesions to qualify for PR (taking as reference the initial baseline measurements), 
nor sufficient increase in a single target lesion to qualify for PD, (taking as reference the smallest disease 
measurement since the treatment started). 
 


Protocol Vers   12-14-2018                           45 
 
Progressive Disease (PD): 40% or more increase in the product of perpendicular diameters of ANY target 
lesion, taking as reference the smallest product observed since the start of treatment, or the 
appearance of one or more new lesions. 
In the rare circumstance that the length of a lesion cannot be determined, then comparison of 2 
dimensional measurements, T x W (product of the longest diameter and its longest perpendicular 
diameter) can be used. 
 
Response Criteria for 2-dimensional target lesions: 
 
Complete Response (CR): Disappearance of all target lesions. 
 
Partial response (PR): ≥50% decrease in the sum of the products of the two 
perpendicular diameters of all target lesions (up to 5), taking as reference the initial baseline 
measurements. 
 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of the two perpendicular 
diameters of all target lesions to qualify for PR (taking as reference the initial baseline measurements), 
nor sufficient increase in a single target lesion to qualify for PD, (taking as reference the smallest disease 
measurement since the treatment started). 
 
Progressive Disease (PD): 25% or more increase in the product of perpendicular 
diameters of ANY target lesion, taking as reference the smallest product observed since the start of 
treatment, or the appearance of one or more new lesions. 
 
Local progression is defined as progression of known residual tumor or the appearance of tumor at 
known prior sites of disease that were at some point without evidence of disease. Distant progression is 
defined as the appearance of tumor at sites other than known prior sites of disease. Distant progression 
most often occurs in the subarachnoid space and may occur at any point within the neuraxis. Although 
rare, extra- CNS metastasis represents distant failure. Combined local and distant progression is defined 
when evaluation of the entire neuraxis reveals local and distant progression. 
 
10.8 Response Criteria for Non-target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions. 
 
Incomplete Response/Stable Disease (IR/SD): The persistence of one or more non-target lesions. 
 
Progressive Disease (PD): The appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. 
 
Also as part of the response evaluation, for patients who have an omaya reservoir for the cystic part and 
who clinically required omaya taps, we will record the frequency of the taps and the amount of the fluid 
removed from the omaya reservoir. 
10.9 Retrospective Response Review 
MRI imaging for all patients on study will undergo retrospective central review following the completion 
of treatment. 


Protocol Vers   12-14-2018                           46 
 
11.0 ADVERSE EVENT REPORTING REQUIREMENTS 
11.1 Purpose 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done 
to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies 
using similar agents. 
 
11.2 Reporting Adverse Events 
This study will be conducted in compliance with the Aflac Cancer & Blood Disorders Service Data Safety 
Monitoring Plan for Phase 1 and 2 studies. In brief, the role of the Data and Safety Monitoring Board is 
to protect the interests of patients and the scientific integrity for all Phase 1 and 2 studies. The DSMB 
consists of 6 members including a chair, a pharmacist, and at least one external member. The DSMB 
meets on a regular basis to review current study results, as well as data available to the DSMB from 
other related studies. The DSMB will provide recommendations for each study reviewed to change the 
study or to continue the study unchanged. Data and Safety Board reports for institutional review boards 
will be prepared. The Principal Investigator assumes responsibility for assuring that the study is carried 
out in accordance with the DSMB. 
 
 
Adverse Event Reporting 
 
Serious adverse event (SAE) or reaction is any untoward medical occurrence (including an abnormal 
laboratory finding) that at any dose: results in death, is life-threatening, requires inpatient 
hospitalization or prolongation of existing hospitalization, results in persistent or significant 
disability/incapacity, is a congenital anomaly/birth defect, or requires medical or surgical intervention in 
order to prevent one of the previous listed outcomes. Medical and scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in other situations, such as important 
medical events that may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in 
the definition above. These should also usually be considered serious. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; or development of 
drug dependency or drug abuse. 
 
Unexpected adverse drug experience means any adverse drug experience, the specificity or severity of 
which is not consistent with the current investigator brochure; or, if an investigator brochure is not 
required or available, the specificity or severity of which is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as amended. 
“Unexpected” as used in this definition, refers to an adverse drug experience that has not been 
previously observed (e.g., included in the investigator brochure) rather than from the perspective of 
such experience not being anticipated from the pharmacological properties of the pharmaceutical 
product. 
 
Attribution: The investigator will be asked to document his/her opinion of the relationship of the event 
to study medication as follows: 
 
The categories are: 
Definite: The adverse event is clearly related to the study drug. 
Probable: The adverse event is most likely related to the study drug. 


Protocol Vers   12-14-2018                           47 
 
Possible: The adverse event may be related to the study drug. 
Unlikely: The adverse event is doubtfully related to the study drugs. 
Unrelated: The adverse event is clearly not related to the study drug. 
 
For an SAE,  the clinical trials coordinator in the Clinical research office should be notified via phone or 
email within 24 hours of the study personnel becoming aware of the event, and she will notify the 
DSMB. A copy of the completed Serious Adverse Event form must also be sent to Shelley Mays within 3 
working days after the incident.  
 
Copies of all serious adverse event reports will be kept on file in the Clinical Research Office of the 
Cancer Center. 
 
12.0 RECORDS AND REPORTING 
Refer to separate packet for reporting and submission guidelines. 
 
12.1   Protocol amendments, or changes in study conduct 
 
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed by IRB.   
Amendments significantly affecting the safety of subjects, the scope of the investigation or the scientific 
quality of the study require additional approval by the IRB. 
 
Examples of amendments requiring such approval are: 
1. Increases in drug dose or duration of exposure of subjects 
2. Significant changes in the study design (e.g. addition or deletion of a control group) 
3. Increases in the number of invasive procedures. 
4. Addition or deletions of a test procedure required for monitoring of safety. 
 
These requirements for approval should in no way prevent any immediate action from being taken by 
the investigator in the interests of preserving the safety of all patients included in the trial.  
If an immediate change to the protocol is felt to be necessary by the investigator, the IRB must be  
informed immediately.  
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB approval but the IRB must be kept informed of such administrative changes.  
 
Examples of administrative changes not requiring formal protocol amendments and IRB approval 
include: 
1. Changes in the staff used to monitor trials. 
2. Minor changes in the packaging or labeling of study drug. 
12.2 Protocol Deviation (NIH Definition): A protocol deviation is any change, divergence, or departure 
from the study design or procedures of a research protocol that is under the investigator’s control and 
that has not been approved by the IRB.  
12.3 Protocol Violation (NIH Definition): Any change, divergence, or departure from the study 
procedures in an IRB-approved research protocol that has a major impact on the subject’s rights, safety, 
or well-being and/or the completeness, accuracy or reliability of the study data.  
 


Protocol Vers   12-14-2018                           48 
 
APPENDIX  1. Performance Status Criteria. 
 
 
 
 
 
 
 


Protocol Vers   12-14-2018                           49 
 
 
Appendix 2A 
Pediatric Functional Assessment of Cancer Therapy – Brain Tumor Survivor (Version 2) 
Patient Version: Age 7-12 (Grade School) 
 
Please tell me during the past 4 weeks, how true each of the following statements has been for you.   
Please mark only one number per line when you answer. 
 
Physical Well-being 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
pP1 I lose my balance or fall down easily ......................................... 
 
0 
1 
2 
3 
4 
pP2 I have trouble getting myself dressed .............................................
 
0 
1 
2 
3 
4 
pP3
a 
I have trouble running like other people  
 
 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
pP4 I get tired easily ...............................................................................
 
0 
1 
2 
3 
4 
pP5 
My arms or legs are weak  
 
 
0 
1 
2 
3 
4 
 
pP6 
I get ill easily ....................................................................................
 
0 
1 
2 
3 
4 
 
I have trouble writing with a pen or pencil 
0 
0 
1 
2 
3 
4 
 
 
Emotional Well-Being & Illness Experience 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
pE1 
I feel happy ......................................................................................
 
0 
1 
2 
3 
4 


Protocol Vers   12-14-2018                           50 
 
pE2 
When I try to do something, I usually believe I will do it well .........
 
0 
1 
2 
3 
4 
pE3 
The illness experience makes me a stronger person ......................
 
0 
1 
2 
3 
4 
pE4 
The illness experience has taught me to appreciate life .................
 
0 
1 
2 
3 
4 
pE5
a 
I often feel that other children are better than me ........................
 
0 
1 
 
2 
 
3 
 
4 
 
pE6 
I worry about being sick again .........................................................
 
0 
 
1 
 
2 
 
3 
 
4 
 
pE7 
I often switch from good moods to bad moods 0 
0 
1 
2 
3 
4 
pE8 
I worry when I go back to the hospital or clinic  
0 
1 
2 
3 
4 
pE9 
I get nervous (frightened) easily 
 
0 
1 
2 
3 
4 
pE1
0
I worry about having a good life in the future  
0 
1 
2 
3 
4 
 
 


Protocol Vers   12-14-2018                           51 
 
 
Social and family Well-Being 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
pSF
1a 
Other people pick on (tease) me 
0 
 
0 
1 
2 
3 
4 
pSF
2a 
I think I have fewer friends than others 0 
 
0 
1 
2 
3 
4 
pSF
3a 
Other people avoid hanging out with me because of my illness 
history 0 
 
0 
1 
2 
3 
4 
pSF
4 
I feel lonely ..........................................................................................
 
0 
1 
2 
3 
4 
pSF
5a 
I WOULD RATHER DO SOMETHING BY MYSELF THAN WITH OTHER PEOPLE 
0 
 
0 
1 
2 
3 
4 
 
 
Additional Concerns 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
pB
1 
(ii) I am bothered by being shorter than other people my 
age 
0 
 
0 
 
1 
 
2 
 
3 
 
4 
 
pB
2 
I am bothered by being unable to see well ......................................
 
0 
1 
2 
3 
4 
pB
3 
I am bothered by being unable to hear well ....................................
 
0 
1 
2 
3 
4 
pB
4 
I am bothered by headaches ............................................................
 
0 
1 
2 
3 
4 
pB
5 
When I speak, people have trouble understanding me 0 
 
0 
1 
2 
3 
4 


Protocol Vers   12-14-2018                           52 
 
pB
6 
I need to work harder than other people to get my school work 
done ..................................................................................................
 
0 
1 
2 
3 
4 
pB
7 
My grades are worse than they were before I was sick ...................
 
0 
1 
2 
3 
4 
pB
8 
I forget things easily .........................................................................
 
0 
1 
2 
3 
4 
pB
9 
It is hard for me to concentrate in school ........................................
 
0 
1 
2 
3 
4 
pB
10 
I have to read things several times so I can understand them ........
 
0 
 
1 
 
2 
 
3 
 
4 
 
pB
11 
When I play games or sports, I react more slowly than most 
people my age ..................................................................................
 
0 
1 
2 
3 
4 
pB
12 
(iii) It is hard for me to find the right words to say what I 
mean 
0 
1 
 
2 
 
3 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Vers   12-14-2018                           53 
 
Appendix 2B. 
Pediatric Functional Assessment of Cancer Therapy – Brain Tumor Survivor (version 2) 
Patient Version (age 12 years and older) 
 
Please tell me during the past 4 weeks, how true each of the following statements has been for you.   
Please mark only one number per line when you answer. 
 
Physical Well-being 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
pP1 I lose my balance or fall down easily ......................................... 
 
0 
1 
2 
3 
4 
pP2 I have trouble getting myself dressed .............................................
 
0 
1 
2 
3 
4 
 
pP3
a 
I have trouble running like other people  
 
 
 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
pP4 I get tired easily ...............................................................................
 
0 
1 
2 
3 
4 
pP5 
My arms or legs are weak  
 
 
0 
1 
2 
3 
4 
 
pP6 
I get ill easily ....................................................................................
 
0 
1 
2 
3 
4 
 
I have trouble writing with a pen or pencil 
0 
0 
1 
2 
3 
4 
 
 
Emotional Well-Being & Illness Experience 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
pE1 
I feel happy ......................................................................................
 
0 
1 
2 
3 
4 
pE2 
When I try to do something, I usually believe I will do it well .........
 
0 
1 
2 
3 
4 


Protocol Vers   12-14-2018                           54 
 
pE3 
The illness experience makes me a stronger person ......................
 
0 
1 
2 
3 
4 
pE4 
The illness experience has taught me to appreciate life .................
 
0 
1 
2 
3 
4 
pE5
a 
I often feel that other people are better than me ..........................
 
   0 
1 
 
2 
 
3 
 
4 
 
pE6 
I worry about being sick again .........................................................
 
0 
 
1 
 
2 
 
3 
 
4 
 
pE7 
I often switch from good moods to bad moods 0 
0 
1 
2 
3 
4 
pE8 
I worry when I go back to the hospital or clinic  
0 
1 
2 
3 
4 
pE9 
I get nervous (frightened) easily 
 
0 
1 
2 
3 
4 
pE1
0
I worry about having a good life in the future  
0 
1 
2 
3 
4 
pE1
1a
I worry about being able to date because of my illness history
0 
1 
2 
3 
4 
pE1
2a 
I worry about being able to go to college because of my illness 
history  
0 
1 
2 
3 
4 
pE1
3a 
I worry about getting a job to support myself because of my 
illness history  
0 
1 
2 
3 
4 
 
 
Social and Family Well-Being 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
pSF
1a 
Other people pick on (tease) me 
0 
 
0 
1 
2 
3 
4 
pSF
2a 
I think I have fewer friends than others 0 
 
0 
1 
2 
3 
4 
pSF
3a 
Other people avoid hanging out with me because of my illness 
history 0 
 
0 
1 
2 
3 
4 


Protocol Vers   12-14-2018                           55 
 
pSF
4 
I feel lonely ..........................................................................................
 
0 
1 
2 
3 
4 
pSF
5a 
I WOULD RATHER DO SOMETHING BY MYSELF THAN WITH OTHER PEOPLE 
0 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
 
 
Additional Concerns 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
pB
1 
(ii) I am bothered by being shorter than other people 
 
0 
 
0 
 
1 
 
2 
 
3 
 
4 
 
pB
2 
I am bothered by being unable to see well ......................................
 
0 
1 
2 
3 
4 
pB
3 
I am bothered by being unable to hear well ....................................
 
0 
1 
2 
3 
4 
pB
4 
I am bothered by headaches ............................................................
 
0 
1 
2 
3 
4 
pB
5 
When I speak, people have trouble understanding me 0 
 
0 
1 
2 
3 
4 
pB
6 
I need to work harder than other people to get my school work 
done ..................................................................................................
 
 
0 
 
1 
 
2 
 
3 
 
4 
pB
7 
My grades are worse than they were before I was sick ...................
 
0 
1 
2 
3 
4 
pB
8 
I forget things easily .........................................................................
 
0 
1 
2 
3 
4 


Protocol Vers   12-14-2018                           56 
 
pB
9 
It is hard for me to concentrate in school ........................................
 
0 
1 
2 
3 
4 
pB
10 
I have to read things several times so I can understand them ........
 
0 
 
1 
 
2 
 
3 
 
4 
 
pB
11 
When I play games or sports, I react more slowly than most 
people my age ..................................................................................
 
 
0 
 
1 
 
2 
 
3 
 
4 
pB
12 
(iii) It is hard for me to find the right words to say what I 
mean 
0 
1 
 
2 
 
3 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Vers   12-14-2018                           57 
 
Appendix 2C. 
Pediatric Functional Assessment of Cancer Therapy – Brain Tumor Survivor (Version 2) 
(iv) Parent Version: Age 12 - adults (High School and Older)  
 
Please tell me during the past 4 weeks, how true each of the following statements has been for your child.   
Please mark only one number per line when you answer. 
 
 
Physical Well-being 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
pP1 My child loses balance or falls down easily ................................ 
 
0 
1 
2 
3 
4 
pP2 My child has trouble getting dressed on his/her own.....................
 
0 
1 
2 
3 
4 
 
pP3
a 
My child has trouble running like other people   
 
 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
pP4 My child gets tired easily .................................................................
 
0 
1 
2 
3 
4 
pP5 
My child’s arms or legs seem weak  
 
 
0 
1 
2 
3 
4 
 
pP6 
My child gets ill easily ......................................................................
 
0 
1 
2 
3 
4 
 
My child has trouble writing with a pen or pencil 
0 
 
0 
1 
2 
3 
4 
 
 
Emotional Well-Being &Illness Experience 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
pE1 My child seems happy .....................................................................
0 
1 
2 
3 
4 


Protocol Vers   12-14-2018                           58 
 
pE2 When my child tries to do something, s/he usually believes 
s/he will do it well............................................................................
0 
1 
2 
3 
4 
pE3 The illness experience makes my child a stronger person ..............
0 
1 
2 
3 
4 
pE4 The illness experience has taught my child to appreciate life ........
0 
1 
2 
3 
4 
pE5
a 
My child often feels inferior to other people ..................................    0 
1 
 
2 
 
3 
 
4 
 
pE6 My child worries about getting another cancer/tumor ..................
0 
 
1 
 
2 
 
3 
 
4 
 
pE7 
My child is moody or irritable 0 
0 
1 
2 
3 
4 
pE8 
My child worries when we go back to the hospital or clinic
 
 
0 
1 
2 
3 
4 
pE9 
My child gets nervous (frightened) easily 
 
0 
1 
2 
3 
4 
 
pE1
0 
My child worries about having a good life in the future  
0 
1 
2 
3 
4 
pE1
1a 
My child worries about being able to have a girlfriend or 
boyfriend because of his/her illness history 
 
0 
1 
2 
3 
4 
pE1
2a 
My child worries about being able to go to college because of 
his/her illness history  
0 
 
1 
 
2 
 
3 
 
4 
 
pE1
3a 
My child worries about getting a job because of his/her illness 
history  
0 
1 
2 
3 
4 
 
 
Social and Family Well-Being 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
pSF
1a 
Other people pick on (tease) my child 0 
 
0 
1 
2 
3 
4 


Protocol Vers   12-14-2018                           59 
 
pSF
2a 
My child has fewer friends than others 0 
 
0 
1 
2 
3 
4 
pSF
3a 
Other people avoid hanging out with my child because of his 
or her illness history 
0 
 
0 
1 
2 
3 
4 
pSF
4 
My child seems lonely ......................................................................
 
0 
1 
2 
3 
4 
pSF
5a 
MY CHILD PREFERS TO DO SOMETHING ALONE 
0 
 
0 
1 
2 
3 
4 
 
 
 
Additional Concerns 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
pB
1 
My child is bothered by being shorter than his/ her peers ................. 
 
0 
 
1 
 
2 
 
3 
 
4 
pB
2 
My child is bothered by poor vision .................................................... 
0 
1 
2 
3 
4 
pB
3 
My child is bothered by poor hearing ................................................. 
0 
1 
2 
3 
4 
pB
4 
My child is bothered by headaches ..................................................... 
0 
1 
2 
3 
4 
pB
5 
My child’s speech is hard for others to understand ............................ 
0 
1 
2 
3 
4 
pB
6 
My child needs to work harder than his/ her peers to get school 
work done ............................................................................................ 
 
0 
 
1 
 
2 
 
3 
 
4 
pB
7 
My child’s school performance is worse than it was before s/he 
was diagnosed ..................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 


Protocol Vers   12-14-2018                           60 
 
pB
8 
My child forgets things easily .............................................................. 
0 
1 
2 
3 
4 
pB
9 
It is hard for my child to concentrate in school ................................... 
0 
1 
2 
3 
4 
pB
10 
My child has to read things several times so s/he can understand 
them .................................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
pB
11 
When my child plays games or sports, s/he reacts more slowly 
than his/ her peers .............................................................................. 
 
0 
 
1 
 
2 
 
3 
 
4 
pB
12 
My child has difficulty using the right words ...................................... 
0 
1 
 
2 
 
3 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Vers   12-14-2018                           61 
 
 
Appendix 2D. 
Pediatric Functional Assessment of Cancer Therapy – Brain Tumor Survivor (Version 2) 
Parent Version: Age  less than  12 years old  
 
Please tell me during the past 4 weeks, how true each of the following statements has been for your child.   
Please mark only one number per line when you answer. 
 
 
Physical Well-being 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
pP1 My child loses balance or falls down easily ................................ 
 
0 
1 
2 
3 
4 
pP2 My child has trouble getting dressed on his/her own.....................
 
0 
1 
2 
3 
4 
 
pP3
a 
My child has trouble running like other people   
 
 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
pP4 My child gets tired easily .................................................................
 
0 
1 
2 
3 
4 
pP5 
My child’s arms or legs seem weak  
 
 
0 
1 
2 
3 
4 
 
pP6 
My child gets ill easily ......................................................................
 
0 
1 
2 
3 
4 
 
My child has trouble writing with a pen or pencil 
0 
 
0 
1 
2 
3 
4 
 
 
Emotional Well-Being &Illness Experience 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 


Protocol Vers   12-14-2018                           62 
 
pE1 My child seems happy .....................................................................
0 
1 
2 
3 
4 
pE2 When my child tries to do something, s/he usually believes 
s/he will do it well............................................................................
0 
1 
2 
3 
4 
pE3 The illness experience makes my child a stronger person ..............
0 
1 
2 
3 
4 
pE4 The illness experience has taught my child to appreciate life ........
0 
1 
2 
3 
4 
pE5
a 
My child often feels inferior to other people ..................................    0 
1 
 
2 
 
3 
 
4 
 
pE6 My child worries about getting another cancer/tumor ..................
0 
 
1 
 
2 
 
3 
 
4 
 
pE7 
My child is moody or irritable 0 
0 
1 
2 
3 
4 
pE8 
My child worries when we go back to the hospital or clinic
 
 
0 
1 
2 
3 
4 
pE9 
My child gets nervous (frightened) easily 
 
0 
1 
2 
3 
4 
 
pE1
0 
My child worries about having a good life in the future  
0 
1 
2 
3 
4 
pE1
1a 
My child worries about being able to have a girlfriend or 
boyfriend because of his/her illness history 
 
0 
1 
2 
3 
4 
pE1
2a 
My child worries about being able to go to college because of 
his/her illness history  
0 
 
1 
 
2 
 
3 
 
4 
 
pE1
3a 
My child worries about getting a job because of his/her illness 
history  
0 
1 
2 
3 
4 
 
 
Social and Family Well-Being 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
pSF
1a 
Other people pick on (tease) my child 0 
 
0 
1 
2 
3 
4 


Protocol Vers   12-14-2018                           63 
 
pSF
2a 
My child has fewer friends than others 0 
 
0 
1 
2 
3 
4 
pSF
3a 
Other people avoid hanging out with my child because of his 
or her illness history 
0 
 
0 
1 
2 
3 
4 
pSF
4 
My child seems lonely ......................................................................
 
0 
1 
2 
3 
4 
pSF
5a 
MY CHILD PREFERS TO DO SOMETHING ALONE 
0 
 
0 
1 
2 
3 
4 
 
 
 
Additional Concerns 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
pB
1 
My child is bothered by being shorter than his/ her peers ................. 
 
0 
 
1 
 
2 
 
3 
 
4 
pB
2 
My child is bothered by poor vision .................................................... 
0 
1 
2 
3 
4 
pB
3 
My child is bothered by poor hearing ................................................. 
0 
1 
2 
3 
4 
pB
4 
My child is bothered by headaches ..................................................... 
0 
1 
2 
3 
4 
pB
5 
My child’s speech is hard for others to understand ............................ 
0 
1 
2 
3 
4 
pB
6 
My child needs to work harder than his/ her peers to get school 
work done ............................................................................................ 
 
0 
 
1 
 
2 
 
3 
 
4 
pB
7 
My child’s school performance is worse than it was before s/he 
was diagnosed ..................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 


Protocol Vers   12-14-2018                           64 
 
pB
8 
My child forgets things easily .............................................................. 
0 
1 
2 
3 
4 
pB
9 
It is hard for my child to concentrate in school ................................... 
0 
1 
2 
3 
4 
pB
10 
My child has to read things several times so s/he can understand 
them .................................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
pB
11 
When my child plays games or sports, s/he reacts more slowly 
than his/ her peers .............................................................................. 
 
0 
 
1 
 
2 
 
3 
 
4 
pB
12 
My child has difficulty using the right words ...................................... 
0 
1 
 
2 
 
3 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Vers   12-14-2018                           65 
 
Appendix 3: Eligibility Checklist  
A Phase II Study Of Pegylated Interferon Alfa-2b In Children With Refractory/ Recurrent  juvenile 
pylocytic astrocytomas or optic gliomas. 
Last Name: __________________ First Name: ______________________ MI: _____________ ID #: 
______________________ Date of Birth: _____________________ (mm/dd/yyyy)  
Age: _____________ Race: ___________ (White, Hispanic, Black, Asian, Other)  
To be eligible, questions 1-10 must be marked Y (Yes) or NA (Not Applicable), and questions 11-14 must 
be marked N (No).  
1. Is the patient older than 3 years and less than or equal to 25 years of age? _______ 
2. Has the patient been diagnosed with an optic pathway  glioma or JPA? _______  
 a. Is there radiographic evidence of optic pathway glioma or JPA? _________ 
3. Has the patient received 5 or fewer chemotherapy regimens? _______  
4. Does the patient have a performance status of more than 50? _______  
5. Does the patient have an adequate bone marrow function as defined below?  
-peripheral absolute granulocyte count of >1000/mm3, _______  
 -hemoglobin >8 gm/dL ________ (transfusion dependent)  
-platelet count >100,000/mm3_________ (transfusion independent)  
6. Does the patient have adequate hepatic function (total bilirubin <2.0x the upper limit of normal and 
direct bilirubin within normal limits and SGPT <2.5 x the upper limit of normal) or for patients with a 
diagnosis of Gilbert’s disease an indirect bilirubin of < 6mg/dl and a direct bilirubin of < .5mg/dl? 
_______ 
7.  Have one of the following two criteria for renal function been met? _______  
 a. Creatinine clearance =60 mL/min/1.73 m2 
b. Maximum age-adjusted normal serum creatinine?  
 i. Five years of age or younger: 0.8 mg/dl  
 ii. Ten years of age or younger, but must be greater than five years of age: 1.0 mg/dl  
 iii. Fifteen years of age or younger, but must be greater than ten years of age: 1.2 mg/dl  
 iv. Greater than fifteen years of age: 1.5 mg/dl  
8. Has the patient, their legal guardian, or a Durable Power of Attorney (for those patients 18 to 21 years 
of age) signed a document of informed consent? _____________ 
9 Does the patient have evidence of measurable disease in  brain MRI?  ____________________ 


Protocol Vers   12-14-2018                           66 
 
10. Has the patient received prior radiation more than 24 months ago?_____________ 
11. Is the patient currently receiving other investigational chemotherapeutic agents? _______   
12. Does the patient have any known hypersensitivity to interferon alpha? _______  
13. Is the patient pregnant or breast-feeding? _______ 
14. Does the patient have any clinically significant unrelated systemic illness which would compromise 
his/her ability to tolerate the Pegylated interferon therapy? _______   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Vers   12-14-2018                           67 
 
 
Appendix 4 Diary Pegylated Interferon 
PEGYLATED INTERFERON MEDICATION DIARY 
Please write down the date, time, and site of administration that you or your child takes pegylated 
interferon.  Also please explain any problems that occurred with taking the drug. Please bring this log 
with you EVERY time you come to clinic.   COURSE #: _______ 
Course Day 
Date 
Time 
Dose and  
Site of Administration 
Problems 
Week 1, Day 1 
 
 
 
 
Week 1, Day 2 
 
 
 
 
Week 1, Day 3 
 
 
 
 
Week 1, Day 4 
 
 
 
 
Week 1, Day 5 
 
 
 
 
Week 1, Day 6 
 
 
 
 
Week 1, Day 7 
 
 
 
 
 
 
 
 
 
Week 2, Day 1 
 
 
 
 
Week 2, Day 2 
 
 
 
 
Week 2, Day 3 
 
 
 
 
Week 2, Day 4 
 
 
 
 
Week 2, Day 5 
 
 
 
 
Week 2, Day 6 
 
 
 
 
Week 2, Day 7 
 
 
 
 
 
 
 
 
 
Week 3, Day 1 
 
 
 
 
Week 3, Day 2 
 
 
 
 


Protocol Vers   12-14-2018                           68 
 
Week 3, Day 3 
 
 
 
 
Week 3, Day 4 
 
 
 
 
Week 3, Day 5 
 
 
 
 
Week 3, Day 6 
 
 
 
 
Week 3, Day 7 
 
 
 
 
 
 
 
 
 
Week 4, Day 1 
 
 
 
 
Week 4, Day 2 
 
 
 
 
Week 4, Day 3 
 
 
 
 
Week 4, Day 4 
 
 
 
 
Week 4, Day 5 
 
 
 
 
Week 4, Day 6 
 
 
 
 
Week 4, Day 7 
 
 
 
 
 
Fax to Brain Tumor Office (404) 785 3511 or Bring to next clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Vers   12-14-2018                           69 
 
 
 
13. References 
 
1. 
Wisoff, J.H., et al., Primary neurosurgery for pediatric low-grade gliomas: a prospective multi-
institutional study from the Children's Oncology Group. Neurosurgery, 2011. 68(6): p. 1548-54; 
discussion 1554-5. 
2. 
Merchant, T.E., et al., Late effects of conformal radiation therapy for pediatric patients with low-
grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol, 
2009. 27(22): p. 3691-7. 
3. 
Ater, J.L., et al., Randomized study of two chemotherapy regimens for treatment of low-grade 
glioma in young children: a report from the Children's Oncology Group. J Clin Oncol, 2012. 
30(21): p. 2641-7. 
4. 
Bouffet, E., et al., Phase II study of weekly vinblastine in recurrent or refractory pediatric low-
grade glioma. J Clin Oncol, 2012. 30(12): p. 1358-63. 
5. 
Packer, R.J., et al., Objective response of multiply recurrent low-grade gliomas to bevacizumab 
and irinotecan. Pediatr Blood Cancer, 2009. 52(7): p. 791-5. 
6. 
Hwang, E.I., et al., Long-term efficacy and toxicity of bevacizumab-based therapy in children with 
recurrent low-grade gliomas. Pediatr Blood Cancer, 2012. 
7. 
Couec, M.L., et al., Bevacizumab and irinotecan in children with recurrent or refractory brain 
tumors: toxicity and efficacy trends. Pediatr Blood Cancer, 2012. 59(1): p. 34-8. 
8. 
Hwang, E.I., et al., Long-term efficacy and toxicity of bevacizumab-based therapy in children with 
recurrent low-grade gliomas. Pediatr Blood Cancer, 2013. 60(5): p. 776-82. 
9. 
Terashima, K., et al., Long-term outcome of centrally located low-grade glioma in children. 
Cancer, 2013. 119(14): p. 2630-8. 
10. 
Nagai, M. and T. Arai, Clinical effect of interferon in malignant brain tumours. Neurosurg Rev, 
1984. 7(1): p. 55-64. 
11. 
Groves, M.D., et al., Two phase II trials of temozolomide with interferon-alpha2b (pegylated and 
non-pegylated) in patients with recurrent glioblastoma multiforme. Br J Cancer, 2009. 101(4): p. 
615-20. 
12. 
Allen, J., et al., Recombinant interferon beta: a phase I-II trial in children with recurrent brain 
tumors. J Clin Oncol, 1991. 9(5): p. 783-8. 
13. 
Packer, R.J., et al., Treatment of children with newly diagnosed brain stem gliomas with 
intravenous recombinant beta-interferon and hyperfractionated radiation therapy: a childrens 
cancer group phase I/II study. Cancer, 1996. 77(10): p. 2150-6. 
14. 
Jakacki, R.I., et al., Phase II evaluation of interferon-alpha-2a for progressive or recurrent 
craniopharyngiomas. J Neurosurg, 2000. 92(2): p. 255-60. 
15. 
Warren, K., et al., A phase 2 study of pegylated interferon alpha-2b (PEG-Intron((R))) in children 
with diffuse intrinsic pontine glioma. Cancer, 2012. 118(14): p. 3607-13. 
16. 
Yeung, J.T., et al., Pegylated interferon-alpha-2b for children with recurrent craniopharyngioma. 
J Neurosurg Pediatr, 2012. 10(6): p. 498-503. 
17. 
Jakacki, R.I., et al., Phase I trial of pegylated interferon-alpha-2b in young patients with plexiform 
neurofibromas. Neurology, 2011. 76(3): p. 265-72. 
18. 
Slaton, J.W., et al., Interferon-alpha-mediated down-regulation of angiogenesis-related genes 
and therapy of bladder cancer are dependent on optimization of biological dose and schedule. 
Clin Cancer Res, 1999. 5(10): p. 2726-34.