Phase II Study of Peginterferon Alfa-2b (Sylatron) for Pediatric Patients With Unresectable or Recurrent Craniopharyngioma
Phase: PHASE2
Conditions: Childhood Craniopharyngioma
Sponsor: Pediatric Brain Tumor Consortium

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
NCI Protocol #: PBTC-039 
Local Protocol #: PBTC-039 
ClinicalTrials.gov Identifier:  NCT01964300  
 
TITLE:  Phase II study of Peginterferon alfa-2b (SYLATRON) for pediatric patients with   
unresectable or recurrent craniopharyngioma 
 
Coordinating Center:  
 
Operations, Biostatistics and Data Management Core (OBDMC) for the Pediatric Brain Tumor 
Consortium (PBTC), St. Jude Children’s Research Hospital 
 
Principal Investigator: 
Stewart Goldman, MD 
Ann & Robert H. Lurie Children’s Hospital of Chicago 
Neuro-Oncology  
 
 
 
 
Co-Chair:  
Ian Pollack, MD 
 
Children's Hospital of Pittsburgh of UPMC 
 
 
 
 
 
 
 
 
 
Co-Investigators: 
Larry Kun, M.D. 
St. Jude Children's Research Hospital 
Dept. of Radiation Oncology 
 
 
 
 
 
 
 
Girish Dhall, MD 
Children's Hospital Los Angeles 
Children's Center for Cancer and Blood Diseases  
Neuro-Oncology Program, 
 
 
 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
 
 
Gary E. Mason, MD MS 
Children's Hospital of Pittsburgh of UPMC 
Pediatric Neuro-Oncologist 
Division of Pediatric Hematology and Oncology  
 
 
 
 
 
 
 
 
Ashok Panigrahy, M.D. 
 
Children’s Hospital of Pittsburgh 
 
Department of Radiology 
 
  
 
 
 
  
 
 
 
 
 
 
 
Donald W. Parsons, MD, PhD 
Texas Children’s Cancer Center 
Baylor College of Medicine 
 
 
 
 
Adekunle M. Adesina, MD, PhD 
Department of Pathology 
Texas Children's Hospital 
Baylor College of Medicine 
 
 
 
  
 
 
 
 
 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
 
 
Biostatistician 
Arzu Onar-Thomas, PhD 
St. Jude Children’s Research Hospital 
Department of Biostatistics 
 
 
 
 
 
 
Biostatistician 
Catherine Billups, MS 
St. Jude Children’s Research 
Hospital 
Department of Biostatistics 
 
 
 
PBTC Protocol Coordinator 
Shujie Han, MD, Ph.D., CCRA 
St. Jude Children’s Research 
Hospital 
Department of Biostatistics 
 
 
 
 
  
 
PBTC Neuroimaging Center 
Tina Young Poussaint, M.D. 
Director, PBTC Neuroimaging Center 
Children’s Hospital of Boston 
Department of Radiology 
 
 
 
 
 
 
Biological Correlates Laboratory 
Adekunle M. Adesina, MD, PhD  
Department of Pathology  
Texas Children's Hospital  
Baylor College of Medicine  
 
 
 
 
 
 
Nursing Committee Rep 
Angela Krol, R.N. 
Children’s Hospital of Pittsburgh 
 
 
 
 
CRA Committee Rep 
Sharon Dibridge 
 
Children’s Hospital of Pittsburgh 
 
 
 
 
This protocol is for research purposes only, and should not be copied, redistributed or used for any other purpose.  The procedures in this 
protocol are intended only for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than 
standard treatment.  A responsible investigator associated with this clinical trial should be consulted before using or attempting any 
procedure in this protocol. Contents of this document may not be extracted without permission from the Study Chair. 
 
 
NCI Supplied Agent:  NA 
 
Commercial Agent: Peginterferon alfa-2b (SYLATRON) Supplied by Merck NSC#: 720033.  
                                   IND Exempt Study per 21 CFR 312.2(b)   
 
Protocol Type / Version # / Version Date: Amendment/Version # 6.0 / Version Date:   March 1, 2018 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
Pediatric Brain Tumor Consortium Institutions and Principal Investigators 
Arzu Onar-Thomas, Ph.D.* 
Executive Director of OBDMC for the PBTC 
St. Jude Children’s Research Hospital 
Department of Biostatistics 
 
 
 
Ira Dunkel, M.D. 
PBTC Steering Committee Chair 
Memorial Sloan Kettering Cancer Center 
Department of Pediatrics 
 
 
 
Patricia Baxter, M.D. 
Texas Children’s Cancer Center 
Baylor College of Medicine 
 
 
 
Girish Dhall, MD 
Children's Hospital Los Angeles 
Children's Center for Cancer and Blood Diseases  
Neuro-Oncology Program, 
 
 
 
 
  
 
Kathleen Dorris, MD 
Children's Hospital Colorado 
 
 
 
Paul Graham Fisher, M.D. 
Stanford University and Lucile Packard Children's Hospital 
Neurology and Pediatrics, Chief, Division of Child Neurology 
 
 
Maryam Fouladi, M.D. 
Cincinnati Children’s Hospital Medical Center 
Dept. Of Hematology/Oncology 
 
 
 
  
 
Stewart Goldman, M.D. 
Ann & Robert H. Lurie Children’s Hospital of Chicago 
Neuro-Oncology 
 
 
 
 
Eugene Hwang, M.D. 
Children's National Medical Center 
Dept. of Neurology 
 
 
 
 
Tobey MacDonald, MD 
Children's Healthcare of Atlanta  
Emory Health Sciences Research Building, E-384 
AFLAC Cancer and Blood Disorders Center 
 
 
Giles Robinson, MD 
St. Jude Children's Research Hospital 
Dept. of Oncology 
 
 
 
Kathy Warren, M.D. 
NIH/NCI/NOB 
National Cancer Institute, Pediatric Oncology Branch,  
 
 
 

NCI Protocol #: PBTC-039 
 
 
 
 
 
 
 
 
 
 
 
 *Does not have patient care responsibilities 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
 
SCHEMA 
 
Stratum 1:  Patients with progressive unresectable or recurrent craniopharyngiomas treated with 
surgery alone who have not received radiation therapy.  Patients with unresectable 
craniopharyngiomas (i.e., residual measurable disease following surgical resection) will be 
enrolled at the time of progression  
 
Stratum 2: Patients with progressive or recurrent craniopharyngiomas following radiation 
therapy.   

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................7 
1 
OBJECTIVES ....................................................................................................................11 
1.1 
Primary Objectives.............................................................................................................11 
1.2 
Secondary Objectives.........................................................................................................11 
2 
BACKGROUND ...............................................................................................................11 
2.1 
Study Disease(s).................................................................................................................11 
2.2 
SYLATRON (Peginterferon alpha-2b) ..............................................................................12 
2.3 
Pediatric Clinical Trials .....................................................................................................14 
2.4 
Rationale for Changing Study Drug PegIntron to SYLATRON .......................................16 
2.5 
Rationale for Correlative Studies .......................................................................................16 
3 
PATIENT SELECTION ....................................................................................................17 
3.1 
Eligibility Criteria ..............................................................................................................17 
3.2 
Exclusion Criteria ..............................................................................................................20 
3.3 
Inclusion of Women and Minorities ..................................................................................20 
3.4 
Treatment at Primary Institution ........................................................................................20 
3.5 
Criteria to Start Treatment .................................................................................................21 
4 
REGISTRATION PROCEDURES ...................................................................................21 
4.1 
General Guidelines.............................................................................................................21 
4.2 
Registration Process ...........................................................................................................21 
5 
TREATMENT PLAN ........................................................................................................21 
5.1 
Agent Administration.........................................................................................................22 
5.2 
Criteria for Starting Subsequent Courses ...........................................................................22 
5.3 
Duration of Therapy ...........................................................................................................22 

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5.4 
Off Treatment Duration of Follow Up ...............................................................................23 
5.5 
Criteria for Removal from Study .......................................................................................23 
5.6 
General Concomitant Medication and Supportive Care Guidelines ..................................24 
6 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................24 
6.1 
Constitutional Symptoms ...................................................................................................24 
6.2 
Transaminase Elevations ...................................................................................................24 
6.3 
Non-hematologic toxicity other than constitutional symptoms .........................................24 
6.4 
Dose Modification for Hematologic Toxicity....................................................................25 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................25 
7.1 
Adverse Events and Potential Risks ..................................................................................26 
7.2 
Expedited Adverse Event Reporting ..................................................................................27 
7.3 
Routine Adverse Event Reporting .....................................................................................29 
7.4 
Secondary Malignancy.......................................................................................................29 
7.5 
Second Malignancy ............................................................................................................30 
8 
PHARMACEUTICAL INFORMATION ..........................................................................30 
8.1 
SYLATRON (PEGINTERFERON ALFA-2B) (NSC # 720033) .....................................30 
9 
PATHOLOGY, CORRELATIVE AND IMAGING STUDIES .......................................31 
9.1 
Pathology and Exploratory Correlative Studies .................................................................32 
9.2 
Central Pathology Review .................................................................................................35 
9.3 
Imaging Studies .................................................................................................................36 
10 
STUDY CALENDAR .......................................................................................................38 
11 
MEASUREMENT OF EFFECT........................................................................................40 
11.1 
Tumor Response Criteria ...................................................................................................40 
12 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................41 
12.1 
Data reporting ....................................................................................................................41 

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12.2 
CTEP Multicenter Guidelines ............................................................................................41 
12.3 
Participant and Data Confidentiality ..................................................................................42 
13 
STATISTICAL CONSIDERATIONS...............................................................................43 
13.1 
Primary Endpoints .............................................................................................................43 
13.2 
Secondary Endpoints .........................................................................................................43 
13.3 
Sample Size/Accrual Rate ..................................................................................................43 
13.4 
Stratification Factors ..........................................................................................................47 
REFERENCES ..............................................................................................................................48 
APPENDIX A  Karnofsky/Lansky PERFORMANCE STATUS .................................................50 
APPENDIX B ................................................................................................................................51 
APPENDIX C ................................................................................................................................53 
APPENDIX D ................................................................................................................................55 
 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
 
1 
OBJECTIVES 
 
1.1 Primary Objectives 
1.1.1 To estimate the 1-year disease stabilization rate associated with the use of 
PEGINTERFERON ALFA-2B in patients with progressive unresectable or recurrent 
craniopharyngiomas following surgery alone who have not received radiation 
therapy.  
1.1.2 To estimate the sustained objective response rate (PR+CR) to PEGINTERFERON 
ALFA-2B in patients with craniopharyngiomas which progress or recur following 
radiation therapy.  
 
1.2 Secondary Objectives 
1.2.1 To estimate the response rate in patients with progressive unresectable or recurrent 
craniopharyngioma treated with PEGINTERFERON ALFA-2B by study stratum. 
1.2.2 To estimate the progression-free survival distribution for patients with unresectable or 
recurrent craniopharyngiomas treated with PEGINTERFERON ALFA-2B by study 
stratum.  
1.2.3 To evaluate the toxicity profile of PEGINTERFERON ALFA-2B in children with 
unresectable or recurrent craniopharyngiomas. 
1.2.4 To compare the protocol specific disease assessment criteria to MacDonald criteria 
during the first year of treatment in stratum I and also at the time of objective 
response and progressive disease in both strata.   
1.2.5 To characterize evidence of WNT and MAPK pathway activation in resected tumor 
tissue in patients with craniopharyngiomas by immunohistochemistry and 
pyrosequencing and correlate these results with outcome and response data. 
 
2 BACKGROUND 
 
2.1 Study Disease(s) 
Craniopharyngiomas account for approximately 4% of brain tumors in patients younger than 15 
years of age.1 They are believed to arise from embryonic squamous cell rests along the 
hypophyseal-pharyngeal duct.2 Complete surgical resection is often not possible without 
significant morbidity because of the tumor’s proximity to the optic chiasm, third cranial nerve, 
hypothalamus and internal carotid arteries and branches.   Despite complete resection, recurrence 
rates range from 20% to as high as 50%.3-5  Subtotal resection followed by radiation therapy 
achieves at least comparable results in terms of recurrence rates and survival.6-8  Therefore, either 
complete resection or subtotal resection followed by radiation therapy is considered standard of 
care for patients with newly diagnosed craniopharyngiomas. 
 
Unfortunately, permanent deleterious effects on behavior, learning and endocrine function 
following surgery and/or radiation therapy are common in children with craniopharyngioma and 
can be devastating.9,10 Multiple endocrinopathies are almost universal, but the effects of 
hypothalamic damage including hypothalamic obesity and impaired socialization and poor 

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academic performance (“hypothalamic syndrome”) are often not remediable. The effects of 
radiation are relatively age dependent, with more significant damage occurring in younger 
children.  An effective medical therapy that can defer the need for radiation therapy, particularly 
for young children, or salvage those tumors that have recurred following radiation therapy would 
be of tremendous benefit both in terms of overall survival as well as quality of life.     
 
2.2 SYLATRON (Peginterferon alpha-2b) 
 
2.2.1 Rationale for alpha-interferon 
The interferons are a family of naturally occurring, small proteins produced and secreted by 
virtually all eukaryotic cells in response to viral infections or to various biologic and synthetic 
inducers. Interferons exert antitumor activity through direct antiproliferative and cytotoxic 
effects as well as modulation of the host immune response.11   Interferon is also a potent inhibitor 
of angiogenesis as evidenced by its utility in the treatment of life-threatening hemangiomas of 
infancy.12 
  
Craniopharyngiomas and squamous cell skin carcinoma are believed to have the same 
embryologic origin. Squamous epithelium, usually with some evidence of keratinization, is 
characteristically 
found 
in 
both the 
cystic 
lining 
and 
the 
solid 
component of 
craniopharyngiomas.2 When administered both intralesionally and systemically, interferon alpha 
has significant activity against squamous cell skin carcinoma.  Intralesional injections of alpha 
interferon for 3 weeks resulted in histologically proven eradication of squamous cell carcinoma 
in 33 out of 34 patients.13 Treatment with subcutaneous alpha-2a interferon (3 million IU/d) and 
oral cis-retinoic acid for two months in patients with advanced squamous cell carcinoma resulted 
in an overall response rate of 68%, and a 93% response rate for those with localized disease.14 
 
Based on this, a Phase II study of alpha-interferon was performed in pediatric patients with 
progressive or recurrent craniopharyngiomas.15 Interferon alpha-2a was administered 
subcutaneously daily for 16 weeks followed by a 32 week maintenance phase where the 
interferon was given three times/week.  Three of 12 evaluable patients showed a minor response 
(n=1), partial response (n=1) or complete response (n=1); the patient with the PR also showed 
improvement in visual fields.  The median time to progression was 25 months (range 3-37+ 
months with 3 patients without progression as of last follow-up).  The cystic component of the 
tumor often increased temporarily during the first several months of treatment. Toxicities 
requiring temporary discontinuation and/or dose reduction were common during the initial 16 
weeks of therapy.  All patients developed fever shortly after receiving the first dose of IFN, 
usually accompanied by chills and myalgias. Two patients with panhypopituitarism developed 
hypotension and lethargy during the fever, requiring stress dose steroids.  Temporary 
discontinuation and/or dose reduction was required for toxicity in nine (60%) of the 15 patients 
during the first 8 weeks of treatment but resolved after temporary discontinuation and/or dose 
reduction. These toxicities included worsening seizures, transaminase elevations, rash and 
anorexia/weight loss.   
 
Intralesional interferon-alpha has also shown efficacy against craniopharyngiomas.  In a multi-
center study, 60 patients with predominantly cystic craniopharyngiomas were treated with every 
other day intra-cystic interferon-alpha. Forty-seven (78%) of the 60 patients had a > 50% 

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decrease in the size of the cyst.16  A separate study of 8 patients with cystic craniopharyngiomas 
treated with intra-cystic alpha-interferon showed an increase in the apoptotic factor soluble FasL 
concentrations in the cyst fluid of all 8 patients as the cyst decreased in size in response to 
treatment, suggesting that interferon works by inducing Fas-mediated apoptosis.17 
 
2.2.2 Rationale for Pegylated Interferon (PEGINTERFERON ALFA-2B) 
In tumor cell lines, continuous and prolonged exposure to interferon optimizes both the anti-
proliferative and anti-angiogenic effect18-21 and the highest response rates in patients with 
metastatic melanoma have been obtained with uninterrupted schedules.18    When interferon was 
removed from the medium, glioma cell line growth rapidly returned to the pretreatment rate.20 
 
Conjugating proteins with poly-ethylene-glycol (PEG) almost invariably lengthens the plasma 
half-life by reducing sensitivity to proteolysis, thereby increasing the area under the curve (AUC) 
and providing protracted activity.22  Pegylation of interferon enhances the therapeutic ratio in 
patients with hepatitis C, and was more effective than a regimen of non-pegylated interferon 
given 3 times/week.23  PegIntron has received FDA approval for this indication at a dose of 1 
mcg/kg/dose/week when given as a single agent.  
 
2.2.3 Rationale for PEGINTERFERON ALFA-2B Dose 
Although interferon-alpha has been used to treat a variety of neoplasms, the optimal dose in 
oncology has not been established.   In vivo studies have not shown a clear dose-response 
relationship in solid tumors, other than possibly for melanoma24.  In CML, low dose interferon is 
just as effective as higher doses25 whereas toxicity is clearly dose-related.   
 
A Phase I study of PegIntron alpha-2b in pediatric patients with neurofibromatosis-related 
plexiform neurofibromas has recently been published.26  The recommended Phase 2 dose 
(RP2D) was 1 mcg/kg/week with fatigue and intolerable behavioral toxicities seen at higher 
doses.  There was only one DLT (myoclonus) in 12 patients treated at the RP2D. This toxicity 
had not been seen previously and was felt to be possibly related, although it continued 
intermittently even after the drug was discontinued.  Only 1 other patient required a dose 
reduction for grade 3 elevation of transaminases.  This dose is also the FDA approved dose for 
the treatment of hepatitis C in adults when used as monotherapy.  Although a higher dose of 
PEGINTERFERON ALFA-2B is used in adult patients with melanoma, where there is a known 
dose-response curve, a dose of 1 mcg/kg/week resulted in a prolonged CR in one of the patients 
in the pilot study.27 
 
Many, if not most patients with craniopharyngiomas have panhypopituitarism and require stress 
doses of steroids to remain hemodynamically stable in the face of high fever and/or chills, which 
are common dose-related side effects of interferon, and almost universally seen with higher 
doses, particularly with short acting interferon. A dose of 1 mcg/kg/week has been found to be 
well tolerated in pediatric patients26, causing only mild to moderate constitutional symptoms 
which subside over time, and has shown efficacy in the pilot study at Children’s Hospital of 
Pittsburgh.27 Therefore, a dose of 1 mcg/kg/week will be utilized for all patients in this protocol, 
regardless of age.   
 

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2.3 Pediatric Clinical Trials 
As stated in Section 2.2.1, a Phase II study of alpha-interferon was performed in pediatric 
patients with progressive or recurrent craniopharyngiomas.15 Interferon alpha-2a was 
administered subcutaneously daily for 16 weeks followed by a 32 week maintenance phase with 
the interferon given three times/week.  Three of 12 evaluable patients had an objective response 
and one patient also showed improvement in visual fields: the median time to progression was 25 
months. 
 
2.3.1 Children’s Hospital of Pittsburgh experience with pegylated interferon 
A single institution pilot study of pegylated interferon in children with recurrent 
craniopharyngiomas has recently been published.27  From 2001-2011, 14 patients at the 
Children’s Hospital of Pittsburgh developed recurrence of their craniopharyngiomas.  Seven 
patients underwent repeat resection, 2 patients underwent 3 gamma-knife procedures and 5 
children were treated with pegylated interferon.  All 5 patients have responded or experienced 
prolonged disease stabilization. Case summaries are provided below:  
 
a. Patient #1 was diagnosed with a craniopharyngioma at the age of 9 years.  The tumor re-grew 
within 3 months of a gross total removal, and she was started on PegIntron.  The 
predominantly cystic tumor initially increased in size during the first 3 months of therapy, 
but then progressively decreased until there was complete disappearance of tumor. She was 
treated with PegIntron for 2 years and has remained NED 10.5 years after beginning 
treatment. 
 
 
Patient #1 
 
 
 
 
Pre-Therapy 
7 Months Later 
10 Years Later 
 
 
b. Patient #2 was diagnosed with a craniopharyngioma at the age of 8 years and underwent a 
subtotal resection followed by radiation therapy.  The tumor regrew 3.6 years later and he 
was treated with PegIntron for 2 years.  The cystic component completely disappeared 4 
months after starting PegIntron and a calcified residual mass remains stable over 5 years 
later. 
 

NCI Protocol #: PBTC-039 
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Patient #2 
 
 
 
 
Pre-Therapy 
Four Months Later 
Six Years Later 
 
 
c. Patient #3 was diagnosed with a craniopharyngioma at the age of 4 years and underwent 
three gross total resections of the tumor over the next 7 years. The tumor recurred 8 months 
after the third surgery and he was treated with PegIntron for 15 months.  He had a complete 
response by 7 months of treatment with PegIntron and remained on treatment for 15 months.  
He remains NED 2 1/2 years after starting treatment. 
 
Patient #3 
 
 
Pre-Therapy 
7 and 21 Months Later 
 
 
d. Patient #4 was diagnosed with a large craniopharyngioma at the age of 13 years and 
underwent a two-staged subtotal resection.  The tumor progressed within a few months and 
he started treatment with PegIntron.  He showed a 30% decrease in the size of the cystic 
component by 4 months, which was maintained until 12 months, when the cyst increased in 
size. 
 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
Patient #4 
 
Pre-Therapy 
Eight Months Later 
 
 
e. Patient #5 was diagnosed at the age of 14 years and underwent a gross total resection. The 
cystic tumor re-grew within 6 months and she started treatment with PegIntron. She remains 
stable 17 months after starting treatment. 
 
These patients were treated for variable amounts of time, but all for > 1 year and at least one 
patient continued to show tumor shrinkage and eventual complete tumor disappearance after 2 
years of treatment.  The duration of treatment for this protocol will therefore be 2 years. 
 
2.4 Rationale for Changing Study Drug PegIntron to SYLATRON 
 
Merck has decided to voluntarily discontinue the manufacture of the PegIntron vials, Injection, 
for subcutaneous use, for distribution in the United States for business reasons. The decision is 
not based on any safety or efficacy findings with this product. This decision is due to scientific 
advancement, changes in treatment practices, and the consequent reduction in the demand for 
PegIntron. SYLATRON, which has the same active ingredient as PegIntron (Peginterferon alfa-
2b) with different Dosage Strength, is proposed to replace PegIntron as the study drug of PBTC-
039.  
 
2.5 Rationale for Correlative Studies 
 
2.5.1 WNT and MAPK pathway activation 
Recent genomic studies have demonstrated that each of the two histologic subtypes of 
craniopharyngioma (adamantinomatous and papillary) is characterized by the presence of a 
specific genetic alteration.28 Adamantinomatous craniopharyngiomas, which are most common 
in children, exhibit near-universal mutation of beta-catenin (CTNNB1), confirming recent 
evidence that craniopharyngiomas arise from activation of beta-catenin (a Wnt pathway gene) in 
pituitary progenitors during embryogenesis29.   Of note, craniopharyngiomas with mutations in 
CTNNB1 can be reliably identified by detection of nuclear immunoreactivity for the beta-catenin 
protein, which is the most commonly-used clinical test for alterations in this gene.  These results 
confirmed an earlier study where all 10 cases of adamantinomatous craniopharyngioma harbored 
beta-catenin mutations and stained for nuclear expression of beta-catenin.30  Papillary 

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craniopharyngiomas, in contrast, are characterized by frequent BRAF V600E mutations, 
indicating activation of the MAPK signaling pathway.28 Although in general mutations in 
CTNNB1 and BRAF are mutually-exclusive in craniopharyngiomas, cases have been identified in 
which both genes are mutated in the same tumor.31 We propose to validate these observations 
using immunohistochemistry for nuclear beta-catenin and pyrosequencing for detection of BRAF 
V600E in FFPE sections in this pediatric series of craniopharyngiomas. 
 
2.5.2 MRI Study 
Standard high resolution MR imaging dedicated to the suprasellar/sellar region with gadolinium 
has been used in previous studies of interferon in patients with recurrent craniopharyngioma.15,27 
Volumetric analyses of tumor size have been reported to more accurately detect change in tumor 
volume than the diameter method.32 
 
The product of the greatest perpendicular linear diameters will be compared to central volumetric 
analysis of the cystic and solid component of the tumor and compared to assessment of disease 
response.  
 
3 PATIENT SELECTION 
 
3.1 Eligibility Criteria 
All subjects must meet the following inclusion and exclusion criteria.  No exceptions will be 
given. Imaging studies to establish eligibility must be done within three (3) weeks prior to 
registration and 4 weeks of starting therapy. All subjects must have baseline MRI scans of the 
brain with thin cuts through the sella (see Section 9.3). 
 
All other evaluations necessary to establish eligibility for study entry must be done within two 
(2) weeks prior to registration. 
 
3.1.1 
Tumor 
Patient must have a histologically verified diagnosis of craniopharyngioma.  
 
Stratum 1:  Patients with progressive unresectable or recurrent craniopharyngiomas treated with 
surgery alone, who have not received radiation therapy.  Patients with unresectable 
craniopharyngiomas, (i.e. residual measurable disease following surgical resection) will be 
enrolled at the time of progression.   
 
Stratum 2:  Patients with progressive or recurrent craniopharyngiomas following radiation 
therapy. The patient must be at least 6 months post-irradiation to be eligible.  
 
3.1.2 Disease Status 
All patients must have measurable residual disease defined as tumor measurable in two 
perpendicular diameters on MRI. Measurements are required for both the solid and cystic 
components  
 
3.1.3 Prior Therapy 
Subjects must have recovered from the acute toxicities of all prior therapy before entering this 

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study.  For those acute baseline adverse events attributable to prior therapy, recovery is defined 
as a toxicity Grade ≤ 2, using CTCAE v.4.0, unless otherwise specified in the Inclusion and 
Exclusion Criteria. 
 
3.1.4 Myelosuppressive chemotherapy:  
Subjects must have received their last dose of known myelosuppressive anticancer chemotherapy 
at least three (3) weeks prior to study registration or at least six (6) weeks if nitrosourea. 
 
3.1.5 Investigational / Biologic agent:  
Subjects must have received their last dose of investigational or biologic agent ≥ 7 days prior to 
study registration.   
• In the event that a subject has received an investigational or biologic agent and has 
experienced ≥ Grade 2 myelosuppression, then at least three (3) weeks must have elapsed 
prior to registration.  
• If the investigational or biologic agent has a prolonged half-life (≥ 7 days) then at least 
three (3) weeks must have elapsed prior to registration.  
 
3.1.6 Monoclonal antibody treatment:  
Subjects must have completed at least 3 half-life periods from the last dose of monoclonal 
antibody prior to registration.   
Note: A list of half-lives of commonly used monoclonal antibodies is available on the PBTC 
website under Generic Forms and Templates  
 
3.1.7 Radiation  
Stratum 1: Patients must not have received radiation therapy. 
Stratum 2: Patients must have received radiation therapy, which may include gamma knife or 
P32: 
• More than 6 months from the time of enrollment if the recurrence is predominantly 
solid  
• More than 12 months from the time of enrollment if the recurrence is predominantly 
cystic 
 
3.1.8 Growth factors:  
At least 7 days since the completion of therapy with a hematopoietic growth agent (filgrastim, 
sargramostim, and erythropoietin) and 14 days for long-acting formulations. 
 
3.1.9 Performance Status 
Karnofsky Performance Scale (KPS for ≥ 16 yrs of age) or Lansky Performance Score (LPS for 
< 16 years of age) ≥ 60 assessed within two weeks prior to registration (See Appendix A) 
 
3.1.10 Age:   
18 months – 25 years (Minimum weight 20 Kilogram is required to be eligible for the study, 
since the minimum injection volume of SYLATRON is 0.05 ml, 20 mcg, SQ as suggested by 
Merck) 
 
3.1.11 Organ Function:  

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Patients must have evidence of normal organ function as defined by:   
• ANC≥ 1000/µl (unsupported)  
• Platelets ≥ 100,000/µl (unsupported)  
• Hg≥ 8g/dL (unsupported) 
• ALT ≤ 2.5 x the upper limit of institutional normal 
• Total bilirubin ≤ x 1.5 upper limit of institutional normal 
• Serum creatinine ≤ 1.5 x the upper limit of normal for age, or calculated creatinine 
clearance or nuclear GFR ≥ 70 ml/min/1.73 m2 
 
 
Table 1 
Serum Creatinine for Age/Gender 
Age 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz formula 
for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and 
stature data published by the CDC. 
 
 
3.1.12 Radiographic Progression 
 
Patients must have evidence of radiographic progression as defined below: 
• Stratum 1:  
o  defined as ≥ 25% increase in the product of the greatest perpendicular diameters 
of the tumor as a whole (solid and cystic component) AND ≥ 0.4 cm increase in 
each of at least two dimensions of the tumor as a whole OR any new or worsening 
neurologic/vision deficit in conjunction with a lesser change in the solid or cystic 
component.     
• Stratum 2:   
o For patients more than 6 months following RT (including radiosurgery or P32), 
progression is defined as a ≥ 25% increase in the product of the greatest 
perpendicular diameters of the solid component AND ≥ 0.4 cm increase in each of 
at least two dimensions of the solid component;  
 
o For patients more than 12 months following RT (including radiosurgery or P32), 
progression is defined as ≥ 25% increase in each of the product of the greatest 
perpendicular diameters of the solid tumor AND ≥ 0.4 cm increase in each of at 
least two dimensions of the solid tumor.  Patients demonstrating predominantly 
cystic progression more than 12 months after RT must show a continued increase 
in the cystic component on two serial MRI scans performed at least 4 weeks apart 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
OR re-accumulation of the cyst following one or more cyst aspirations.  Patients 
with progressive neurologic signs and/or symptoms associated with isolated cyst 
formation or progression are eligible if the neurologic signs and/or symptoms do 
not improve within 4 weeks of cyst aspiration. 
 
3.1.13 Pregnancy Status:  
Female subjects of childbearing potential must not be pregnant or breast-feeding.  Female 
subjects of childbearing potential must have a negative serum or urine pregnancy test.  
(Pregnancy test must be repeated within 72 hours prior to the start of therapy). 
 
3.1.14 Pregnancy Prevention:  
Subjects of childbearing or child fathering potential must be willing to use a medically 
acceptable form of birth control, which includes abstinence, while being treated on this study. 
 
3.1.15 Informed Consent:  
Ability to understand and the willingness to sign a written informed consent document 
 
3.2 Exclusion Criteria 
3.2.1 Stratum 1 patients: must not have had > 3 surgical debulking procedures/resections. 
 
3.2.2 Patients may not have received prior interferon, either systemic or intra-cystic. 
 
3.2.3 Patients must not have evidence of metastatic tumor or other cancer.  
 
3.2.4 Patients must not be on steroids other than for physiologic replacement.   
 
3.2.5 Patients must not have a severe psychiatric illness, including major depression or any 
previous suicide attempts. 
 
3.2.6 Patients must not be on phenytoin, warfarin or methadone due to potential drug 
interactions. 
 
3.2.7 Patients must not have known hypersensitivity reactions, such as urticaria, angioedema, 
bronchoconstriction, anaphylaxis, Steven-Johnson syndrome, and toxic epidermal 
necrolysis to interferon alpha or any other products component. 
 
3.2.8 Subjects with inability to return for follow-up visits or obtain follow-up studies required 
to assess toxicity to therapy.  
 
3.3 Inclusion of Women and Minorities 
Both males and females of all races and ethnic groups are eligible for this trial.   
 
3.4 Treatment at Primary Institution  
All experimental protocol therapy should be dispensed and all imaging studies must be obtained 
at the primary institution. Laboratory studies, excluding pharmacokinetic and biologic assays, 
may be performed at a CLIA-certified laboratory of the investigator’s choice. 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
 
3.5 Criteria to Start Treatment 
3.5.1 Subjects must start therapy within seven (7) days of registration. 
 
3.5.2 Laboratory tests used to assess eligibility must be repeated if therapy starts more than 
seven (7) days after obtaining labs to assess eligibility. If a test that is repeated after 
registration and prior to start of therapy is outside the limits for eligibility, it must be 
rechecked 48 hours prior to the start of therapy. If the recheck is still outside the limits for 
eligibility, the subject may not receive protocol therapy and will be considered off study.  
3.5.3 A urine or serum pregnancy test must be repeated and be negative within 72 hours of 
beginning the study agent for all females of childbearing potential. 
 
4 REGISTRATION PROCEDURES 
 
4.1 General Guidelines 
4.1.1 Prior to Consent 
Prior to consent the protocol’s status should be verified via the PBTC Protocol Status web page, 
to ensure study is open to accrual. 
 
4.1.2 Informed Consent 
Informed consent must be obtained prior to subject registration. Furthermore, consent should be 
obtained prior to the initiation of any clinical procedures or assessments performed for the 
purpose of determining protocol eligibility, which would not otherwise be consistent with the 
institution’s standards of clinical practice.  
 
4.2 Registration Process 
Subjects must be registered prior to any protocol treatment.  Subject registration is only available 
to authorized personnel using the PBTC automated registration system.  The registration 
procedures are available in the CRA manual, which is posted on the PBTC members’ website. 
The PBTC Protocol Coordinator listed on the protocol cover page for assistance in the 
registration process. 
 
Reservations may also be made through the registration system providing time to assess the 
subject’s eligibility.  Reservations will be held for a maximum of seven (7) calendar days by 
which time the subject must have been registered on study. The subject’s reservation should be 
canceled as soon as it is determined that the subject is not eligible or that the family/subject has 
decided not to consent to the trial. 
 
5 TREATMENT PLAN 
• Stratum 1:  Patients with progressive unresectable or recurrent craniopharyngiomas 
treated with surgery alone, who have not received radiation therapy.  Patients with 
unresectable craniopharyngiomas (i.e. residual measurable disease following surgical 
resection) will be enrolled at the time of progression. 
 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
• Stratum 2:  Patients with progressive or recurrent craniopharyngiomas following 
radiation therapy.   
 
5.1 Agent Administration 
SYLATRON will be administered as a weekly subcutaneous injection for up to 18 courses with 
6 injections per course.  Six consecutive weeks will constitute one course and subsequent courses 
will immediately follow, with no break in the administration of the drug.  All patients will 
receive a dose of 1 mcg/kg/week.   The patient’s actual weight (in kilograms) should be used 
when calculating the dose of SYLATRON and doses should be re-adjusted if necessary at the 
time of each clinic evaluation.  See Appendix C for the SYLATRON dosage calculation and 
dosage chart.  Patients or parents will be taught to administer the medication in the outpatient 
setting (see Appendix B for a parent handout on administering subcutaneous injections).  Patients 
or their guardians will keep a diary to document SYLATRON administration (available on the 
PBTC-039 webpage). 
 
Since constitutional symptoms (e.g., fatigue, myalgias, fever) are generally the most severe after 
the first few doses, acetaminophen (15 mg/kg up to max dose of 1000 mg) should be given 30 
minutes prior to administering the first six doses (first course) of SYLATRON and prior to 
subsequent doses if needed.  For fever that develops after a dose of SYLATRON, 
Acetaminophen (15 mg/kg up to max dose of 650 mg PO) can be given q 4-6 hours as needed, 
but should not exceed 75 mg/kg/day for a total dose of up to 3000 mg/day.  Acetaminophen can 
also be alternated with ibuprofen (10 mg/kg up to a max dose of 600 mg) every 6-8 hours as 
needed.  Patients who are on replacement steroids for adrenal insufficiency should receive stress 
dose steroids for any fever > 101 degrees Fahrenheit (38.3 degrees Centigrade).  Please see 
Appendix D for suggested stress steroid dosing for SYLATRON related fever. 
 
It is recommended that a follow-up call be placed to the patient or parent within 72 hours of 
the first dose to evaluate for toxicities and review optimal management. 
 
5.2 Criteria for Starting Subsequent Courses 
A course may be repeated every 6 weeks if the subject has no evidence of progression and has 
again met laboratory parameters as defined in Section 3.1.11.  If a subject does not meet these 
parameters at the end of the treatment course, then SYLATRON should be held until parameters 
meet the eligibility criteria.  If the next course is delayed >21 days due to failure to meet 
laboratory parameters of eligibility criteria or drug-related toxicity, the subject should be taken 
off protocol therapy.   
 
5.3 Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue for up to 18 
courses: 
 
5.3.1 On-Study Data Submission Schedule 
Pre-treatment, on-study and off-treatment data, as well as subject response data are to be 
recorded in the electronic data collection screens using the PBTC RDC database. See the 
Required Data and Timetable for Submission form located on the PBTC-039 protocol and 
resources webpage for the schedule. For assistance, contact the PBTC Protocol Coordinator, 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
listed on the cover page of the protocol. An optional roadmap is located on the PBTC-039 
protocol and resources webpage.  
 
5.3.2 Off Treatment Criteria 
At the discontinuation of treatment, the “Off Treatment Date” is to be recorded in the eCRF and 
is to be consistent with the reason given for going off treatment. The “Last Treatment Date” is 
defined as the last date that the patient received protocol based therapy.  Date of “off treatment” 
must be the greatest of the date of last treatment, date of procedure, date of patient assessment, 
notification of patient/family decision, or decision made by the physician that resulted in the 
patient being taken off protocol treatment.  The reason for discontinuation of treatment must be 
documented by the attending investigator in the medical record and recorded in the eCRF.  
• Disease progression as defined in Section 11.1.3 
• Development of a medical or psychiatric illness that in the investigator’s judgment 
renders the patient incapable of further therapy on this protocol. 
• Unacceptable toxicity as outlined in sections 6. 
• Patient, parent or legal guardian refuses further treatment on this protocol 
• Pregnancy or breastfeeding 
• Subject is unable to complete the study evaluations/visits  
• Patients who develop significant depression and/or suicidal ideations will be taken off 
treatment.  
 
5.4 Off Treatment Duration of Follow Up 
Patients who are off protocol therapy must be followed until an “Off Study Criterion” is met (see 
section 5.6).   
5.4.1 Patients who have had progression/recurrence will be followed for 30 days after the last 
dose of SYLATRON or until the resolution of all SYLATRON related toxicities, 
whichever is longer.   
5.4.2 Patients who discontinue for reasons other than progression/recurrence of disease should 
continue to be followed for progression/recurrence, i.e. until they meet the Off Study 
criteria (below).  Follow-up data will be required.   
5.4.3 Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event and they meet one of the Off Study criteria 
(below).   
 
5.5 Criteria for Removal from Study 
The date and reason for the subject coming off study must be documented in the eCRF and the 
Operations, Biostatistics and Data Management Core must be notified according to standard 
reporting guidelines (see Section 7 and the Required Data and Timetable Submission form 
located on the PBTC-039 protocol and resources webpage).  
• Subject determined to be ineligible.  
• Parent, subject, or guardian withdraws consent for continued participation.  
• Subject death while on study. The IRB, Study Chair and OBDMC must be notified as per 
Section 7.  
• Subject has completed all trial-specified evaluations and follow-up. 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
• Subject has started another therapy or experienced disease progression (section 11.1.3).  
 
5.5.1 Off-Study Data Submission Schedule  
No data will be collected documenting treatment or reporting events or disease status that occur 
subsequent to the official “off study” date with the exception of adverse events with an 
attribution of possible, probable, or definite that occur after the “off study” date (per protocol 
Section 7).  
 
5.6 General Concomitant Medication and Supportive Care Guidelines 
The only contraindicated medications are Phenytoin, Warfarin, and Methadone, which are listed 
in the eligibility/exclusion criteria.  Patients should be asked and should inform their healthcare 
providers about any OTC medications that they are taking, particularly those containing 
acetaminophen, in order to avoid over-dosage. 
 
6 DOSING DELAYS/DOSE MODIFICATIONS 
If patients drop below 20 kg during SYLATRON treatment, they can have SYLATRON held for 
up to 3 weeks for increasing nutrition. If they can gain weight and return to ≥ 20 kg, they could 
restart SYLATRON and not make up lost weeks.  This could happen twice before being removed 
from study. 
 
6.1 Constitutional Symptoms 
Every attempt should be made not to stop the drug for constitutional symptoms during the first 
three weeks, since these symptoms usually improve.  Patients with persistent (i.e. lasting > 48 
hours) grade 2 or higher constitutional symptoms occurring after the fourth dose should have their 
dose reduced to 0.6 mcg/kg/week.  If symptoms do not improve after 3 weeks of the reduced dose, 
patients may have their dose reduced to 0.3 mcg/kg/week.  If symptoms do not improve after 3 
weeks of the second dose reduction, the patient should be taken off treatment.  
 
6.2 Transaminase Elevations 
No delays or dose modifications should be made for grade 1-2 elevation of SGOT/SGPT.  For 
grade 3-4 elevations, the dose modifications below should be followed. 
 
6.3 Non-hematologic toxicity other than constitutional symptoms  
• Subjects who experience a grade 4 non-hematologic toxicity, or subjects who experience 
grade 2 or higher cardiopulmonary toxicity that is at least possibly-related to 
SYLATRON should be removed from protocol treatment and should not restart the drug.   
 
• The development of any other SYLATRON related grade 3 non-hematologic toxicity 
should result in immediate discontinuation of the drug.  Following the discontinuation of 
the drug, patient should be monitored and may restart the drug if following conditions are 
met:   
 
Subjects who develop grade 3 SYLATRON-related non-hematologic toxicity other 
than constitutional symptoms should have the drug withheld until the toxicity 
resolves to grade ≤1.  If the toxicity resolves to Grade 1 or better within 3 weeks of 
discontinuation of SYLATRON, patients may restart therapy at 0.6 mcg/kg/week.  

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
Toxicity that does not resolve within 3 weeks will require the subject to be removed 
from protocol therapy.  If the toxicity recurs at the 0.6 mcg/kg/week dose, the dose 
should be decreased to 0.3 mcg/kg/week, provided toxicity has decreased to Grades 
0-1 within 3 weeks of discontinuation of SYLATRON.  Recurrent Grade 3 non-
hematologic toxicity following two dose reductions will require the subject to be 
removed from protocol therapy.  No subsequent dose escalations are permitted after 
dose reduction for non-hematologic toxicity.   
 
• Subjects who develop persistent (≥7 days) grade 2 non-hematologic  SYLATRON -
related toxicities (other than constitutional symptoms and transaminase elevations) that 
are considered sufficiently medically significant or sufficiently intolerable by patients as 
to warrant treatment interruption and/or dose reduction should have  SYLATRON 
withheld until the toxicity resolves to grade ≤1.  If the toxicity resolves to Grade 1 or 
better within 3 weeks of discontinuation of SYLATRON, patients may restart therapy at 
the same dose.  Toxicity that does not resolve within 3 weeks will require the subject to 
be removed from protocol therapy.  If the grade 2 toxicity recurs, the SYLATRON dose 
should be withheld again until the toxicity resolves to grade 1 or better, at which point the 
dose should be decreased to 0.6 mcg/kg/week, provided toxicity has decreased to Grades 
0-1 within 3 weeks of discontinuation of SYLATRON.  If the toxicity recurs at the 0.6 
mcg/kg/week dose, the dose should be decreased to 0.3 mcg/kg/week, provided toxicity 
has decreased to Grades 0-1 within 3 weeks of discontinuation of SYLATRON.  
Recurrent Grade 2 non-hematologic toxicity following two dose reductions will require 
the subject to be removed from protocol therapy.  No subsequent dose escalations are 
permitted after dose reduction for non-hematologic toxicity.   
 
6.4 Dose Modification for Hematologic Toxicity 
Any subject who has an ANC <1000/µL or platelet count <100,000/µL should have the test 
repeated within 1 week (prior to the next dose of SYLATRON).  The criteria for dose 
modification are as follows: 
• Absolute neutrophil count (grade 4)  <500/µL 
• Platelets (grade 3) <50,000/ µL 
 
Whenever a subject’s blood count(s) drop below the criteria shown above, the SYLATRON will 
be held until the count(s) recover to Grades 0-1 and the dose will be reduced to 0.6 
mcg/kg/week.  Toxicity must recover to Grades 0-1 within 3 weeks of discontinuation of 
SYLATRON in order to allow re-initiation of treatment at the reduced dose. Toxicity that does 
not resolve within 3 weeks will require the subject to be removed from protocol therapy.  Should 
the toxicity recur at the 0.6 mcg/kg/week dose level, a second dose reduction to 0.3 mcg/kg/week 
should be performed provided the toxicity has decreased to Grades 0-1 within 3 weeks of 
discontinuation of SYLATRON. If there is again recurrence of hematologic toxicity meeting the 
above requirements for dose reduction (i.e., following the second dose reduction) treatment with 
SYLATRON will be discontinued permanently. No subsequent dose escalations will be 
permitted after dose reduction for hematologic toxicity. 
 
7 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting (via CTEP-AERS) in addition to 
routine reporting.   
 
7.1 Adverse Events and Potential Risks 
7.1.1 Adverse Event List(s) for SYLATRON (Peginterferon alfa-2b). See package insert for 
further information.  
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Peginterferon alfa-2b, more than 20 and up to 100 may have: 
• Nausea, vomiting, loss of appetite 
• Chills, fever 
• Reaction during or following injection of the drug which may cause fever, chills, rash, low 
blood pressure 
• Swelling and redness at the site of the medication injection 
• Tiredness 
• Pain 
• Dizziness, headache 
• Depression 
• Hair loss 
• Liver damage which may cause belly pain 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Peginterferon alfa-2b, from 4 to 20 may have: 
• Anemia which may require blood transfusions 
• Abnormal heartbeat which may cause fainting 
• Heart attack or heart failure which may cause shortness of breath, swelling of ankles, cough 
or tiredness 
• Bleeding of the eye 
• Bruising, bleeding 
• Confusion 
• Change in personality 
• Sensing things that are not there 
• State of mind that involves a "loss of contact with reality" 
• Thoughts of suicide or harming others 
• Low blood pressure 
 
RARE, AND SERIOUS 
In 100 people receiving Peginterferon alfa-2b, 3 or fewer may have: 
• Blood clot 
• Blurred vision with chance of blindness 
 
 
 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
Adverse Event Characteristics  
 
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for recording AEs in the RDC database.  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized until March 31, 2018 for expedited AE reporting.  CTCAE version 5.0 will be 
utilized for expedited AE reporting beginning April 1, 2018. All appropriate treatment areas 
should have access to a copy of the CTCAE versions 4.0 and 5.0.  A copy of the CTCAE 
versions 
4.0 
and 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.2 Expedited Adverse Event Reporting 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP website (http://ctep.cancer.gov).  The reporting procedures to be 
followed are presented in the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded 
from the CTEP website (http://ctep.cancer.gov).  These requirements are briefly outlined in the 
tables below (Section 7.2.1). 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made by 
telephone at 901-595-2715 to the PBTC Operations Office for instances when the Internet fails.  
Once Internet connectivity is restored, the 24-hour notification phoned in must be entered 
electronically into CTEP-AERS by the original submitter at the site. Also, if internet 
connectivity is not re-established within 24 hours, notify the following by telephone and or 
email. 
 
 
PBTC-039 Study Chair: 
PBTC OBDMC: 
Stewart Goldman, MD 
Ann & Robert H. Lurie Children’s 
Hospital of Chicago 
Neuro-Oncology  
 
 
 
 
 
Shujie Han, MD, Ph.D., CCRA  
St. Jude Children’s Research Hospital 
Department of Biostatistics 
 
 
 
 
 
Local IRB 
 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
individuals:  Study Coordinator of the PBTC, Principal Investigator, and the local treating 
physician.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
The OBDMC will fax the SAE / CTEP-AERS  report, within 48 hours of their awareness of the 
event to Merck Sharp & Dohme, Corp worldwide product safety (Attn: Worldwide Product 
Safety; FAX 215 993-1220). Additionally, any pregnancy occurring in association with use of a 
Merck Product will be reported to Merck Sharp & Dohme Corp. (Attn: Worldwide Product 
Safety; FAX 215 993-1220). 
 
Merck Sharp & Dohme, Corp will submit a report of the SAE to the FDA using the FDA‘s 
reporting form (FDA 3500A MedWatch Form) and guidelines. The report should describe the 
event as fully as possible. Supporting documentation (lab reports, summary notes, and autopsy 
report) should accompany the report. A fatal or immediately life-threatening SAE will be 
reported to the FDA within 7 calendar days of the receipt of the initial report by the sponsor. A 
non-fatal, no-life threatening SAE will be reported to the FDA within 15 calendar days of receipt 
of the initial report by the Sponsor.  
 
A copy of all 15 Day Reports  and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators by the investigator. This submission will be cross referenced according to local 
regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the time of 
submission.  Additionally, a copy of these reports will be submitted to Merck Sharp & Dohme 
Corp. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
 
7.2.1 Expedited Reporting Guidelines 
Use the NCI protocol number and the PBTC patient accession number assigned during trial 
registration on all reports. 
 
Note:  A death on treatment requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies within 30 Days of the Last Administration of the Investigational 
Agent/Intervention1, 2 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.3 Routine Adverse Event Reporting 
Adverse Events must be reported in routine study data submissions as outlined below:   
• Any baseline (pretreatment) abnormalities observed during the initial physical examination 
should be recorded in the PBTC RDC database. 
• Only record adverse events Grades 1 and 2 if the attribution is at least possibly related to 
SYLATRON.  Record all adverse events Grades 3 through 4 and deaths (while on treatment 
or within 30 days of treatment), regardless of attribution on the electronic case report forms 
(PBTC RDC database).   
 
7.4 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 Three options are available to describe the event:  
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia i.e. AML)  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.5 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified.  
 
8 PHARMACEUTICAL INFORMATION 
Merck has decided to voluntarily discontinue the manufacture of the PegIntron vials, Injection, 
for subcutaneous use, for distribution in the United States for business reasons. The decision is 
not based on any safety or efficacy findings with this product. This decision is due to scientific 
advancement, changes in treatment practices, and the consequent reduction in the demand for 
PegIntron. SYLATRON, which has the same active ingredient as PegIntron (Peginterferon alfa-
2b) with different Dosage Strength, is proposed to replace PegIntron as the study drug of PBTC-
039.  
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
8.1 SYLATRON (PEGINTERFERON ALFA-2B) (NSC # 720033)   
PEG12000-IFN is a covalent conjugate of recombinant Intron A with monomethoxy polyethylene 
glycol (PEG, with an average molecular weight of 12,000 daltons). The conjugate is synthesized 
by reacting Intron A with an electrophilic derivative of PEG.  
 
8.1.1 Agent Ordering 
Study Agent/s may be requested by the Principal Investigator (or their authorized designees) at 
each participating institution. All regulatory document requirements, as described by the PBTC, 
must be current and up to date prior to requesting study agents. 
 
8.1.2 Drug Requests: 
Drug request forms and instructions can be found on the PBTC-039 protocol and resources 
webpage. Peginterferon alfa-2b (SYLATRON) drug requests should be sent to Almac Clinical 
Services. 
Brandon Sortman 
Project Manager - Distribution 
Almac Clinical Services 
 
 
  

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
 
8.1.3  Product description:   
PEG12000-IFN Powder is a white to off-white lyophilized powder supplied in 2-ml vials for 
subcutaneous use.   
 
8.1.4 Solution preparation: 
Each vial of SYLATRON contains 296 mcg of PEGINTERFERON ALFA-2B with dibasic 
sodium phosphate, monobasic sodium phosphate, sucrose and polysorbate 80.  Following 
reconstitution with 0.7 mL of Sterile Water for Injection USP (or equivalent), each 0.5 mL 
contains 200 mcg PEGINTERFERON ALFA-2B. No more than 0.5 mL should be taken from 
any single vial.  This allows for an overfill volume to compensate for residual volume in the vial 
and syringe/needle hub during withdrawal, as well as for volume displacement by the excipients 
during reconstitution.  The clear, colorless solution has a pH of 6.5 to 7.1, is iso-osmotic, and 
unless otherwise specified, is intended to be used directly from the vial for SQ injection. 
 
8.1.5 Storage requirements:   
SYLATRON should be stored at 25°C, excursions permitted to 15-30°C. Do not freeze.  Keep 
away from heat. After reconstitution with supplied diluent, the solution should be used 
immediately, but may be stored up to 24 hours at 2 to 8°C. The reconstituted solution contains no 
preservative, is clear and colorless.  Upon completion of the study, all remaining study drug will 
be destroyed and disposed of pursuant to the ICH/GCP Guidelines and Institutional policies. 
 
8.1.6 Stability:   
The reconstituted solution is stable for 24 hours when stored refrigerated between 2-8°C (36-
46°F).  However, it is recommended that the solution be used within 3 hours after mixing. 
 
8.1.7 
Route of administration:  
SYLATRON (PEGINTERFERON ALFA-2B) will be administered subcutaneously.  The 
following syringes and needles are recommended:  B-D disposable syringes (Tuberculin 
syringes), B-D Number 30963; Needle gauge:  27; Length:  1/2 inches (13 mm).  Dosing 
instructions are provided in Appendix C  
 
9 PATHOLOGY, CORRELATIVE AND IMAGING STUDIES 
Information for the collection, shipping and handling for all exploratory correlative studies, 
neuropathology review and research imaging is located in this section.  The table below 
identifies the tests, sample type and amount, analyzing laboratory and whether it is required or 
optional.  For additional details, please review the associated section below.  
 
Test Name 
 
Sample Type 
and Amount 
Analyzing 
Laboratory 
Required or 
Optional 
Section 
ID 
Tumor Biology 
• IHC for WNT Pathway 
• Pyrosequencing for BRAF V600E mutation 
FFPE 
unstained 
slides and  
Scrolls 
Adekunle 
Adesina, TXCCC 
Optional 
9.1 
Neuropathology Review 
1 H&E slide 
PBTC CRB 
Required 
9.2 
Imaging 
Routine MRI 
NIC 
Required 
9.3 
 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
 
9.1 Pathology and Exploratory Correlative Studies 
As of July 19, 2015, the decision was reached to ship the existing PBTC-039 FFPE tumor 
material collected for the required Tumor Biology studies to the PBTC Central Review and 
Biorepository (CRB) for distribution to the Correlative laboratory for analysis.   Patients enrolled 
prior to this amendment who are still in follow-up should be asked to consider tissue submission 
to the PBTC CRB.   The PBTC CRB’s function is to collect, distribute and store specimens for 
central pathology review and planned correlative studies which support the laboratory objectives 
of this protocol.   
 
The CRB will also serve as a central repository for left over tumor tissue, from consenting 
patients on this protocol.  These samples will be stored in the repository for undefined future 
studies which support the mission of the PBTC.  If the patient does not consent to participation in 
the storage for future studies, remaining correlative study samples for the biology objective will 
be destroyed once the PBTC-039 analysis is complete. 
 
9.1.1 Specimens from Existing Patients 
Formalin fixed, paraffin embedded (FFPE) tumor materials which have been prepared and are 
pending shipment are to be labeled with the PBTC Accession # and the PBTC study for which 
the sample is provided.   These samples are to be shipped to the repository (see section 9.1.4) for 
distribution to the Correlative laboratory for analysis.    
 
If the samples have not been prepared and the patient is available, please discuss submission to 
the repository for analysis and storage for future studies. If the patient consents to participate in 
the repository, follow the guidance in Section 9.1.2 to prepare the samples for submission.    
If the patient does not consent to the repository, prepare the samples as described in Section 9.1.7 
and ship to the repository (see Section 9.1.4) for distribution to the Correlative lab for analysis.  
Unused samples will be destroyed once the PBTC-039 analysis is complete unless the patient has 
consented to long term storage of unused sample.  
 
9.1.2 Specimens from Future Patients 
If the patient consents to provide slides for submission to the repository at the time of 
participation in a PBTC trial the following should be submitted:  
• Tumor material 
Slides from the original and/or recurrent surgery should be prepared for storage. The site 
should provide up to twenty (20) unstained sections cut at 4µm in thickness on (+) slides 
from the most representative section.  Microcentrifuge tubes containing 3 x20 µm scrolls 
are also requested. Preference is for tissue that has not previously been frozen.   The 
corresponding pathology report (s) including immunohistochemical, special stains, and 
molecular/genetic results is to be uploaded to the PBTC using the secure File Upload 
system.  These reports will be made available to the pathologist via a link in ProtoLab. 
 
• Suitability of sections should be established by preparing one (1) H&E to ensure that the 
sections meet the following criteria:  
o histologically representative of the reported lesion 
for unstained slides, tissue should contain at least 60% viable tumor 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
o no more than 40% necrosis 
o for scrolls, tissue blocks with greater than 80% tumor component are preferred. 
 
• Peripheral Blood Mononuclear Cells 
PBMC may be collected by processing a 2-5 mL whole blood specimen with Ficoll or 
collecting the specimen in a BD Vacutainer™ CPT™ Cell Preparation Tube with Sodium 
Citrate as noted below. Once separated, all pellets must be snap frozen and stored at least 
at -20oC prior to dry ice shipment.  
 
Specimen Collection and Processing by Ficoll tube 
• Collect 2 - 5mL of fresh blood into an EDTA tube. 
• Transfer blood into a sterile 50-mL tube and add double the amount of PBS. MIX 
GENTLY. 
• Set up another tube containing half of its total volume of Ficoll. For example, if there is 
15 mL of blood + PBS, then use 7.5 mL of Ficoll (2:1 ratio). 
• At very slow pace (approx. 2 mL/minute), layer the blood + PBS mixture onto the Ficoll 
so that the solutions DO NOT MIX. Spin the blood/Ficoll at 750 g in slow mode for 30 
minutes @ 25ºC. After spin you will see four distinct layers: plasma (top layer), white 
fluffy ring (2nd layer), Ficoll (3rd layer), and blood (bottom layer). 
• Remove plasma layer down to about 1 mL above the white fluffy ring and discard.  
• Collect the entire white fluffy ring. If ring is hard to see, also take extra liquid above. 
Then discard everything else. 
• Place this fraction of white blood cells into a fresh 50 mL sterile tube with 20 mL of PBS.  
Spin down for 10 minutes @ 25ºC, 750 g in fast mode. Remove the supernatant. Add 
back to pellet 1 mL of PBS and spin for 5 min. at 4°C at 10000rpm. Remove supernatant.  
• Freeze the pellet of WBCs and store at -80ºC until shipment. 
• Ensure that all tubes are clearly labeled with the PBTC patient accession number. Please 
ensure that the labeling system used is designed to withstand temperatures down to -
80oC. Samples should be stored at -80ºC until shipment. For short term storage (2-3 
weeks) -20ºC is acceptable. NOTE 4ºC IS NOT ACCEPTABLE STORAGE.  
If it is not possible to collect the PBMC by Ficoll gradient then separation of PBMC can be 
conducted using CPT tube separation as an alternative. However the PBMC pellet MUST BE 
frozen immediately and stored at -80oC. 
 
 
Collection and Processing by CPT tube 
• Peripheral blood should be collected in a BD Vacutainer CPT™ Cell Preparation Tube 
with Sodium Citrate. 8 mL and 4 mL CPT tubes can be obtained from Fisher Scientific 
(Cat# 02-685-125, 02-688-81) or Becton-Dickinson (BD No.362761, 362760).  The 8 mL 
tubes have a 6 mL minimum draw and the 4 mL tubes have a 3 mL minimum draw.  
• Centrifuge the CPT™ tube at 1500 x g for 30 minutes at room temperature (20o C to 25o 
C). DO NOT APPLY THE BREAK ON THE CENTRIFUGE.  Use acceleration 5, brake 
0 (“slow mode”).   
• It may be necessary to spin the tube longer to ensure that all of the red blood cell 
components have been separated from the plasma layer through the polyester gel barrier. 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
• The tube should be removed immediately from the centrifuge. The mononuclear layer 
and plasma lie above the polyester gel plug. 
• Using a sterile pipette, remove as much of the plasma component (upper half of the CPT 
tube) without disturbing the mononuclear layer if possible and discard. 
• Transfer mononuclear cell layer (and some residual plasma layer) to a labeled 15- mL 
conical centrifuge tube and add 5 mL sterile room temperature magnesium or calcium-
free phosphate buffered saline (PBS) to fill the conical tube and recap. 
• Centrifuge at 450 x g for 10 minutes at room temperature (20o C to 25o C).  Use 
acceleration 9, brake (“fast mode”).  
• Remove supernatant, being careful not to aspirate the cellular pellet at the bottom of the 
tube.  
• Add 1 mL of sterile PBS to the pellet and gently re-suspend by pipetting up and down. 
Transfer the entire suspended pellet to the labeled cryovial.   
• Centrifuge the cryovial at 450 x g for 5 minutes (or spin down the microcentrifuge tube at 
1300 x g for 5 minutes) at room temperature. Discard the supernatant. Store the cell pellet 
cryovial frozen at -80ºC. For short term storage (2-3 weeks) -20o C is acceptable. 
 
If the patient consents to other correlative studies as outlined in sections 9.1.5, the following 
specimens may also be submitted to the CRB for distribution and storage:  
• Scrolls: if sufficient tissue is available, 2 scrolls at 10 micron thickness 
 
9.1.3 Handling of Specimens 
• Slides are to be labeled with the patient PBTC Accession # and these slides should be 
designated as PBTCRB # (where the # assigned from 1 to 20, or the highest number of 
unstained sections prepared, sequentially) or PBTCCRB H&E for the H&E stained 
section.  The tubes containing scrolls are to be labeled with the PBTC Accession # and 
the PBTC study for which the sample is provided.   
 
• Scrolls of Formalin Fixed, Paraffin Embedded (FFPE) tumor materials are to be labeled 
with the PBTC Accession # and the PBTC study for which the sample is provided.  
Scrolls of FFPE tumor material should be shipped at room temperature.  
 
• PBMCs are to be labeled with the PBTC Accession # and the PBTC study for which the 
sample is provided.  Samples should be shipped overnight in a separate box with a 2-day 
supply of dry ice. 
 
9.1.4 Shipment of Specimens 
Samples collected for distribution and storage in the repository should be sent to the PBTC CRB 
via FedEx by completing the Internet form at http://www.fedex.com/us/ and using the cc 
function to email PBTC CRB, the repository contact. FedEx user ID and password for pathology 
shipping can be found at PBTC-039 protocol. Samples are to be shipped to: 
 
PBTC CRB 
Research Support and Biorepository Services 
Children’s Hospital Los Angeles 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
 
 
 
 
9.1.5 Assessment of WNT and MAPK Pathway Activation  
FFPE tissue is obtained for diagnostic purposes in virtually all brain tumor resections, unlike 
frozen tumor material, which is obtained at the discretion of the neurosurgeon. Tumor material 
submission is optional but strongly encouraged for exploration for evidence of WNT pathway 
activation by immunohistochemistry (IHC) for nuclear beta-catenin protein and MAPK pathway 
activation by pyrosequencing for BRAF V600E mutation in tumor tissue. Investigators should 
make every effort possible to obtain tissue when available and must review with the study chair 
or co-chair if tissue is not available.  
 
• WNT Pathway Activation IHC :  
FFPE tumor sections will be evaluated for evidence of WNT pathway activation through staining 
for nuclear and cytoplasmic beta-catenin expression (phospho-β catenin, β-catenin supplied by 
New England Biolabs, Beverly, MA).  The assays have been developed and validated previously 
on medulloblastoma samples. 33 
 
• Detection of BRAF V600E mutation by pyrosequencing  
FFPE tumor sections will be evaluated for evidence of MAPK pathway activation through 
detection of the BRAF V600E mutation by pyrosequencing, using protocols currently in use in 
the Molecular Neuropathology laboratory, Department of Pathology, Texas Children’s Hospital.   
 
9.1.6 Collection of Specimen(s) 
• Twenty slides (5-6 µm) of unstained FFPE tissue are requested for IHC of WNT pathway 
to evaluate evidence of WNT pathway activation in resected tumor tissue.  The referring 
pathology departments should cut and send slides to the PBTC-CRB see Section 9.1.4.  
• Scrolls should be cut (3 x 20 µm) into 1.5ml microfuge tubes. Tubes should be labeled 
with the patient’s PBTC Accession number.  
 
9.1.7 Site Performing Correlative Study 
Analysis will be performed by Adekunle M. Adesina, MD, PhD, in the Department of Pathology 
Texas Children's Hospital/Baylor College of Medicine.  
 
9.2 Central Pathology Review 
Central pathology review is required for this study. Pathologist review for this study will include 
the following elements:  
• For each subject one H&E stained slide per one representative block from the brain 
tumor, removed either at initial diagnosis or relapse, should be submitted for review. 
• Review of the corresponding pathology report(s) of the immunohistochemical, special 
stains, and molecular/genetic results from current and/or original primary tumor 
• If necessary, review of immunohistochemical or special stained slides. Slides submitted 
to the PBTC CRB will be digitized to 40X. H&E stained sections will be retained and 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
filed at the CRB.  Original immunohistochemical or special stain slides will be returned 
to the submitting institution. 
 
9.2.1 Pathology Central Review and Data Collection 
The slides from the submitting institution will be sent to the PBTC CRB for central review.  The 
accompanying complete pathology evaluation should be uploaded to the PBTC using the secure 
File Upload system.  The slides will be logged into ProtoLab to document receipt of the samples.  
Slides will then be scanned at 40X using Leica Aperio Whole Slide Scanner.  The slides will be 
made available for remote review by the assigned reviewer and the corresponding reports will be 
available via a link in ProtoLab. The reviewer will be able to access the Protolab database to 
enter and review results via a VPN connection accessed by assigned usernames/passwords.  
 
9.3 Imaging Studies  
 
9.3.1 Description of the study: 
Brain MR with and without gadolinium focused on the sellar and suprasellar regions will be 
obtained preferably on the 3T magnet consisting of high resolution sagittal T1 images (slice 
thickness 3mm skip 0, 20cm FOV), high resolution coronal T1 images (slice thickness 3mm skip 
0, 16 cm FOV), axial T2 images (slice thickness 2.5mm thickness skip 0, 20 cm FOV), axial T2 
FLAIR images(slice thickness 4.0 mm, 20 cm FOV), high resolution coronal T2 images (slice 
thickness 2.0mm FOV 16cm), post gadolinium high resolution coronal T1 images (slice 
thickness 3mm skip 0, 16 cm FOV) and post gadolinium sagittal T1 high resolution images (slice 
thickness 3mm skip 0, FOV 16 cm) followed by axial T1 post-gadolinium images through the 
whole brain (slice thickness 4mm skip 0, FOV 20 cm).   
 
Imaging protocol sequences will be sent to the participating sites of the PBTC. Imaging specific 
protocols will also be sent for 1.5T magnets with the following parameters: high resolution 
sagittal T1 (slice thickness 3.0mm skip 0, FOV 20 cm), axial T2 images of the whole brain (slice 
thickness 4.0mm skip 0, FOV 20cm), axial T2 FLAIR of whole brain(slice thickness 4.0 mm 
skip 0, FOV 20cm), axial T1 images of the whole brain (slice thickness 4mm skip 0, FOV 
20cm), coronal FSE T2(slice thickness 3 mm, interleaved, FOV 16 cm), coronal T1 (slice 
thickness 3mm interleaved, FOV 16 cm), post-gadolinium high resolution coronal T1 and 
sagittal T1 images (3mm skip 0, FOV 16 cm).  
 
9.3.2 Outcome Measure 
See section 11 for the linear parameters used to assess response, depending on the stratum and 
whether the tumor is predominantly solid or cystic or both.  
 
9.3.3 Timing of Assessment 
Imaging studies will be done at baseline prior to PEGINTERFERON ALFA-2B therapy and 
every 12 weeks for the first 9 courses (approximately 1 year) then every 18 weeks thereafter until 
subjects develop evidence of disease progression, unacceptable toxicity or completion of 18 
courses (approximately 2 years) of PEGINTERFERON ALFA-2B therapy.   
 
9.3.4 Image Transfer 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
Only the MRI scans specified below for the two strata will be electronically transferred to the 
PBTC to be submitted to the PBTC Neuroimaging Center (NIC). All subject specific data will be 
stripped from the images and will be replaced with PBTC Accession numbers by the PBTC prior 
to sending images to the NIC. All image data transfer is accomplished using PGP (pretty-good-
privacy) 128-bit encryption, which meets industry standard for secure communication. 
 
Stratum I: 
All imaging studies obtained during the first 9 courses of treatment (approximately 1 year) will 
be centrally reviewed by the NIC.  In addition if they occur beyond the first 9 courses of 
treatment imaging studies documenting smallest disease measurement recorded since the start of 
protocol, responses, confirmation of responses (follow-up scan approximately 3 months later) 
and documenting PD will also centrally reviewed and the protocol criteria for disease assessment 
will be compared to the MacDonald criteria.    
 
Stratum II: 
Central review of imaging studies will be carried out only in patients with a response or 
progressive disease while on study.  For these patients, central review of smallest disease 
measurement recorded since the start of protocol, imaging studies documenting responses, 
confirmation of responses (follow-up scan approximately 3 months later) and studies 
documenting PD will be carried out and the protocol criteria for disease assessment will be 
compared to the MacDonald criteria.  

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
 
10 STUDY CALENDAR 
 
Table 2 
Standard Clinical and Laboratory Assessments  
 
Pre-
Therapy 
Course 1 
Course 2-9 
Course 10-18 
End of 
Treatment 
PHYSICAL ASSESSMENTS 
 
 
 
 
 
Complete History   
X 
 
 
 
 
Interval History 
 
XA 
XC 
XF 
X 
Psychiatric History** 
X 
XA 
XC 
XF 
X 
Performance status 
X 
XA 
XC 
XF 
X 
Physical including neurologic exam  
X 
XA 
XC 
XF 
X 
Visual field evaluation (as feasible) 
X 
 
XC 
XF 
 
Ophthalmology evaluation 
X 
 
XC 
XF 
 
Vital signs  
X 
XA 
XC 
XF 
X 
LABORATORY EVALUATION 
 
 
 
 
 
CBC (WBC, Hgb, Hct, Platelets, ANC, ALC) 
X 
XA 
XC 
XF 
X 
Serum Chemistries (Electrolytes, BUN, 
Creatinine,  SGOT(AST), SGPT(ALT), Total 
Bilirubin, TSH 
X 
XA 
XC 
XF 
X 
Urinalysis for protein (Urine Dip) 
X 
XA 
XC 
XF 
X 
Serum or urine pregnancy test (for females of 
childbearing potential)  
X 
XC 
XC 
XF 
 
IMAGING EVALUATION 
 
 
 
 
 
Brain MRI with thin cuts through the sellaD 
X 
 
XB 
XG 
X 
OTHER 
 
 
 
 
 
Biology Studies (assessment of WNT and 
MAPK pathway activation) 
XE 
 
 
 
 
FFPE tumor tissue for PBTC CRB 
XE 
 
 
 
 
PBMC for PBTC CRB 
XE 
 
 
 
 
A 
Assessments should be done prior to starting course 2, i.e. prior to the 7th injection. 
B 
Obtain every 12 weeks at time of visit and at time of progression as feasible 
C 
Obtain every 12 weeks at time of visit  
D 
See section 9.3 9.3.1 
E 
See section 9.1. 
F 
Obtain every 18 weeks at time of visit 
G 
Obtain every 18 weeks at time of visit and at time of progression as feasible 
 
* NOTE: Patients who do not have a Brain MRI performed at or after 9 courses (approximately 12 months) 
will be considered failures for the purpose of assessing the primary objective according to the statistical 
design.  See section 13.4.1. 
 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
** Psychiatric History: patient/family will be queried about mood, depression and suicidal ideations at each study 
visit. If there are any concerns about significant depression or any suicidal ideation, patient should be referred to 
Psychiatrist.  

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
 
11 MEASUREMENT OF EFFECT 
Response will be assessed on MRI scans, neurologic examinations and visual field evaluations 
when applicable.  Best response will be defined as below, based on the definitions used in the 
pilot study of non-pegylated interferon15:     
 
11.1 
Tumor Response Criteria 
Please note, measurements are required for both the solid and cystic components 
 
11.1.1 Complete response (CR):    
Total disappearance of all radiographically detectable tumor. Response must be sustained on the 
follow-up scan 3 months later. 
 
11.1.2 Partial response (PR):    
At least 50% decrease in the product of the greatest perpendicular diameters of the tumor as a 
whole, i.e., solid and cystic components.  Response must be sustained on the follow-up scan 3 
months later.   
 
11.1.3 Progressive disease (PD):  
The definitions of PD vary by strata and time on treatment given that transient increases in cyst 
size can be seen both during interferon therapy as well as for a prolonged period of time after 
radiation therapy. 
 
Stratum 1:   
o Within the first 12 months of treatment:  ≥ 25% increase in the product of the greatest 
perpendicular diameters of the solid component AND ≥ 0.4 cm increase in each of at 
least two dimensions of the solid component (note that these do not have to be the same 
measurements used to determine the product of the greatest perpendicular diameters) 
compared to the smallest disease measurement recorded since the start of protocol OR 
any new or worsening significant neurologic/vision deficit in conjunction with a lesser 
change in the solid component OR any new or worsening significant neurologic/vision 
deficit associated with solely a change in the cystic component that does not at least 
stabilize following a simple cyst aspiration. Isolated cystic enlargement is not considered 
progressive disease during the first 12 months of treatment unless more than 1 cyst 
aspiration is required for symptom control. 
 
o After the first 12 months of treatment:  ≥ 25% increase in the product of the greatest 
perpendicular diameters of the tumor as a whole (solid and cystic component) AND ≥ 0.4 
cm increase in each of at least two dimensions of the tumor as a whole compared to the 
smallest disease measurement recorded since the start of protocol OR any new or 
worsening significant neurologic/vision deficit in conjunction with a lesser change in the 
tumor as a whole.  If cyst aspiration is required for symptom control, the patient will be 
considered to have PD. 
 
Stratum 2:   
o Within the first 12 months of treatment:  ≥ 25% increase in the product of the greatest 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
perpendicular diameters of the solid component AND ≥ 0.4 cm increase in each of at 
least two dimensions of the solid component (note that these do not have to be the same 
measurements used to determine the product of the greatest perpendicular diameters) 
compared to the smallest disease measurement recorded since the start of protocol OR 
any new or worsening significant neurologic/vision deficit in conjunction with a lesser 
change in the solid component. Isolated cystic enlargement in the post- irradiation cohort 
is not considered progressive disease during the first 12 months of treatment, and it is 
anticipated that patients may already have or may need an Ommaya reservoir for repeated 
cyst taps as needed to control symptoms. 
 
o After the first 12 months of treatment:  ≥ 25% increase in the product of the greatest 
perpendicular diameters of the solid component AND ≥ 0.4 cm increase in each of at 
least two dimensions of the solid component of the tumor compared to the smallest 
disease measurement recorded since the start of protocol OR any new or worsening 
significant neurologic/vision deficit in conjunction with a lesser change in the solid 
component. An isolated increase in the cystic component in an asymptomatic patient is 
not considered progressive disease. Patients with progressive neurologic signs and/or 
symptoms associated with isolated cyst formation or progression will be considered to 
have PD if the neurologic signs and/or symptoms do not improve within 4 weeks of cyst 
aspiration or if > 2 cyst aspirations are required to control symptoms. 
11.1.4 Stable disease (SD):   
Those patients don’t meet the criteria for PD or response.   
 
12 DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data reporting 
12.1.1 On-Study Data Submission Schedule  
Pre-treatment, on-study and off-treatment data, as well as subject response data are to be 
recorded in the electronic data collection screens using the PBTC RDC database. See the 
Required Data and Timetable for Submission form located on the PBTC-039 protocol and 
resources webpage for the schedule. For assistance, contact the PBTC Protocol Coordinator, 
listed on the protocol title page. An optional roadmap is located on the PBTC-039 protocol and 
resources webpage.  
 
12.1.2 Method  
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  A 
protocol and subject-specific CDUS “Abbreviated” data set will be submitted electronically to 
CTEP on a quarterly basis, either by FTP burst of data or via the CDS web application. Reports 
are due January 31, April 30, July 31, and October 31. Instructions for submitting data using the 
CDUS can be found on the CTEP website (http://ctep.cancer.gov/reporting/cdus.html). 
12.2 
CTEP Multicenter Guidelines 
NA 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
12.3 
Participant and Data Confidentiality 
Participant confidentiality is strictly held in trust by the participating investigators, and their 
staff.  This confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to the clinical information relating to participants.  Therefore, the study protocol, 
documentation, data and all other information generated will be held in strict confidence. No 
information concerning the study and the data will be released to an unauthorized third party 
without the prior written approval of the Pediatric Brain Tumor Consortium (PBTC).  
 
The PBTC protocol coordinators, other authorized representatives of the sponsor, regulatory 
representatives,  PBTC auditors,  representatives of the IRB or the pharmaceutical collaborator 
supplying study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study.  The clinical study site will permit access to 
such records. 
 
Source documents which are the original records of clinical findings, observations or activities in 
a clinical trial are to be maintained at each participating site.  Sites must upload all source 
documentation which supports the eligibility of the participant to the PBTC. In the event the 
patient experiences unexpected events, additional source documentation may be requested to 
complete the event review. These documents may include but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda and radiographic images.   
 
Study participant study related data, which is for purposes of statistical analysis and scientific 
reporting will be submitted to the Pediatric Brain Tumor Consortium.  This will not include the 
participant's contact or identifying information.  Rather, research participants and their research 
data will be identified by a unique study identification number assigned at the time of screening 
or registration.  The study participant's contact information will be securely stored at each 
clinical site for internal use during the study.  At the end of the study, all records will continue to 
be kept in a secure location for as long a period as dictated by local IRB and institutional 
regulations. 
 
The study data entry and study management systems used by clinical sites and by the PBTC will 
be secured and password protected.  At the end of the study, all study data is maintained on a 
secure server.  
 
After the study is completed, the data collected will be maintained on a server and may be used 
by other investigators, including those outside the study.  With the participant's approval and as 
approved by local IRBs, biological samples labeled only with the participant's protocol specific 
identification number will be stored at the PBTC Central Review and Biorepository and could be 
made available to other investigators for future unspecified research.  Investigators conducting 
future studies will not have access to the key for stored data collected while the participant is on 
study.  Clinical data will be de-identified before it is shared with other investigators.  
 
If the participant agrees to submit a repository sample, those samples contain genetic information 
that may be used for research related to brain tumors and their treatment.  They may also be used 
to develop tests/assays to improve diagnosis and treatment of these diseases in the future.  

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
Genetic research may consist of the analysis of one or more genes or the analysis of genetic 
markers throughout the genome. 
 
13 STATISTICAL CONSIDERATIONS 
 
13.1 
Primary Endpoints 
 
Stratum 1: Rate of disease stabilization for 1 year (i.e. 9 courses of treatment). 
Stratum 2: Sustained Objective Response (PR+CR) rate in the cystic and/or soft tissue 
component observed during the first year of treatment (i.e. 9 courses of treatment). Response 
must be sustained for 3 months. 
 
13.2 
Secondary Endpoints 
 
Stratum 1: Sustained objective response rate and progression free survival 
Stratum 2: Progression free survival 
 
13.3 
Sample Size/Accrual Rate 
 
Stratum 1:  
The design will be based on proportion of patients who complete 9 courses of treatment 
(approximately 1-Year) without an event (PD or death for any reason). Even though the primary 
outcome variable for this stratum has a long duration, since the PBTC (or the COG) has no 
historical data available on which we could base a design, we chose to use a binomial endpoint. 
While the use of a binomial outcome variable results in some loss of information, it allows us to 
avoid making distributional assumptions which cannot be checked due to unavailability of 
historical data. Patients in stratum 1 will be enrolled at the time of progression.  
 
A summary of the proposed design for this stratum are provided in the table below. For patients 
who have never received radiation, >50% 1-year disease stabilization rate is felt to be the 
minimal acceptable threshold, since radiation can achieve high rates of disease control for at 
least a year with reported long term disease control rates of 75-90%13-15. In this study we are 
targeting 75% as the desirable rate for 1-year disease stabilization.  More specifically, 
PEGINTERFERON ALFA-2B will be deemed not worthy of further investigation in this patient 
population, if the true 1-year disease stabilization rate is less than 50% and the design will have 
90% statistical power for a true disease stabilization rate of 75%. These parameter settings 
coupled with type I error rate set at 10% lead to a sample size of 28 eligible and evaluable 
patients based on a 1-sample 1-sided exact binomial design. If 18 or more patients experience 
disease stabilization that lasts for at least 1 year, then we will conclude that PEGINTERFERON 
ALFA-2B is sufficiently active in this disease to warrant recommendation for continued 
investigation. We will conduct an interim analysis for futility once 12 patients have been 
enrolled and followed for 1 year (accrual will not be stopped for interim analysis).  If we observe 
6 or fewer patients who complete 1-year without an event among the 1st twelve patients treated, 
then we will stop accrual early for lack of evidence of adequate activity. If the true 1-year disease 
stabilization rate is 50%, there is a 61.6% chance that the trial will stop early for lack of efficacy. 
On the other hand, if the true 1-year disease stabilization rate is 75%, the probability that we will 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
stop early is 5.0%. The attained significance level and power of this design are 0.082 and 0.902, 
respectively. 
 
Table 3 
 
One-Sample Group Sequential Exact Binomial Design for Efficacy Monitoring 
Efficacy: Unacceptable ≤ 50%, Desirable ≥ 75% 
(α=β=0.1) 
 
 
n 
Efficacy 
Stage 1 
12 
Stop if number of “successes” ≤ 6 
Final 
28 
Reject if number of “successes”  ≤ 17 
 
 
Accrual Duration:  
Based on our informal survey prior to the initiation of this study, PBTC sites estimated that they 
each saw 1-2 patients per year who would be eligible to enroll on this stratum. Hence we 
originally estimated that it will take approximately 2.5-3 years to complete accrual taking into 
account the long outcome assessment window which is our main reason for not considering a 
Simon-type design where accrual would have to be suspended at the time of the interim analysis.  
As of amendment 3, the actual accrual rate proved to be substantially slower than this estimate 
with approximately 4 patients per year, taking into account the initial period when sites put the 
protocol through their IRBs etc. So based on this revised accrual estimate, we expect to complete 
accrual to this stratum in 5-6 years. The timing of the interim analysis is difficult to estimate but 
we expect that it will occur approximately 3.0-3.5 years after initiating accrual. 
 
 
Stratum 2:  
Objective response (CR+PR) rate observed during the first year of treatment (more specifically 
during the first 9 courses) is the primary endpoint for this stratum. In order to count towards the 
success criteria, objective responses observed during the first year must be sustained for 3 
months. Simon’s optimal two-stage design will be employed in this stratum, where accrual will 
stop, i.e. the trial will terminate early if evidence accumulates that the efficacy is lower than the 
specified acceptable levels. For patients who have failed radiation, >10% response rate will be 
the minimal acceptable threshold for response, but > 35% will be the threshold to establish 
efficacy.  More specifically PEGINTERFERON ALFA-2B will be deemed not worthy of further 
investigation in this patient population if the true sustained objective response (CR+PR) rate 
during the first year of treatment is less than 10% and the design will have 90% statistical power 
for a true response rate of 35%. These parameter settings coupled with type I and II error rates 
set at 10% lead to a sample size of 19 eligible and evaluable patients based on a Simon’s optimal 
design. Eleven (11) patients will be accrued in the first stage and if one (1) or fewer sustained 
objective responses are observed among the first 11 patients during their 1st year of treatment, the 
stratum will be closed to accrual and we will conclude that PEGINTERFERON ALFA-2B does 
not merit continued investigation in this disease due to lack of efficacy. Otherwise accrual will 
continue until 19 evaluable patients have been treated and assessed for objective response and 
toxicity. If four or more (≥4) patients experience sustained objective responses (CR+PR), then 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
we will conclude that PEGINTERFERON ALFA-2B is sufficiently active in this disease to 
warrant recommendation for continued investigation. With this design if the true response rate is 
10%, the probability that the trial will stop early is 70%. However, if the 'true' response 
probability is 35%, then there is a 6% chance that the trial will terminate in stage 1. While it is 
possible that the study will be closed to accrual for an extended period (up to 15 months) to 
assess outcome at the time of the interim analysis, considering the very low efficacy thresholds 
established for this stratum, and the relatively slow expected accrual rate, it is unlikely that this 
will be the case. If we reach 10 patients and we only have 1 response, it would be prudent to 
suspend accrual until the outcome for the last patient is available in order to avoid exposing 
additional patients to an ineffective agent. 
 
Table 4 
 
Simon’s Optimal Two-Stage Design for Efficacy Monitoring 
Efficacy: Unacceptable ≤ 10%, Acceptable ≥ 35% (α=β=0.1) 
 
 
n 
Efficacy 
Stage 1 
11 
Stop if number of “successes” ≤ 1 
Final 
19 
Reject if number of “successes”  ≤ 3 
 
 
Accrual Duration:  
During the planning stages of the trial, the PBTC sites estimated similar numbers (perhaps 
slightly lower than Stratum I) for accrual in this stratum (i.e., 1-2 patients per year/site). Based 
on this information, we estimated that it will take Approximately 1.5 years to reach the interim 
analysis sample size and approximately 2.5 years to finish accrual (not including any prolonged 
closure at the time of the interim analysis). As of amendment 3, based on the slower than 
expected accrual rate, we are revising the accrual estimates to 6 patients per year and thus we 
estimate that the trial will complete accrual in 3-4 years with an expected interim analysis to be 
performed approximately 2 years after initiating accrual. 
 
Combined accrual for Strata I and II: 
This is the first PBTC study for this patient population and therefore we do not have specific 
accrual data for patients with craniopharyngiomas. Thus the estimates in the table below are 
based on enrollment information from recent PBTC studies for other brain tumors. The 
maximum total planned accrual to this trial is 47 eligible and evaluable patients. Taking into 
account the possibility of some patients being declared ineligible or inevaluable, we estimate that 
we will enroll no more than 52 patients on this trial.  
 
Table 5 
 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
3 
4 
7 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
Non-Hispanic 
23 
22 
45 
Ethnic Category: Total of All Subjects 
26 
26 
52 
Racial Categories 
American Indian/Alaskan Native 
0 
0 
0 
Asian 
1 
1 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
Black or African American 
3 
4 
7 
White 
20 
19 
39 
More Than One Race 
2 
2 
4 
Racial Categories: Total of All Subjects 
26 
26 
52 
 
Analysis Plan: 
At the time of reporting, exact confidence interval estimates will be provided for the true, 
unknown rates of objective response for each stratum separately and 1-year disease stabilization 
rate for stratum 1. In addition to the usual estimates of response, we will estimate the confirmed 
sustained objective response rate (CR+PR) observed during treatment by cumulative incidence 
functions for each stratum. This provides not only an overall estimate of the objective response 
rate, but also an estimate of the timing of responses as a function of number of months of 
treatment. In this analysis, patients who are removed from treatment (due to disease progression, 
death or unacceptable toxicity) will be considered as having had a competing event. Patients who 
have stable disease and acceptable toxicity as of their last date of treatment will be censored on 
that date in the analysis.  Note that this secondary analysis will include sustained objective 
responses that may be observed beyond the first year of treatment. 
 
Kaplan-Meier estimates of distributions of PFS for all eligible patients who receive at least one 
dose of PI will be provided separately for each stratum. PFS will be measured from the date of 
initial treatment to the earliest date of disease progression, second malignancy or death for any 
reason for patients who fail; and to the date of last contact for patients who remain at risk for 
failure. 
 
Both for objective response assessments as well as PFS calculations, the assessments made at the 
treating site will be used. Any discrepancies between the treating sites’ assessments and the 
central review will be recorded and described. 
 
Toxicity data will be summarized via frequency tables both for episodes and for number of 
patients separately for each stratum. We will also tabulate the data related to dose reductions and 
treatment discontinuation due to toxicity. 
 
Analysis Plan for Central Imaging Review: 
All imaging studies obtained during the first year of treatment in Stratum I as well as all scans 
with the smallest disease measurement recorded since the start of protocol and scans 
documenting objective response or progressive disease in both strata will be centrally reviewed 
at the end of the study. We will summarize any discordance between site’s assessment and the 
central review across patients within a stratum as well as on a per patient basis taking into 
account the longitudinal data that will be available especially in Stratum I. Specific attention will 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
be given to PD assessment as we anticipate that there will be cases where PD criteria will be 
satisfied based on protocol definition but not by MacDonald criteria and vice-versa.  
 
Analysis Plan for the WNT pathway activation data: 
We will summarize the frequency of nuclear beta-catenin by IHC in FFPE tumor sections. We 
will also explore associations between presence of nuclear beta-catenin and outcome. Separately 
in each stratum, if we observe 10 or more responses among patients from whom biology data are 
available, we will use exploratory logistic regression models to look for associations between 
biological markers and response. Similarly, if we observe 10 or more progressions among 
patients from whom biology data are available in a stratum, we will explore associations between 
biological markers and PFS. Otherwise association with response and PFS will be summarized 
descriptively.  
 
13.4 
Stratification Factors 
Stratum 1:  Patients with progressive unresectable or recurrent craniopharyngiomas treated with 
surgery alone, who have not received radiation therapy.   
 
Stratum 2:  Patients with progressive or recurrent craniopharyngiomas following radiation 
therapy.     
 
13.4.1 Definition of Evaluable Patients 
In both strata, all patients who receive at least 1 dose of PEGINTERFERON ALFA-2B will be 
considered evaluable for the purposes of assessing the primary objectives of this trial. 
 
In both strata, patients who withdraw, are lost to follow-up, and/or are removed from treatment 
and who fail to be evaluated for the primary outcome will be counted as failures. 

NCI Protocol #: PBTC-039 
Version Date: March 1, 2018 
 
 
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Merchant TE, Kiehna EN, Sanford RA, et al. Craniopharyngioma: the St. Jude Children's 
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Minniti G, Saran F, Traish D, et al. Fractionated stereotactic conformal radiotherapy 
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DeVile CJ, Grant DB, Hayward RD, Stanhope R. Growth and endocrine sequelae of 
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Pierre-Kahn A, Recassens C, Pinto G, et al. Social and psycho-intellectual outcome 
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Sen GC, Lengyel P. The interferon system. A bird's eye view of it's biochemistry. J Biol 
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Ezekowitz RAB, Mulliken JB, Folkman J. Inerferon alfa-2a therapy for life-threatening 
hemangiomas of infancy. N Engl J Med. 1992;326:1456-1463. 
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Edwards L BB, Greenway H et al:. Eradication of squamous cell carcinoma by 
intralesional interferon alpha 2-b therapy. J Interferon Res. 1991;11((1)):594. 
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Lippman SM, Kavanagh JJ, Paredes-Espinoza M, et al. 13-cis-retinoic acid plus 
interferon alpha-2a: highly active systemic therapy for squamous cell carcinoma of the 
cervix. J Natl Cancer Inst. Feb 19 1992;84(4):241-245. 
15. 
Jakacki RI, Cohen BH, Jamison C, et al. Phase II evaluation of interferon-alpha-2a for 
progressive or recurrent craniopharyngiomas. J Neurosurg. Feb 2000;92(2):255-260. 
16. 
Cavalheiro S, Di Rocco C, Valenzuela S, et al. Craniopharyngiomas: intratumoral 
chemotherapy with interferon-alpha: a multicenter preliminary study with 60 cases. 
Neurosurg Focus. Apr 2010;28(4):E12. 
17. 
Ierardi DF, Fernandes MJ, Silva IR, et al. Apoptosis in alpha interferon (IFN-alpha) 
intratumoral chemotherapy for cystic craniopharyngiomas. Childs Nerv Syst. Sep 
2007;23(9):1041-1046. 

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18. 
Legha SS. The role of interferon alfa in the treatment of metastatic melanoma. Semin 
Oncol. 1997;24 (suppl):24-31. 
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Singh RK, Gutman M, Bucana CD, Sanchez R, Llansa N, Fidler IJ. Interferons-alpha and 
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Yung WK, Steck PA, Kelleher PJ, Moser RP, Rosenblum MG. Growth inhibitory effect 
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Slaton JW, Perrotte P, Inoue K, Dinney CP, Fidler IJ. Interferon-alpha-mediated down-
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22. 
Nucci M, et al. The therapeutic value of polyethylene glycol-modified proteins. Adv Drug 
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23. 
Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic 
hepatitis C. N Engl J Med. 2000;343:1666-1672. 
24. 
Wheatley K, Ives N, Hancock B, Gore M, Eggermont A, Suciu S. Does adjuvant 
interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis 
of the randomised trials. Cancer treatment reviews. Aug 2003;29(4):241-252. 
25. 
Kluin-Nelemans HC, Buck G, Le Cessie S, et al. Randomized comparison of low-dose 
versus high-dose interferon-alfa in chronic myeloid leukemia: prospective collaboration 
of 3 joint trials by the MRC and HOVON groups. Blood. 2004;103:4408-4415. 
26. 
Jakacki RI, Dombi E, Potter DM, et al. Phase I trial of pegylated interferon-{alpha}-2b in 
young patients with plexiform neurofibromas. Neurology. Jan 18 2011;76(3):265-272. 
27. 
Yeung JT, Pollack IF, Panigrahy A, Jakacki RI. Pegylated interferon-alpha-2b for 
children with recurrent craniopharyngioma. J Neurosurg Pediatr. Dec 2012;10(6):498-
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28. 
Brastianos PK, Taylor-Weiner A, Manley PE, et al. Exome sequencing identifies BRAF 
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Gaston-Massuet C, Andoniadou CL, Signore M, et al. Increased Wingless (Wnt) 
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30. 
Sekine S, Shibata T, Kokubu A, et al. Craniopharyngiomas of adamantinomatous type 
harbor beta-catenin gene mutations. The American journal of pathology. Dec 
2002;161(6):1997-2001. 
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Larkin SJ, Preda V, Karavitaki N, Grossman A, Ansorge O. BRAF V600E mutations are 
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Sorensen AG, Patel S, Harmath C, et al. Comparison of diameter and perimeter methods 
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American Society of Clinical Oncology. Jan 15 2001;19(2):551-557. 
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developmental origins. Nature. Dec 23 2010;468(7327):1095-1099. 
 

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APPENDIX A  Karnofsky/Lansky PERFORMANCE STATUS 
 
The Karnofsky Scale is designed for recipients aged 16 years and older, and the Lansky Scale is 
designed for recipients less than 16 years old. Use the table below to determine the score (10-
100) that best represents the recipient’s activity status at the requested time point. 
 
 
 
 
 

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APPENDIX B Instructions for Administration of Subcutaneous Injections 
 
Subcutaneous injections are given beneath the skin and not in a muscle. For small children, two 
persons may be needed. One holds and distracts the child and the other gives the injection. 
Before the injection is given, EMLA cream or ice can be applied to numb the area. 
 
You will need: 
• Alcohol swabs 
• Syringe and needles 
• Medication vial (powder) 
• Diluent vial (liquid) 
• Band-Aid 
 
Procedure for Preparing the Medication: 
• Select an area away from food and pets. 
• Gather all of the equipment 
• Wash your hands 
• Open the syringe 
• Clean the top of the vials (bottles) with alcohol 
• Remove the cap from the syringe. Do not touch the needle. 
• Pull back the plunger and fill the syringe with 0.7cc of air. Put the needle into the diluent 
(liquid) vial, and inject the air. 
• Repeat the step above for the vial with the medicine (powder) 
• With the tip of the needle in the vial with the liquid, turn the vial upside down and pull the 
plunger back to fill the syringe with 0.7 cc of the liquid. (Remember to keep the needle 
below the level of liquid). 
• Remove the syringe and needle from the vial. 
• Hold the syringe upright and tap on the sides to remove any air bubbles from the syringe. 
• Push the plunger gently to remove bubbles. 
• Recheck the syringe to make sure there is 0.7 cc of liquid. 
• With the tip of the needle in the vial with the powder push the plunger and inject the liquid 
into the vial. 
• Swirl the vial, do not shake, until the powder is dissolved. When the powder is completely 
dissolved it will be clear, colorless and without particles. 
• After the powder is dissolved, clean the vial with an alcohol swab again. 
• Take the second syringe, pull back the plunger and fill the syringe with the amount of air that 
is the same as your prescribed dose. 
• With the tip of the needle in the vial, turn the vial upside down and pull the plunger back to 
fill the syringe with the cc amount of your prescribed dose. (Remember to keep the needle 
below the level of liquid). 
• Hold the syringe upright and tap on the sides to remove any air bubbles from the syringe. 
• Push the plunger gently to remove bubbles. 
• Recheck the syringe to make sure there is the correct amount of cc in the syringe. 

NCI Protocol #: PBTC-039 
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• Replace the cap loosely onto the syringe. 
 
Procedure for Giving the Medication: 
• Remove clothing from the injection site 
• Clean the injection area with alcohol using a circular motion. Start in the center and move 
outward. 
• Let the skin air dry. 
• Remove the cap from the needle. 
• Grasp and raise the skin ½ to 1 inch. 
• Insert the needle into the skin with a quick darting motion at a 45-90 degree angle. 
• Release your grasp on the skin. 
• Pull back the plunger and check for any blood in the syringe. 
• If there is blood, remove the needle from the skin and begin again using a new needle. 
• If there is no blood, push the plunger slowly until the syringe is empty. 
• Remove the syringe quickly from the skin. 
• If necessary, put a Band-Aid over the injection site. 
• Make sure to throw the syringe into a puncture resistant container. 
• Keep a record on your medication diary. 
 
Storage:  SYLATRON (PEGINTERFERON ALFA-2B) should be stored at 25°C, excursions 
permitted to 15-30°C. Do not freeze. Keep away from heat. After reconstitution with supplied 
diluent, the solution should be used immediately, but may be stored up to 24 hours at 2 to 8°C.  
However it is recommended that the solution be used within 3 hours after mixing. The 
reconstituted solution contains no preservative, is clear and colorless.  
.

NCI Protocol #: PBTC-039 
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APPENDIX C SYLATRON (PEGINTERFERON ALFA-2B) Dosage Calculation and Chart 
 
Dosage calculation: 
The total dose of SYLATRON is calculated based on subject weight. The following formula 
should be used to calculate the dose: 
 
Dose in mL = 
  Weight (kg) x Dose (“X” µ/kg) 
 
 
__________________________ 
 
 
Reconstituted Vial Strength (µ/ml) 
 
Note: Vials are available in  200 mcg per 0.5 mL 
 
Example  
 
Vial Strength= 200 µg/0.5mL ( 400 µg/ml) 
Subject Weight=60 kg 
 
Dose in mL=  60 kg x 1.0     µg/kg 
                      ___________ 
                            400 µg/mL 
 
Dose            =     0.15 mL  SYLATRON 
 
* Reconstitute vial with 0.7 ml and use no more than 0.5 ml from each vial. 
 
 
Weight 20 kg to 120 kg (patients with weights less than 20 kg are ineligible) 
 
Weight 
(Kilogram, Kg) 
 
Dosage Strength 
Volume to be 
administered 
subcutaneously 
 
Dose to administer 
20 
200 mcg/0.5ml 
0.05 ml 
20 mcg 
24 
200 mcg/0.5ml 
0.06 ml 
24 mcg 
28 
200 mcg/0.5ml 
0.07 ml 
28 mcg 
32 
200 mcg/0.5ml 
0.08 ml 
32 mcg 
36 
200 mcg/0.5ml 
0.09 ml 
36 mcg 
40 
200 mcg/0.5ml 
0.1 ml 
40 mcg 
44 
200 mcg/0.5ml 
0.11 ml 
44 mcg 
48 
200 mcg/0.5ml 
0.12 ml 
48 mcg 
52 
200 mcg/0.5ml 
0.13 ml 
52 mcg 
56 
200 mcg/0.5ml 
0.14 ml 
56 mcg 
60 
200 mcg/0.5ml 
0.15 ml 
60 mcg 
64 
200 mcg/0.5ml 
0.16 ml 
64 mcg 

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68 
200 mcg/0.5ml 
0.17 ml 
68 mcg 
72 
200 mcg/0.5ml 
0.18 ml 
72 mcg 
76 
200 mcg/0.5ml 
0.19 ml 
76 mcg 
80 
200 mcg/0.5ml 
0.2 ml  
80 mcg 
84 
200 mcg/0.5ml 
0.21 ml 
84 mcg 
88 
200 mcg/0.5ml 
0.22 ml  
88 mcg 
92 
200 mcg/0.5ml 
0.23 ml 
92 mcg 
96 
200 mcg/0.5ml 
0.24 ml 
96 mcg 
100 
200 mcg/0.5ml 
0.25 ml 
100 mcg 
104 
200 mcg/0.5ml 
0.26 ml 
104 mcg 
108 
200 mcg/0.5ml 
0.27 ml 
108 mcg 
112 
200 mcg/0.5ml 
0.28 ml 
112 mcg 
116 
200 mcg/0.5ml 
0.29 ml 
116 mcg 
120 
200 mcg/0.5ml 
0.3 ml 
120 mcg 
 

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APPENDIX D Stress-Dose Steroid Dosing 
 
Suggested stress-dose steroid dosing for patients on physiologic replacement hydrocortisone  
• If the patient develops fever between 38-40 degrees Celsius without vomiting within 72 
hours of a dose of PEGINTERFERON ALFA-2B, the next dose of hydrocortisone should 
be doubled. 
• If the patient develops fever > 40 degrees Celsius without vomiting within 72 hours of a 
dose of PEGINTERFERON ALFA-2B, the next dose of hydrocortisone should be tripled. 
• If the patient develops vomiting or poor perfusion and is not able to tolerate PO meds, 
100 mg IM hydrocortisone should be administered.