Conditions: Recurrent Childhood Ependymoma
Keywords: Ependymoma Anaplastic Ependymoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the anti-tumor activity of Everolimus among children with recurrent or progressive ependymoma. Recurrent or progressive ependymoma is incurable and has very limited treatment options. The rationale for this study is based upon both pre-clinical and clinical considerations: Immunohistochemistry studies have demonstrated that 20 out of 23 (87%) pediatric ependymomas are immunoreactive for phosphorylated S6, a biomarker that often predicts response to mTOR pathway-targeted therapy. Furthermore, children with with multiply recurrent ependymomas have had objective and durable responses to the mTOR inhibitor, Sirolimus (Rapamune, Pfizer). As a result of this pre-clinical and clinical data, this study will further investigate the activity of an mTOR pathway inhibitor, Everolimus, against children with recurrent or progressive ependymomas. In this study, Everolimus will be administered at a dose and schedule that have previously been demonstrated as safe and effective in children. Children may take Everolimus for up to 2 years on this study, until tumor progression or unacceptable toxicity.

Detailed description:
Ependymoma is the third most common central nervous system neoplasm in children, accounting for approximately 10% of childhood brain tumors. Although the prognosis for children with newly-diagnosed completely resected ependymomas is often good, children with incompletely resected tumors often suffer repeated episodes of tumor progression and die as a result of their tumor. The prognosis for children with recurrent or progressive ependymomas is especially dismal and the majority of children with recurrent or progressive ependymomas will eventually succumb to their tumor within 8.7 to 24 months. At the time of tumor recurrence, therapeutic options are limited. A recent report by Merchant and co-workers described several long-term survivors after tumor recurrence when treated with a second course of radiation therapy.

Unfortunately, although chemotherapy occasionally demonstrates anti-tumor activity against recurrent ependymoma, but responses are rarely durable.12 Indeed, a recent review by Bouffet and co-workers concluded that the frequency of durable responses of recurrent ependymomas to chemotherapy was disappointing and encouraged a re-evaluation of the current chemotherapeutic approach to intracranial ependymoma and that studies are needed to identify new biological targets to inform future clinical trials.

Everolimus is a novel derivative of rapamycin. It has been in clinical development since 1996 as an immunosuppressant in solid organ transplantation. Everolimus is approved in Europe and other global markets (trade name: Certican®) for cardiac and renal transplantation, and in the United States (trade name: Zortress®) for the prevention of organ rejection of kidney transplantation. Everolimus was developed in oncology as Afinitor® and was approved for advanced renal cell carcinoma (RCC) in 2009. In 2010, Afinitor® received United States (US) approval for patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS). Everolimus is also available as Votubia® in the European Union (EU) for patients with SEGA associated with TS. Afinitor® was approved for "progressive pancreatic neuroendocrine tumor (PNET) in patients with unresectable, locally advanced, or metastatic disease" in 2011 in various countries, including the US and Europe. In 2012, Afinitor® received approval for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2- negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole. Furthermore in 2012, Afinitor® received approval for the treatment of adult patients with TSC who have renal angiomyolipoma not requiring immediate surgery.

At the cellular and molecular level, Everolimus acts as a signal transduction inhibitor. It selectively inhibits mTOR (mammalian target of rapamycin), a key protein kinase which regulates cell growth, proliferation and survival. The mTOR kinase is mainly activated via the phosphatidylinositol 3-kinase (PI3-Kinase) pathway through AKT/PKB and the tuberous sclerosis complex (TSC1/2). Mutations in these components or in PTEN, a negative regulator of PI3-kinase, may result in their dysregulation. Abnormal functioning of various components of the signaling pathways contributes to the pathophysiology of numerous human cancers. Various preclinical models have confirmed the role of this pathway in tumor development.

The main known functions of mTOR include the following:

* mTOR functions as a sensor of mitogens, growth factors and energy and nutrient levels;
* Facilitating cell-cycle progression from G1-S phase in appropriate growth conditions;
* The PI3K/mTOR pathway itself is frequently dysregulated in many human cancers, and oncogenic transformation may sensitize tumor cells to mTOR inhibitors;
* PI3-kinase mutations have been reported in the primary tumor in 10-20% of human colorectal cancers;16,17
* The loss of PTEN protein, either through gene deletion or functional silencing (promoter hypermethylation), is reported in approximately 60% of primary human colorectal cancers;
* The mTOR pathway is involved in the production of pro-angiogenic factors (i.e., VEGF) and inhibition of endothelial cell growth and proliferation;
* Through inactivating eukaryotic initiation factor 4E binding proteins and activating the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates protein translation, including the HIF-1 proteins. Inhibition of mTOR is expected to lead to decreased expression of HIF-1.

Everolimus inhibits the proliferation of a range of human tumor cell lines in vitro including lines originating from lung, breast, prostate, colon, melanoma and glioblastoma. IC50s range from sub/low nM to µM. Everolimus also inhibits the proliferation of human umbilical vein endothelial cells (HUVECS) in vitro, with particular potency against VEGF-induced proliferation suggesting that Everolimus may also act as an anti-angiogenic agent. The anti-angiogenic activity of Everolimus was confirmed in vivo. Everolimus selectively inhibited VEGF-dependent angiogenic response at well tolerated doses. Mice with primary and metastatic tumors treated with Everolimus showed a significant reduction in blood vessel density when compared to controls.

The potential of Everolimus as an anti-cancer agent was shown in rodent models. Everolimus is orally bioavailable, residing longer in tumor tissue than in plasma in a subcutaneous mouse xenograft model, and demonstrating high tumor penetration in a rat pancreatic tumor model. The pharmacokinetic profile of Everolimus indicates sufficient tumor penetration, above that needed to inhibit the proliferation of endothelial cells and tumor cell lines deemed sensitive to Everolimus in vitro.

Everolimus administered orally daily was a potent inhibitor of tumor growth, at well tolerated doses, in 11 different mouse xenograft models (including pancreatic, colon, epidermoid, lung and melanoma) and two syngeneic models (rat pancreatic, mouse orthotopic melanoma). These models included tumor lines considered sensitive and "relatively resistant" in vitro. In general, Everolimus was better tolerated in mouse xenograft models than standard cytotoxic agents (i.e., doxorubicin and 5-fluorouracil), while possessing similar anti-tumor activity. Additionally, activity in a VEGF-impregnated subcutaneous implant model of angiogenesis and reduced vascularity (vessel density) of Everolimus-treated tumors (murine melanoma) provided evidence of in vivo effects of angiogenesis.

It is not clear which molecular determinants predict responsiveness of tumor cells to Everolimus. Molecular analysis has revealed that relative sensitivity to Everolimus in vitro correlates with the degree of phosphorylation (activation) of the AKT/PKB protein kinase and the S6 ribosomal protein; in some cases (i.e., glioblastoma) there is also a correlation with PTEN status.

In vivo studies investigating the anti-tumor activity of Everolimus in experimental animal tumor models showed that Everolimus monotherapy typically reduced tumor cell growth rates rather than produced regressions. These effects occurred within the dose range of 2.5 mg to 10 mg/kg, orally once a day.

In preclinical models, the administration of Everolimus is associated with reduction of protein phosphorylation in target proteins downstream of mTOR, notably phosphorylated S6 and phosphorylated 4EBP1, and occasionally with an increase in phosphorylated AKT, a protein upstream of mTOR signaling pathway.

All significant adverse events observed in toxicology studies with Everolimus in mice, rats, monkeys and mini-pigs were consistent with its anticipated pharmacological action as an anti-proliferative and immunosuppressant and at least in part reversible after a 2 or 4-week recovery period with the exception of the changes in male reproductive organs, most notably testes.

Rationale: The purpose of this study is to evaluate the anti-tumor activity of Everolimus among children with recurrent or progressive ependymoma. The rationale for this study is based upon both pre-clinical and clinical considerations. Recurrent or progressive ependymoma is incurable and has very limited treatment options. In 2011, the investigators group published a case report describing a young child with a multiply recurrent ependymoma after 4 chemotherapy regimens and several courses of radiation therapy and who had an objective and long lasting response to sirolimus (Rapamune, Pfizer). This patient, who had been treated with various regimens over a span of 20 months without response, subsequently had a near complete response to sirolimus of 18 months duration. Subsequently a second child with a recurrent ependymoma was treated with sirolimus and oral etoposide and had a near-complete response of 18 months duration. Furthermore, immunohistochemistry studies have revealed that 20 out of 23 (87%) pediatric ependymomas were immunoreactive for phosphorylated S6, a biomarker that often predicts response to mTOR pathway-targeted therapy.

Existing data regarding the anti-tumor activity of mTOR inhibitors among children has demonstrated that mTOR inhibitors are well tolerated and have activity against pediatric brain tumors. For example, Franz et al. reported five children with tuberous sclerosis complex and progressive subependymal giant cell astrocytomas who were treated with sirolimus to achieve target trough concentrations between 5 - 15 ng/mL. All tumors demonstrated objective responses to sirolimus. One patient who interrupted sirolimus therapy experienced tumor progression that responded to resumption of sirolimus therapy. A subsequent phase III study of everolimus compared responses of 78 patients treated with everolimus versus 39 patients treated with placebo. 27 of 78 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (p\<0.0001). Adverse events were mostly grade 1 or 2 and no patients discontinued treatment because of adverse events.

Biomarkers of mTOR pathway activation and sensitivity to mTOR inhibitors, including phosphorylated S6235/236, phosphorylated S6240/244, phosphorylated 4EBP1, phosphorylated PRAS40 (pT246), phosphorylated P70S6K, and PTEN expression, will be performed. Although these biomarkers have, to varying degrees, been correlated with mTOR pathway activation and sensitivity to mTOR inhibitors, these studies are considered to be exploratory in the context of this clinical trial.

Arms:
arm 1: The recommended dose of Everolimus is 4.5 mg/m2/dose, once daily for up to 2 years, until disease progression or unacceptable toxicity occurs.

Interventions: intervention 1: Everolimus
Intervention descriptions: intervention 1: The recommended dose of Everolimus is 4.5 mg/m2/dose, once daily for up to 2 years, until disease progression or unacceptable toxicity occurs.

Protocol document:
Prot_SAP_002.pdf: 
 
STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
Official title: PHASE II STUDY OF EVEROLIMUS (RAD001, AFINITOR®) 
FOR CHILDREN WITH RECURRENT OR PROGRESSIVE EPENDYMOMA 
NCT number: NCT02155920 
IRB Approved Document date: 02-17-2021 


 
 
Version 1.7: August 15, 2018 
 
 
 
 
 
 
 
STU052014-038, Bowers, FormA3-ResearchProtocol, Mod_29, 02-17-21 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
 
PHASE II STUDY OF EVEROLIMUS (RAD001, AFINITOR®) FOR CHILDREN WITH 
RECURRENT OR PROGRESSIVE EPENDYMOMA  
 
 
 
Principal Investigator:  
Daniel C. Bowers, MD 
 
 
 
 
Division of Pediatric Hematology-Oncology 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd 
 
 
 
 
Dallas, TX 75390-9063 
 
 
 
 
(214) 648-8495  
 
 
 
 
(214) 648-3122 
 
 
 
 
Daniel.Bowers@utsouthwestern.edu  
 
Sub-Investigator(s): 
 
Laura J. Klesse, MD, PhD 
 
 
 
 
Division of Pediatric Hematology-Oncology 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd 
 
 
 
 
Dallas, TX 75390-9063 
 
 
 
 
(214) 648-8495  
 
 
 
 
(214) 648-3122 
 
 
 
 
Laura.Klesse@utsouthwestern.edu  
 
Collaborating Site Principal Investigators:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Jack Su, MD, MS 
 
 
 
 
Texas Children’s Cancer Center 
 
 
 
 
Baylor College of Medicine 
 
 
 
 
6701 Fannin Street, CC1510 
 
 
 
 
Houston, Texas 77030 
 
 
 
 
(832) 822-4306 
 
 
 
 
(832) 825-1503 
 
 
 
 
jmsu@txch.org  
 
 
 
 
 
Sharon Gardner, MD 
 
 
 
 
New York University Langone Medical Center 
 
 
 
 
Steven D. Hassenfeld Children’s Center for Cancer and Blood Disorders 
 
 
 
 
New York, New York 10016 
 
 
 
 
(212) 263-8400 
 
 
 
 
sharon.gardner@nyumc.org  
 
 
 
 
 
Sonia Partap, MD 
 
 
 
 
Lucile Packard Children’s Hospital at Stanford 
 
 
 
 
750 Welch Road, Suite 317 
 
 
 
 
Palo Alto, CA 94304 
 
 
 
 
(650) 736-0885 
 
 
 
 
spartap@stanford.edu  
 
 


 
 
Version 1.7: August 15, 2018 
 
 
 
 
 
 
 
STU052014-038, Bowers, FormA3-ResearchProtocol, Mod_29, 02-17-21 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
 
 
 
 
Biostatistician: 
 
Chul Ahn, PhD 
 
 
 
 
Department of Clinical Science 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd 
 
 
 
 
Dallas, TX 75390-9063 
 
 
 
 
(214)648-9418 
 
 
 
 
(214)648-3934 
 
 
 
 
Chul.Ahn@UTSouthwestern.edu  
 
Study Drug: 
 
 
Everolimus (RAD001, Afinitor®) 
 
IND Number: 
 
 
IND Exempt per the FDA 
 
 
 
 
Cross-Reference IND 66,279 for RAD001 
 
Funding Source:  
Investigator-Initiated Study, funded by Novartis Pharmaceuticals. 
 
Initial version:  
 
October 16, 2014 
Amended: 
 
 
V1.2: May 27, 2015 
 
 
 
V1.3: September 4, 2015 
 
 
 
V1.4: March 8, 2016 
 
 
 
V1.5: April 11, 2017   
 
 
 
V1.6: July 31, 2017 
 
 
 
V1.7: August 15, 2018 
 
 
UT Southwestern Medical Center at Dallas 
Harold C. Simmons Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 


 
 
Version 1.7: August 15, 2018 
 
 
 
 
 
 
 
STU052014-038, Bowers, FormA3-ResearchProtocol, Mod_29, 02-17-21 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
 
 
Signature Page 
Protocol Version 1.7, August 15, 2018 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS............................................................................................................. 1 
STUDY SCHEMA ............................................................................................................................ 2 
STUDY SUMMARY ......................................................................................................................... 2 
1.0 
BACKGROUND AND RATIONALE .................................................................................... 3 
1.1 
Disease Background........................................................................................................ 3 
1.2 
Everolimus: Background and Associated Known Toxicities ............................................ 3 
1.3 
Rationale .......................................................................................................................... 6 
1.4 
Rational for Targeted Dose ............................................................................................. 7 
1.5 
Correlative Studies .......................................................................................................... 7 
2.0 
STUDY OBJECTIVES ......................................................................................................... 8 
2.1 
Primary Objectives ........................................................................................................... 8 
2.2 
Secondary Objectives ...................................................................................................... 8 
2.3 
Endpoints ......................................................................................................................... 8 
3.0 
PATIENT ELIGIBILITY ........................................................................................................ 9 
3.1 
Inclusion Criteria .............................................................................................................. 9 
3.2 
Exclusion Criteria ........................................................................................................... 10 
4.0 
TREATMENT PLAN .......................................................................................................... 13 
4.1 
Treatment Dosage and Administration .......................................................................... 13 
4.2 
Treatment Assignment................................................................................................... 13 
4.3 
Medication Formulations, Dosage and Administration .................................................. 14 
4.4 
Medication Supply and Accountability ........................................................................... 15 
4.5 
Recommended Dose of Everolimus .............................................................................. 15 
4.6 
Concomitant Medications .............................................................................................. 22 
4.7 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 24 


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4.8 
Duration of Therapy ....................................................................................................... 24 
4.9 
Duration of Follow Up .................................................................................................... 25 
4.10 
Removal of Patients from Protocol Therapy .................................................................. 25 
4.11 
Patient Replacement ..................................................................................................... 25 
5.0 
STUDY PROCEDURES ..................................................................................................... 25 
5.1 
Screening/Baseline Procedures .................................................................................... 25 
5.2 
Procedures During Treatment ....................................................................................... 26 
5.3 
Follow-up Procedures .................................................................................................... 27 
5.4 
Time and Events Table .................................................................................................. 27 
5.5 
Removal of Subjects from Study ................................................................................... 27 
6.0 
MEASUREMENT OF EFFECT .......................................................................................... 28 
6.1 
Response Assessment .................................................................................................. 28 
6.2 
Safety/tolerability ........................................................................................................... 31 
7.0 
ADVERSE EVENTS .......................................................................................................... 31 
7.1 
Experimental Therapy.................................................................................................... 31 
7.2 
Adverse Event Monitoring  ............................................................................................ 31 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting .............. 36 
7.5 
Pregnancy ...................................................................................................................... 38 
7.6 
Stopping Rules .............................................................................................................. 38 
8.0 
CORRELATIVE STUDIES ................................................................................................. 38 
8.1 
FFPE .............................................................................................................................. 38 
8.2 
Immunohistochemistry ................................................................................................... 38 
9.0 
CONSIDERATIONS ........................................................................................................... 39 
9.1 
Study Design/Study Endpoints ...................................................................................... 39 
9.2 
Sample Size and Accrual .............................................................................................. 39 
9.3 
Data Analyses Plans...................................................................................................... 40 


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10.0 
STUDY MANAGEMENT .................................................................................................... 40 
10.1 
Conflict of Interest .......................................................................................................... 40 
10.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 40 
10.3 
Required Documentation (for multi-site studies) ........................................................... 40 
10.4 
Registration Procedures ................................................................................................ 41 
10.5 
Data Management and Monitoring / Auditing ................................................................ 41 
10.6 
Adherence to the Protocol ............................................................................................. 42 
10.7 
Amendments to the Protocol ......................................................................................... 43 
10.8 
Record Retention ........................................................................................................... 43 
10.9 
Obligations of Investigators ........................................................................................... 43 
11.0 
REFERENCES ................................................................................................................... 44 
APPENDIX I: Inclusion / Exclusion Checklist............................................................................ 46 
APPENDIX II: Time and Events Table ........................................................................................ 47 
APPENDIX III:  Patient Drug Diary .............................................................................................. 49 


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LIST OF ABBREVIATIONS 
 
Examples Include: 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DOT 
Disease Oriented Team 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
INR 
International Normalized Ratio 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
p.o. 
peros/by mouth/orally 
PR 
Partial Response 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
 
 
 


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STUDY SCHEMA 
 
 
 
 
 
STUDY SUMMARY 
Title 
Phase II Study of Everolimus (RAD001, Afinitor®) for Children with 
Recurrent or Progressive Ependymoma 
Short Title 
Everolimus (RAD001, Afinitor®) for Children with Recurrent or 
Progressive Ependymoma 
Protocol Number 
CRAD001CUS224T 
Phase 
Phase II 
Methodology 
Single Arm, Open Labeled Clinical Trial 
Study Duration 
5 years 
Study Center(s) 
UT Southwestern Medical Center and approved subsites. 
Objectives 
• Determine the Objective Response Rate (ORR = Complete Response 
Rate + Partial Response Rate + Prolonged Stable Disease Rate) 
following treatment with everolimus for children with recurrent or 
progressive ependymomas. 
• Determine the duration of response, progression free survival (PFS) and 
event free survival (EFS) following treatment with everolimus for 
children with recurrent or progressive ependymomas. 
• Determine safety and tolerability of everolimus among children with 
recurrent or progressive ependymomas. 
• Descriptive analysis and correlation of response rate to biological 
markers of mTOR pathway activation, including phosphorylated 
S6235/236, phosphorylated S6240/244, phosphorylated PRAS40 (pT246), 
phosphorylated 4EBP1, phosphorylated P70S6K, and PTEN expression. 
Number of Subjects 
18 Patients 
Diagnosis and Main 
Inclusion Criteria 
Recurrent or Progressive Ependymoma 
Study Product(s), Dose, 
Route, Regimen 
Everolimus (RAD001, Afinitor®) orally once a day. 
Duration of administration 
Up to 2 years. 
Reference therapy 
None 
Statistical Methodology 
Objective response rate and the corresponding 95% confidence interval 
will be estimated using the exact binomial method. Kaplan-Meier method 
will be used to estimate the duration of response, progression free 
survival (PFS) and event free survival (EFS). Exploratory analysis will be 
conducted for correlative studies.  
 
 
 
• Everolimus 4.5 mg/m2/dose orally once a day 
• Adjust dose to achieve trough concentrations of 5 – 15 
ng/ml 
Enrollment on Study 


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
 
Recurrent Ependymoma: Ependymoma is the third most common central nervous system 
neoplasm in children, accounting for approximately 10% of childhood brain tumors.1 
Although the prognosis for children with newly-diagnosed completely resected 
ependymomas is often good,2-5 children with incompletely resected tumors often suffer 
repeated episodes of tumor progression and die as a result of their tumor.6-8 The prognosis 
for children with recurrent or progressive ependymomas is especially dismal and the 
majority of children with recurrent or progressive ependymomas will eventually succumb 
to their tumor within 8.7 to 24 months.9,10 At the time of tumor recurrence, therapeutic 
options are limited. A recent report by Merchant and co-workers described several long-
term survivors after tumor recurrence when treated with a second course of radiation 
therapy.11 Unfortunately, although chemotherapy occasionally demonstrates anti-tumor 
activity against recurrent ependymoma, responses are rarely durable.12 Indeed, a recent 
review by Bouffet and co-workers concluded that the frequency of durable responses of 
recurrent ependymomas to chemotherapy was disappointing and encouraged a re-
evaluation of the current chemotherapeutic approach to intracranial ependymoma and that 
studies are needed to identify new biological targets to inform future clinical trials.9 
1.2 
Everolimus: Background and Associated Known Toxicities 
 
Everolimus is a novel derivative of rapamycin. It has been in clinical development since 
1996 as an immunosuppressant in solid organ transplantation. Everolimus is approved in 
Europe and other global markets (trade name: Certican®) for cardiac and renal 
transplantation, and in the United States (trade name: Zortress®) for the prevention of 
organ rejection of kidney transplantation. 
 
Everolimus was developed in oncology as Afinitor® and was approved for advanced renal 
cell carcinoma (RCC) in 2009. In 2010, Afinitor® received United States (US) approval for 
patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous 
sclerosis (TS). Everolimus is also available as Votubia® in the European Union (EU) for 
patients with SEGA associated with TS. Afinitor® was approved for “progressive pancreatic 
neuroendocrine tumor (PNET) in patients with unresectable, locally advanced, or 
metastatic disease” in 2011 in various countries, including the US and Europe. In 2012 
Afinitor® received approval for the treatment of postmenopausal women with advanced 
hormone receptor-positive, HER2- negative breast cancer (advanced HR+ BC) in 
combination with exemestane, after failure of treatment with letrozole or anastrozole. 
Furthermore in 2012, Afinitor® received approval for the treatment of adult patients with 
tuberous sclerosis complex (TSC) who have renal angiomyolipoma not requiring 
immediate surgery. 
 
 
Approximately 30,582 cancer patients have been treated with everolimus as of 
September 30, 2013: 
 
• 
16,671 patients in Novartis-sponsored clinical trials 
• 
1,911 patients in the individual patient supply program 
• 
> 12,000 patients in investigator-sponsored studies. 
 
 


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The following is a brief summary of the main characteristics of Everolimus. More complete 
information can be obtained from the Everolimus Investigator’s Brochure (IB). 
 
Overview of Everolimus: Everolimus is a derivative of rapamycin which acts as a signal 
transduction inhibitor (Table 1-1, Figure 1-1). Everolimus selectively inhibits mTOR 
(mammalian target of rapamycin), specifically targeting the mTOR-raptor signal 
transduction complex. mTOR is a key serine-threonine kinase in the PI3K/AKT signaling 
cascade, which is known to be dysregulated in a wide spectrum of human cancers.13 
 
Everolimus is being investigated as an anticancer agent based on its potential to act: 
• 
directly on the tumor cells by inhibiting tumor cell growth and proliferation; 
• 
indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent 
inhibition of tumor cell VEGF (vascular endothelial growth factor) production and 
VEGF-induced proliferation of endothelial cells). 
Table 1-1 
Everolimus - Drug substance 
Chemical name 
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-
dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-
methylethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-
tricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-tetraene-2,3,10,14,20-pentaone 
International non-
proprietary name 
Everolimus 
Figure 1-1 
Chemical structure of Everolimus 
 
 
mTOR Pathway and Cancer: At the cellular and molecular level, Everolimus acts as a signal 
transduction inhibitor. It selectively inhibits mTOR (mammalian target of rapamycin), a key 
protein kinase which regulates cell growth, proliferation and survival. The mTOR kinase is 
mainly activated via the phosphatidylinositol 3-kinase (PI3-Kinase) pathway through AKT/PKB 
and the tuberous sclerosis complex (TSC1/2). Mutations in these components or in PTEN, a 
negative regulator of PI3-kinase, may result in their dysregulation. Abnormal functioning of 
various components of the signaling pathways contributes to the pathophysiology of numerous 
human cancers. Various preclinical models have confirmed the role of this pathway in tumor 
development.14 
 
 
 


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The main known functions of mTOR include the following:15 
• 
mTOR functions as a sensor of mitogens, growth factors and energy and nutrient 
levels; 
• 
Facilitating cell-cycle progression from G1-S phase in appropriate growth conditions; 
• 
The PI3K/mTOR pathway itself is frequently dysregulated in many human cancers, 
and oncogenic transformation may sensitize tumor cells to mTOR inhibitors; 
• 
PI3-kinase mutations have been reported in the primary tumor in 10-20% of human 
colorectal cancers;16,17 
• 
The loss of PTEN protein, either through gene deletion or functional silencing 
(promoter hypermethylation), is reported in approximately 60% of primary human 
colorectal cancers;18 
• 
The mTOR pathway is involved in the production of pro-angiogenic factors (i.e., VEGF) 
and inhibition of endothelial cell growth and proliferation; 
• 
Through inactivating eukaryotic initiation factor 4E binding proteins and activating the 
40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates protein translation, 
including the HIF-1 proteins. Inhibition of mTOR is expected to lead to decreased 
expression of HIF-1. 
 
Non-clinical experience: Everolimus inhibits the proliferation of a range of human tumor 
cell lines in vitro including lines originating from lung, breast, prostate, colon, melanoma 
and glioblastoma. IC50s range from sub/low nM to µM. Everolimus also inhibits the 
proliferation of human umbilical vein endothelial cells (HUVECS) in vitro, with particular 
potency against VEGF-induced proliferation suggesting that Everolimus may also act as 
an anti-angiogenic agent. The anti-angiogenic activity of Everolimus was confirmed in vivo. 
Everolimus selectively inhibited VEGF-dependent angiogenic response at well tolerated 
doses. Mice with primary and metastatic tumors treated with Everolimus showed a 
significant reduction in blood vessel density when compared to controls. 
 
The potential of Everolimus as an anti-cancer agent was shown in rodent models. 
Everolimus is orally bioavailable, residing longer in tumor tissue than in plasma in a 
subcutaneous mouse xenograft model, and demonstrating high tumor penetration in a rat 
pancreatic tumor model. The pharmacokinetic profile of Everolimus indicates sufficient 
tumor penetration, above that needed to inhibit the proliferation of endothelial cells and 
tumor cell lines deemed sensitive to Everolimus in vitro. 
 
Everolimus administered orally daily was a potent inhibitor of tumor growth, at well tolerated 
doses, in 11 different mouse xenograft models (including pancreatic, colon, epidermoid, 
lung and melanoma) and two syngeneic models (rat pancreatic, mouse orthotopic 
melanoma). These models included tumor lines considered sensitive and “relatively 
resistant” in vitro. In general, Everolimus was better tolerated in mouse xenograft models 
than standard cytotoxic agents (i.e., doxorubicin and 5-fluorouracil), while possessing 
similar anti-tumor activity. Additionally, activity in a VEGF-impregnated subcutaneous 
implant model of angiogenesis and reduced vascularity (vessel density) of Everolimus-
treated tumors (murine melanoma) provided evidence of in vivo effects of angiogenesis. 
 
It is not clear which molecular determinants predict responsiveness of tumor cells to 
Everolimus. Molecular analysis has revealed that relative sensitivity to Everolimus in vitro 
correlates with the degree of phosphorylation (activation) of the AKT/PKB protein kinase 
and the S6 ribosomal protein; in some cases (i.e., glioblastoma) there is also a correlation 
with PTEN status. 
 
In vivo studies investigating the anti-tumor activity of Everolimus in experimental animal 
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rates rather than produced regressions. These effects occurred within the dose range of 
2.5 mg to 10 mg/kg, orally once a day. 
 
In preclinical models, the administration of Everolimus is associated with reduction of 
protein phosphorylation in target proteins downstream of mTOR, notably phosphorylated 
S6 (p-S6) and p-4E-BP1, and occasionally with an increase in phosphorylated AKT, a 
protein upstream of mTOR signaling pathway. 
 
All significant adverse events observed in toxicology studies with Everolimus in mice, rats, 
monkeys and mini-pigs were consistent with its anticipated pharmacological action as an 
anti-proliferative and immunosuppressant and at least in part reversible after a 2 or 4-week 
recovery period with the exception of the changes in male reproductive organs, most 
notably testes. 
 
Further details can be found in the Everolimus Investigator’s Brochure. 
1.3 
Rationale  
 
The purpose of this study is to evaluate the anti-tumor activity of Everolimus among 
children with recurrent or progressive ependymoma. The rationale for this study is based 
upon both pre-clinical and clinical considerations. Recurrent or progressive ependymoma 
is incurable and has very limited treatment options. In 2011, our group published a case 
report describing a young child with a multiply recurrent ependymoma after 4 
chemotherapy regimens and several courses of radiation therapy and who had an objective 
and long lasting response to sirolimus (Rapamune, Pfizer).19 This patient, who had been 
treated with various regimens over a span of 20 months without response, subsequently 
had a near complete response to sirolimus of 18 months duration. Subsequently, a second 
child with a recurrent ependymoma was treated with sirolimus and oral etoposide and had 
a near-complete response of 18 months duration. Furthermore, immunohistochemistry 
studies have revealed that 20 out of 23 (87%) pediatric ependymomas were 
immunoreactive for phosphorylated S6, a biomarker that often predicts response to mTOR 
pathway-targeted therapy.20,21 Finally, a study from Rogers and co-workers identified P-
AKT protein expression, indicating PI3K-mTOR pathway activation, was present in 72% of 
169 pediatric ependymomas tumors.22 P-AKT expression was found to be an independent 
marker of a poorer progression-free survival. A significant association between PI3K 
pathway activation and cell proliferation was identified, suggesting that pathway activation 
was influencing this process. They concluded that PI3K-mTOR pathway activation could 
be a biomarker and potential therapeutic target for pediatric ependymomas. 
 
Existing data regarding the anti-tumor activity of mTOR inhibitors among children has 
demonstrated that mTOR inhibitors are well tolerated and have activity against pediatric 
brain tumors. For example, Franz et al. reported five children with tuberous sclerosis 
complex and progressive subependymal giant cell astrocytomas who were treated with 
sirolimus to achieve target trough concentrations between 5 – 15 ng/mL.23 All tumors 
demonstrated objective responses to sirolimus. One patient who interrupted sirolimus 
therapy experienced tumor progression that responded to resumption of sirolimus therapy. 
A subsequent phase III study of everolimus compared responses of 78 patients treated 
with everolimus versus 39 patients treated with placebo. 27 of 78 (35%) patients in the 
everolimus group had at least 50% reduction in the volume of subependymal giant cell 
astrocytomas versus none in the placebo group (p<0.0001). Adverse events were mostly 
grade 1 or 2 and no patients discontinued treatment because of adverse events. 24 A phase 
I study of everolimus by Fouladi et al. evaluated everolimus at doses between 3 - 6.5 
mg/m2/day.25 No children in this study had objective tumor responses, 6 of 18 children who 
were assessable for response had stable disease for 4 to 14 months. In this study there 
were 4 children with ependymomas, one who had prolonged stable disease and three other 
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enrolled on this study, tumors from 13 of 14 patients demonstrated immunoreactivity 
against phosphorylated S6 [average of 33%; range = 10% - 90%)]. In this study, no 
relationship was observed between the level of phosphorylated S6 immunoreactivity in 
pretreatment tumor samples and patients’ tumor response. 
 
The poor in vivo and in vitro response of a single ependymoma cell line to sirolimus in a 
study from the Pediatric Preclinical Testing Program26 and the heterogeneity observed in 
ependymoma response in the phase I study of everolimus in children Fouladi et al.25 may 
be explained by differential activation of mTORC1 in tumors. Indeed, our analysis of 
phosphorylated S6 is consistent with this notion. S6 is a protein of the small ribosomal 
subunit that is phosphorylated by S6 kinase 1 (S6K1) and 2 (S6K2), which in turn are 
regulated by mTORC1, and while S6K is regulated by kinases other than mTORC1, 
phosphorylated S6 tends to correlate with mTORC1 activation and phospho-S6 appears 
to be associated with tumor sensitivity to mTORC1 inhibitors.27-30 In our series of eleven 
cases of Grade II infratentorial ependymomas, 7 cases showed phosphorylated S6 but 4 
did not. Since it would be expected that only those tumors with active mTORC1 would 
respond to mTORC1 inhibitors, and this was the case in our two patients, it would be fitting 
that clinical trials examining the role of mTORC1 inhibitors for this disease would evaluate 
patients in which there was evidence of mTORC1 activation in the tumor.  
1.4 
Rational for Targeted Dose 
 
A concern regarding the use of Everolimus in oncology is the potential for 
immunosuppression during treatment. Consequently, in addition to individualizing the 
Everolimus dose according to the patient’s body surface area, this protocol requires the 
upward titration of the dose from 4.5 mg/m2, subject to tolerability, with the objective of 
achieving trough Everolimus levels in the range of 5-15 ng/mL. This range is based on the 
Phase II data from a TSC study conducted at the Cincinnati Children’s Hospital Medical 
Center.24 In this study, patients were treated with Everolimus from a starting dose of 3 
mg/m2 with subsequent upward titration to attain a RAD001 trough in the range 5-15 
ng/mL. This regimen was efficacious (35% of patients had >50% shrinkage at 6 months) 
and showed acceptable tolerability. The starting dose of 4.5 mg/m2 is based upon separate 
data from a phase I pediatric oncology study concluded that the maximum tolerated dose 
of everolimus in children is 5 mg/m2/day.25 In order to optimize patient safety, and to ensure 
that excessive exposure does not occur, trough concentrations will be assessed initially 
and monitored as appropriate throughout the study. 
  
Pharmacokinetics of RAD001 in patients with TSC: 
 
During Study RAD001M2301, in patients with TSC who have SEGA, pre-dose (Cmin) and 
2-hour post-dose (C2h) PK blood samples were collected at steady-state. Ages of patients 
in the Everolimus arm of study ranged from 1 to 23.9 years. Patients in this study received 
a starting dose of 4.5 mg/m2/day which was subsequently titrated to a whole blood trough 
concentration of 5-15 ng/mL. This is the starting dose and trough range approved for this 
indication. 
1.5 
Correlative Studies 
 
Biomarkers of mTOR pathway activation and sensitivity to mTOR inhibitors, including 
phosphorylated 
S6235/236, 
phosphorylated 
S6240/244, 
phosphorylated 
4EBP1, 
phosphorylated PRAS40 (pT246), phosphorylated P70S6K, and PTEN expression, will be 
performed. Although these biomarkers have, to varying degrees, been correlated with 
mTOR pathway activation and sensitivity to mTOR inhibitors, these studies are considered 
to be exploratory in the context of this clinical trial. 
 
 


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1.6 
Examination of H3.K27me3 Expression in Ependymoma 
 
Since 2011, several studies have been published that have segregated pediatric posterior 
fossa ependymomas by DNA methylation-based methods into subtypes labeled Group A 
and Group B.31 Group A ependymomas occur more frequently among children and males 
and have a poor survival; whereas Group B ependymomas occur more frequently among 
adults, have equal percentages of males and females, and have a relatively good 
survival.31  Panawalker et al. recently identified expression of H3.K27me3 by 
immunohistochemistry as correlating very closely with DNA methylation-based subtyping 
with very high sensitivity (99%) and specificity (100%) in the ability to distinguish Group A 
posterior fossa ependymoma from Group B posterior fossa ependymoma.32 Furthermore, 
this study and others have determined that low levels of expression of H3.K27me3 by 
immunohistochemistry are associated with poor event free and overall survival for children 
with ependymoma.32-34  
 
For tumors from subjects enrolled on this protocol, we will perform immunohistochemistry 
for H3.K27me3 on existing and available FFPE slides on enrolled subjects (and controls) 
according to established methods to determine ependymoma subtype (either Group A or 
Group B). Given the population of patients with recurrent ependymoma enrolled on this 
study, we predict that the majority of enrolled tumors will be classified as Group A. A 
description of the results will be reported in the manuscript.  
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
 
Determine the objective response rate (ORR = Complete Response Rate + Partial 
Response Rate + Prolonged Stable Disease Rate) following treatment with everolimus 
for children with recurrent or progressive ependymomas. 
2.2 
Secondary Objectives 
2.2.1 
Determine the duration of response, progression free survival (PFS) and event free 
survival (EFS) following treatment with everolimus for children with recurrent or 
progressive ependymomas. 
2.2.2 
Determine safety and tolerability of everolimus among children with recurrent or 
progressive ependymomas. 
2.2.3 
Descriptive analysis and correlation of response rate to biological markers of 
mTOR pathway activation, including phosphorylated S6235/236, phosphorylated 
S6240/244, 
phosphorylated 
PRAS40 
(pT246), 
phosphorylated 
4EBP1, 
phosphorylated P70S6K, and PTEN expression. 
2.3 
Endpoints 
 
2.3.1 
Objective Response Rate = Complete Response Rate + Partial Response Rate + 
Prolonged Stable Disease Rate. 
 
2.3.2 
Duration of Response 
 
2.3.3 
Progression Free Survival 
 


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2.3.4 
Overall Survival 
 
2.4.5 
Dose limiting toxicities 
 
2.4.6 
Biological markers of mTOR pathway activation, including phosphorylated 
S6235/236, phosphorylated S6240/244, phosphorylated 4EBP1, phosphorylated 
PRAS40 (pT246), phosphorylated P70S6K, and PTEN expression. 
 
3.0 
PATIENT ELIGIBILITY 
 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria. Results of all baseline evaluations, which assure that all 
inclusion and exclusion criteria have been satisfied, must be reviewed by the Principal 
Investigator or his/her designee prior to enrollment of that patient (See Section 9.4) for 
registration procedures. In addition, the patient must be thoroughly informed about all aspects of 
the study, including the study visit schedule and required evaluations and all regulatory 
requirements for informed consent. The signed informed consent must be obtained from the 
patient prior to enrollment. The following criteria apply to all patients enrolled onto the study 
unless otherwise specified.  All screening procedures must be performed within 14 days prior to 
initiation of study therapy (Course 1 Day 1) unless otherwise stated. 
 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be registered to the study. Study treatment may not begin until a subject is registered. 
 
 
3.1 
Inclusion Criteria 
3.1.1 
Diagnosis and Age: Ependymoma (WHO grade II) or Anaplastic Ependymoma 
(WHO grade III) that has relapsed or become refractory to standard therapy. 
Patients must have had histologic verification of their malignancy at original 
diagnosis or time of recurrence. Age must be ≥ 2 years and ≤ 21 years of age at 
study entry. 
 
3.1.2 
Performance status: Lansky ≥ 50% for patients ≤ 10 years of age or Karnofsky ≥ 
50% for patients > 10 years of age. 
 
3.1.3 
Adequate bone marrow function as shown by: ANC ≥ 1000/mm3, platelets ≥ 
100,000/mm3 and hemoglobin > 9.0 g/dL. Note: these lab parameters must be 
transfusion-independent 
 
3.1.4 
Adequate liver function as shown by: 
3.1.4.1 Total serum bilirubin ≤ 2.0 mg/dL. 
3.1.4.2 ALT and AST ≤ 2.5x ULN  
3.1.4.3 INR ≤ 2. 
 
3.1.5 
Adequate renal function: serum creatinine ≤ 1.5x ULN. 
 
3.1.6 
Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting 
triglycerides ≤ 2.5x ULN. NOTE: In case one or both of these thresholds are 
exceeded, the patient can only be included after initiation of appropriate lipid 
lowering medication. 
 
3.1.7 
Signed informed consent obtained prior to any screening procedures. 
 


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3.1.8 
Patients must have measurable residual disease, defined as tumor that is 
measurable in two diameters on MRI. Diffuse leptomeningeal disease is not 
considered measurable. 
 
3.1.9 
Prior Therapy: Patients must have fully recovered from the acute toxic effects of 
all prior chemotherapy, immunotherapy, and radiotherapy prior to participating in 
this trial. 
3.1.9.1 No prior myelosupressive chemotherapy for at least 21 days prior to study 
enrollment. 
3.1.9.2 Must not have received craniospinal radiation therapy within 24 weeks 
prior to study entry and no involved field radiation therapy for 12 weeks 
prior to study enrollment. 
3.1.9.3 If patients received prior monoclonal antibody treatment, at least three 
half-lives must be elapsed by the time of treatment initiation. 
3.1.9.4 No investigational drugs for 4 weeks prior to study enrollment.  
3.1.9.5 No prior therapy with mTOR inhibitors (including sirolimus, temsirolimus 
or everolimus). 
 
3.1.10 MRI of the brain and the complete spine: All patients must have had an MRI of the 
brain and spine that has measurable tumor (not only diffuse leptomeningeal tumor) 
within 14 days prior to study enrollment.  Note: Submission of MRIs for central 
review is required, but is not required to begin therapy.  Completion of central 
review is not required prior to starting treatment (See Protocol Section 6.1.9 for 
details). 
 
3.1.11 If available, tumor tissue from either initial diagnosis or subsequent surgery will be 
submitted on Formalin Fixed Paraffin Embedded (FFPE) slides (n = 12) to the 
Pathology Laboratory at Children’s Medical Center-Dallas for correlative biological 
studies 
(including 
phosphorylated 
S6235/236, 
phosphorylated 
S6240/244, 
phosphorylated 4EBP1, phosphorylated PRAS40 (pT246), phosphorylated 
P70S6K, and PTEN expression.)  See Section 8.0 for details about submission of 
these slides.  Note: Completion of central review is not required prior to starting 
therapy. 
3.2 
Exclusion Criteria 
3.2.1 
Known intolerance or hypersensitivity to Everolimus or other rapamycin analogs 
(e.g. sirolimus, temsirolimus). 
 
3.2.2 
Concomitant use of medications known to have strong inhibition or induction of 
CYP3A enzymes is discouraged and should be discussed with the study PI (see 
Table 4-7 and 4-8 for a list of prohibited medications). Note that systemic 
corticosteroids (e.g., dexamethasone is a CYP3A inducer) are not allowed. Inhaled 
corticosteroids are allowed. 
 
3.2.3 
Known impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of oral Everolimus. 
 
3.2.4 
Uncontrolled diabetes mellitus as defined by HbA1c > 8% despite adequate 
therapy. Patients with a known history of impaired fasting glucose or diabetes 
mellitus (DM) may be included, however blood glucose and antidiabetic treatment 
must be monitored closely throughout the trial and adjusted as necessary per 
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3.2.5 
Patients who have any severe and/or uncontrolled medical conditions such as:  
3.2.5.1 Unstable angina pectoris, symptomatic congestive heart failure, 
myocardial infarction ≤6 months prior to start of Everolimus 
3.2.5.2 Serious uncontrolled cardiac arrhythmia, or any other clinically significant 
cardiac disease.  
3.2.5.3 Symptomatic congestive heart failure of New York Heart Association Class 
III or IV 
3.2.5.4 Active (acute or chronic) or uncontrolled severe infection,  
3.2.5.5 Liver disease such as cirrhosis, decompensated liver disease, and chronic 
hepatitis  
3.2.5.6 Known severely impaired lung function (spirometry and DLCO 50% or less 
of normal and O2 saturation 88% or less at rest on room air) 
3.2.5.7 Active bleeding diathesis 
 
3.2.6 
Known history of HIV sero-positivity. 
 
3.2.7 
Patients who have received live attenuated vaccines within 1 week of start of 
everolimus and during the study. Patient should also avoid close contact with 
others who have received live attenuated vaccines. Examples of live attenuated 
vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, 
yellow fever, varicella and TY21a typhoid vaccines. 
 
3.2.8 
Patients who have a history of another primary malignancy, with the exceptions of: 
non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast 
from which the patient has been disease free for ≥3 years. 
 
3.2.9 
Patients with a history of non-compliance to medical regimens or who are 
considered potentially unreliable or will not be able to complete the entire study. 
 
3.2.10 Patients who are currently part of or have participated in any clinical investigation 
with an investigational drug within 1 month prior to dosing. 
 
3.2.11 Pregnant or nursing (lactating) women. 
 
3.2.12 Women of child-bearing potential (WOCBP), defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective methods of 
contraception during dosing of study treatment. Women of childbearing potential 
should be advised to use a highly effective method of contraception while receiving 
everolimus, and for up to 8 weeks after ending treatment. Highly effective 
contraception is defined as either: 
• 
Total abstinence: When this is in line with the preferred and usual lifestyle of 
the subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception] 
• 
Sterilization: have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. 
In case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment  
• 
Male partner sterilization (with the appropriate post-vasectomy documentation 
of the absence of sperm in the ejaculate). [For female subjects on the study, 
the vasectomized male partner should be the sole partner for that subject].  
• 
Use of a combination of any two of the following (a+b or a+c or b+c): 
a. Use of oral, injected, implanted or other hormonal methods of 
contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 


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c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/vaginal 
suppository 
• 
In case of use of oral contraception women should have been stable on the 
oral agent before taking study treatment. 
 
3.2.13 Contraception Use 
• 
During the course of the clinical trial, sexually active males must use a 
condom during intercourse while taking the drug and should not father a child 
in this period and for up to 8 weeks after stopping treatment.  
• 
A condom is required to be used also by vasectomized men in order to prevent 
delivery of the drug via seminal fluid. 
• 
Female partners of male patients must also be advised to use one of the 
following contraception methods: Use of (1) oral, injected, implanted or other 
hormonal methods of contraception, or (2) intrauterine device (IUD) or 
intrauterine system (IUS), or (3) prior male/female sterilization. 
Female patients of childbearing potential must have a negative beta-human 
chorionic gonadotropin (β-hCG) pregnancy test at time of screening (urine or 
serum test is acceptable however, positive urine tests must be confirmed with 
serum testing) 
 
3.2.14 Screening for hepatitis B:  
Prior to start of Everolimus, the following three categories of patients should be 
tested for hepatitis B viral load and serologic markers, that is, HBV-DNA, HBsAg, 
HBs Ab, and HBc Ab. 
 
3.2.14.1 All patients who currently live in (or have lived in) Asia, Africa, Central 
and South America, Eastern Europe, Spain, Portugal and Greece. 
[http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-
diseases-related-to-travel/hepatitis-b.htm] 
 
3.2.14.2 Patients with any of the following risk factors: 
• 
known or suspected past hepatitis B infection, 
• 
blood transfusion(s) prior to 1990, 
• 
current or prior IV drug users, 
• 
current or prior dialysis, 
• 
household contact with hepatitis B infected patient(s), 
• 
current or prior high-risk sexual activity, 
• 
body piercing or tattoos, 
• 
mother known to have hepatitis B 
• 
history suggestive of hepatitis B infection, e.g., dark urine, jaundice, 
right upper quadrant pain. 
• 
Additional patients at the discretion of the investigator 
 
3.2.14.3 Screening for hepatitis C: Patients with any of the following risk factors 
for hepatitis C should be tested using quantitative RNA-PCR: 
• known or suspected past hepatitis C infection (including patients with 
past interferon ‘curative’ treatment), 
• blood transfusions prior to 1990, 
• current or prior IV drug users, 
• current or prior dialysis, 
• household contact of hepatitis C infected patient(s), 
• current or prior high-risk sexual activity, 
• body piercing or tattoos. 
 


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3.2.14.4 At the discretion of the investigator, additional patients may also be 
tested for hepatitis C. 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration  
The investigational treatment is Everolimus; it will be administered in conjunction with 
best supportive care. Best supportive care includes all care provided to patients deemed 
necessary by the treating physician, such as analgesics and anti-diarrheal therapies. 
 
• 
Everolimus will be administered by mouth at a starting dose of 4.5 mg/m2/day. Each 
course of therapy will last for 28 days for up to 24 courses. 
• 
The starting dose 4.5 mg/m2 of Everolimus will be titrated upward (or downward), 
subject to tolerability, with the objective of achieving trough Everolimus levels in the 
range of 5-15 ng/mL. 
• 
All dosages prescribed and dispensed to the patient and all dose changes during the 
study must be recorded. 
• 
Medication labels will comply with US legal requirements and be printed in English.  
Additional labels may be used in the primary language of the study participant. They 
will supply no information about the patient. The storage conditions for Everolimus 
will be described on the medication label. 
4.2 
Treatment Assignment 
 
This is a single arm, open label, phase II study of Everolimus for children with recurrent 
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Dosing Regimen 
 
The investigator should promote adherence by instructing the patient to take the study 
drug exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient should be instructed to contact the 
investigator if he/she is unable for any reason to take the study drug as prescribed. 
4.3 
Medication Formulations, Dosage and Administration 
4.3.1 
Everolimus is supplied by Novartis. Everolimus should be administered orally, 
once daily at the same time every day either consistently with food or consistently 
without food. Everolimus is available as dispersible tablets.  
4.3.2 
The dose of Everolimus is 4.5 mg/m2/day administered once a day. The initial 
calculated dose of Everolimus will be rounded either up or down to the nearest 
possible dose based upon available Dispersible Tablets (see section 4.4.3 below).   
4.3.3 
Everolimus will be supplied in the form of Dispersible Tablets (also referred to as 
‘tablets for oral suspension’): 2 mg, 3 mg and 5 mg.  
4.3.4 
Everolimus may be administered by either of the following two methods: 
4.3.5 
Method 1, Using an oral syringe: The required number of dispersible tablets 
(maximum of five 2 mg tablets, three 3 mg tablets, or two 5 mg tablets) should be 
placed into a 10 mL oral syringe. The plunger should be inserted and pushed 
inward to make contact with the dispersible tablet(s). A sufficient volume of water 
(approximately 5 mL) should be drawn up from a glass to cover the dispersible 
tablet(s). In addition, approximately 4 mL of air should be drawn up into the oral 
syringe. The filled oral syringe should be placed in a glass (tip up) and the contents 
left to disintegrate for 3 minutes. Prior to administration, the oral syringe should be 
inverted gently five times. While holding the oral syringe in an upright (tip up) 
position, excess air should be removed carefully. The full contents of the oral 
syringe should be immediately dispensed into the mouth of the patient, slowly and 
gently.  The same volume of water and air should then be drawn up into the oral 
syringe, and the contents should be swirled to suspend any remaining particles. 
The contents should be administered as previously described to ensure the entire 
dose is administered. 
4.3.6 
Method 2, Using a small drinking glass: The required number of dispersible 
tablets (maximum of five 2 mg tablets, three 3 mg tablets, or two 5 mg tablets) 
should be placed into a small drinking glass (maximum size 100 mL) containing 
approximately 25 mL of water. The tablets should be left to disintegrate for 3 
minutes. The contents should be stirred gently with a spoon, immediately prior to 
drinking. The glass should be rinsed with the same volume of water and stirred 
with the same spoon to suspend any remaining tablet particles. The rinse should 
be swallowed to ensure the entire dose is administered. 
4.3.7 
If vomiting occurs, no attempt should be made to replace the vomited dose. 
Patients should be instructed that if they miss a dose on one day, they must not 
take any extra dose the next day, but instead to immediately contact the study 
center as soon as possible to ask for advice.  


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4.4 
Medication Supply and Accountability 
4.4.1 
Supplier: Everolimus tablets are supplied by Novartis and distributed through 
Biologics.  Do not use commercial supply. 
4.4.2 
Agent Ordering:  Sites will be provided the information for ordering drug supplies 
in the Study Procedures Manual. 
4.4.3 
Agent Accountability:  The investigator is responsible for study medication 
accountability, reconciliation, and record maintenance.  In accordance with local 
regulatory requirements, the investigator, designated site staff, or head of the 
medical institution (where applicable) must document the amount of investigational 
product dispensed and/or administered to study subjects, the amount returned by 
study subjects (if applicable), and the amount received from and returned to 
Biologics, when applicable.  Product accountability records must be maintained 
throughout the course of the study. 
After completion of the study, a final inventory of accountability records and 
unused study medications will be performed by the study monitor and site 
personnel.  A record of the number of tablets dispensed to and returned by each 
subject at each visit must be maintained and reconciled with the study 
medication and compliance records in the eCRF.  The cause of any missed 
doses should be discussed and documented. 
 
Any AE(s) associated with missed doses must be recorded in the eCRF.  
Subjects should be instructed for the importance of compliance to study 
treatments. 
 
An example study drug diary log is included in the protocol in Appendix III.  
4.5 
Recommended Dose of Everolimus 
 
The recommended starting dose is 4.5 mg/m2/dose, once daily. Continue treatment for 
up to 2 years, until disease progression or unacceptable toxicity occurs. After 2 years of 
therapy, patients will complete the study protocol, but may continue therapy using 
commercially available drug based upon the clinical judgment of their treating physician 
and the child’s parents or guardians. 
4.5.1 
Dose modification and dose delay 
4.5.1.1 Therapeutic drug monitoring: Therapeutic drug monitoring of Everolimus 
blood concentrations is required for patients enrolled on study and taking 
Everolimus. Testing is to be performed by Quest Diagnostics using a 
validated bioanalytical LC/MS method (test code 18883X). Trough 
concentrations should be assessed 2 weeks (+/- 4 days) after the initial 
dose, after any change in dose or formulation, after an initiation or 
change in co-administration of CYP3A4 inducers or inhibitors, or after 
any change in hepatic status.  
4.5.1.2 Dosing modifications:  
 
 
 
   Titrate the dose to attain trough concentrations of 5 to 15 ng/mL. 
• 
For trough concentrations less than 5 ng/mL, increase the daily dose by 
2 mg and repeat trough concentration in 2 weeks (+/- 4 days).   
• 
For trough concentrations greater than 15 ng/mL, reduce the daily dose 
by 2 mg and repeat trough concentration in 2 weeks (+/- 4 days). 
• 
The lowest possible dose level of Everolimus is 2 mg daily.  
• 
If dose reduction is required for patients receiving the lowest available 
strength, administer every other day. 


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• 
For patients who do not tolerate the protocol-specified dosing schedule, 
dose adjustments are permitted in order to allow the patient to continue 
the study treatment. Dose levels are as follows: Level -2 = 3 mg/m2/dose, 
Level -1 = 3.8 mg/m2/dose, Level 0 = 4.5 mg/m2/dose, Level +1 = 5.2 
mg/m2/dose and Level +2 = 6 mg/m2/dose. If dose adjustments need to 
be made for toxicity, patients’ doses of Everolimus should not be 
targeted to achieve a trough level of 5 – 15 ng/mL.  
 
Table 4-1 
Dosing guidelines for Everolimus-related non-hematologic toxicities 
Toxicity 
Action 
Non-Infectious Pneumonitis 
Please refer to Table 4-3. 
Reactivation of HBV or HCV flare 
Please refer to Table 4-5. 
AST or ALT elevation 
Grade 1 (> ULN - 3.0 x ULN) 
Grade 2 (> 3.0 - 5.0 x ULN) 
Maintain current dose level 
AST or ALT elevation 
Grade 3 (> 5.0 - 20.0 ULN)* 
Interrupt Everolimus administration until resolution to ≤ grade 1 
(or ≤ grade 2 if baseline values were within the range of grade 
2). If resolution occurs ≤ 7 days, Everolimus should be re-started 
at the dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, 
hold Everolimus until recovery to ≤ grade 1 or baseline grade / 
value and reintroduce Everolimus at one dose level lower, if 
available. 
AST or ALT elevation 
Grade 4 (> 20 x ULN)* 
 
Interrupt Everolimus administration until resolution to ≤ grade 1 
(or ≤ grade 2 if baseline values were within the range of grade 
2). If resolution occurs ≤ 7 days, Everolimus should be re-started 
at one dose level lower. If resolution takes > 7 days, discontinue 
Everolimus. 
Recurrence of Grade 4 AST or 
ALT elevation after dose reduction 
or toxicity requiring Everolimus 
interruption for > 28 days 
Discontinue Everolimus. 
Intolerable grade 2 mucositis, or 
grade 3 AE, except hyperglycemia 
or hypertriglyceridemia or 
hypercholesterolemia 
Interrupt Everolimus administration until resolution to ≤ grade 1 
or baseline grade / value. 
If resolution occurs within ≤ 7 days, Everolimus should be re-
started at the dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, 
hold Everolimus until recovery to ≤ grade 1 or baseline grade / 
value and reintroduce Everolimus at one dose level lower, if 
available. 
Patients will be withdrawn from the study if they fail to recover to 
≤ grade 1 or baseline grade / value within 28 days. 
Any other grade 4 
Hold Everolimus until recovery to grade ≤ 1 or baseline value 
Reintroduce Everolimus at one dose level lower, if available. 
Grade 3 or 4 clinical liver failure 
(asterixis or encephalopathy/coma) 
Discontinue Everolimus 
Recurrence of intolerable grade 2 
mucositis or grade 3 event after 
dose reduction 
Reduce dose to the next lower dose level, if available. The 
lowest possible dose level of Everolimus is 2 mg daily. Below 
this level, Everolimus must be discontinued. 
Recurrence of grade 4 after dose 
reduction 
Discontinue Everolimus 
Any non-hematologic toxicity 
requiring Everolimus interruption 
for > 28 days 
Discontinue Everolimus 
* Should HCV flare be confirmed, the guidelines for flare must take precedence (Table 4-4). 


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Table 4-2 
Dosing guidelines for Everolimus-related hematologic toxicities 
Toxicity 
Action 
Grade 2 thrombocytopenia (platelets 
<75, ≥ 50x109/L) 
Interrupt Everolimus until resolution to grade ≤1  
If resolution occurs ≤ 7 days, reintroduce Everolimus at the 
dose level prior to interruption. 
If resolution occurs > 7 days, or event occurs within 28 days, 
reintroduce Everolimus at one dose level lower, if available. 
Grade 3 thrombocytopenia (platelets 
<50, ≥ 25 x109/L) 
Interrupt Everolimus until resolution to grade ≤1  
If resolution occurs ≤ 7 days, reintroduce Everolimus at the 
dose level prior to interruption. 
If resolution occurs > 7 days, or event occurs within 28 days, 
reintroduce Everolimus at one dose level lower, if available. 
Grade 4 thrombocytopenia (platelets 
< 25 x109/L) 
Interrupt Everolimus until recovery to grade ≤ 1. Then 
reintroduce Everolimus at one dose level lower, if available. 
Grade 3 neutropenia or anemia 
(neutrophil <1, ≥0.5 x109/L) 
Interrupt Everolimus until resolution to grade ≤2 or baseline 
value 
If AE resolution occurs ≤ 7 days, reintroduce Everolimus at 
the same dose level. 
If AE resolution occurs > 7 days, or event occurs within 28 
days, reintroduce Everolimus at one dose level lower, if 
available. 
Grade 4 neutropenia or anemia 
Interrupt Everolimus until recovery to grade ≤ 2 or baseline 
value. Reintroduce Everolimus at one dose level lower, if 
available.* 
Grade 3 febrile neutropenia  
Interrupt Everolimus until resolution to grade ≤ 1 (or baseline 
value) and no fever. Reintroduce Everolimus at one dose 
level lower, if available.* 
Grade 4 febrile neutropenia 
Discontinue treatment 
Recurrence of grade 3 toxicity after 
dose reduction 
Reduce dose to the next lower dose level, if available. The 
lowest possible dose level of Everolimus is 2 mg daily.Below 
this level, Everolimus must be discontinued. 
*Recurrence of grade 4 toxicity 
(including febrile neutropenia) after 
dose reduction 
Discontinue Everolimus 
*Any hematologic toxicity requiring 
Everolimus interruption for > 28 days 
Discontinue Everolimus 
4.5.2 
Management of specific toxicities 
 
Overall, safety data available from completed, controlled and uncontrolled studies 
indicate that everolimus is generally well tolerated at weekly or daily dose 
schedules. The safety profile is characterized by manageable adverse events 
(AEs). These AEs are generally reversible and non-cumulative. 
Adverse events most frequently observed with everolimus are rash, stomatitis /oral 
mucositis, non-infectious pneumonitis, fatigue, headache, anorexia, nausea, 
vomiting, diarrhea, and infections. Overall, the most frequently observed laboratory 
abnormalities include neutropenia, thrombocytopenia, hypercholesterolemia, 
and/or hypertriglyceridemia. The majority of these AEs have been of mild to 
moderate severity (NCI CTC grade 1-2). Recommendations for dose adjustments, 
should any of these treatment-related adverse events occur, are given in Table 4-
1, 4-2, 4-3, 4-4, 4-5 and 4-6. 
4.5.3 
Management of infections 
 


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Everolimus has immunosuppressive properties and may predispose patients to 
bacterial, fungal, viral or protozoal infections, including infections with opportunistic 
pathogens. Localized and systemic infections, including pneumonia, other 
bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis 
and viral infections including reactivation of hepatitis B virus, have been described 
in patients taking Everolimus Some of these infections have been severe (e.g. 
leading to respiratory or hepatic failure) and occasionally have had a fatal outcome. 
Physicians and patients should be aware of the increased risk of infection with 
Everolimus. Treat pre-existing infections prior to starting treatment with Everolimus. 
While taking Everolimus, be vigilant for symptoms and signs of infection; if a 
diagnosis of infection is made, institute appropriate treatment promptly and 
consider interruption or discontinuation of Everolimus. 
If a diagnosis of invasive systemic fungal infection is made, discontinue Everolimus 
and treat with appropriate antifungal therapy. 
4.5.4 
Management of skin toxicity 
 
For patients with grade 1 toxicity, no specific supportive care is usually needed or 
indicated. Rash must be reported as an AE. Patients with grade 2 or higher toxicity 
may be treated with the following suggested supportive measures at the discretion 
of the investigator: oral minocycline, topical tetracycline, topical clindamycin, 
topical silver sulfadiazine, diphenhydramine, oral prednisolone (short course), 
topical corticosteroids, or pimecrolimus. 
4.5.5 
Management of stomatitis / oral mucositis / mouth ulcers 
 
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with 
gastrointestinal morbidity associated with mouth/dental infections, irritation of 
esophageal mucosa e.g. gastroesophageal reflux disease (GERD) and pre-
existing stomatitis/mucositis must be monitored even more closely. Patients 
should be instructed to report the first onset of buccal mucosa irritation/reddening 
to their study physician immediately. 
 
Stomatitis/oral mucositis/mouth ulcers due to Everolimus should be treated using 
local supportive care. Please note that investigators in earlier trials have described 
the oral toxicities associated with Everolimus as mouth ulcers, rather than 
mucositis or stomatitis. If your examination reveals mouth ulcers rather than a 
more general inflammation of the mouth, please classify the adverse event as such. 
Please follow the paradigm below for treatment of stomatitis/oral mucositis/mouth 
ulcers: 
1. 
For mild toxicity (grade 1), use conservative measures such as non-
alcoholic mouth wash or salt water (0.9%) mouth wash several times a 
day until resolution. 
2. 
For more severe toxicity (grade 2 in which case patients have pain but are 
able to maintain adequate oral alimentation, or grade 3 in which case 
patients cannot maintain adequate oral alimentation), the suggested 
treatments are topical analgesic mouth treatments (i.e., local anesthetics 
such as, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) with or without topical corticosteroids, such as 
triamcinolone oral paste 0.1% (Kenalog in Orabase®). 
3. 
Agents containing alcohol, hydrogen peroxide, iodine, and thyme 
derivatives may tend to worsen mouth ulcers. It is preferable to avoid these 
agents. 
4. 
Antifungal agents should be avoided unless a fungal infection is diagnosed. 
In particular, systemic imidazole antifungal agents (ketoconazole, 
fluconazole, itraconazole, etc.) should be avoided in all patients due to 


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their strong inhibition of Everolimus metabolism, therefore leading to 
higher Everolimus exposures. Therefore, topical antifungal agents are 
preferred if an infection is diagnosed. 
4.5.6 
Management of diarrhea 
Appearance of grade 1-2 diarrhea attributed to study drug toxicity may be treated 
with supportive care such as loperamide, initiated at the earliest onset at age and 
weight appropriate doses. 
4.5.7 
Management of hyperlipidemia and hyperglycemia 
Treatment of hyperlipidemia should take into account the pre-treatment status and 
dietary habits of the patient. Grade 2 or higher hypercholesterolemia (>300 mg/dL 
or 7.75 mmol/L) or grade 2 hypertriglyceridemia or higher (>2.5x upper normal 
limit) should be treated with lifestyle and dietary changes, in addition to an 
appropriate triglyceride-lowering medication approved for children, such as fish oil 
or fenofibrate.31 
Hyperglycemia has been reported in clinical trials. Monitoring of fasting serum 
glucose is recommended prior to the start of Everolimus and periodically thereafter. 
Optimal glycemic control should be achieved before starting a patient on 
Everolimus. 
4.5.8 
Management of non-infectious pneumonitis 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of 
non-infectious pneumonitis (including interstitial lung disease) have also been 
described in patients taking Everolimus. Some of these have been severe and on 
rare occasions, a fatal outcome was observed. 
• 
A diagnosis of non-infectious pneumonitis should be considered in 
patients presenting with non-specific respiratory signs and symptoms such as 
hypoxia, pleural effusion, cough or dyspnea, and in whom infectious, neoplastic 
and other non-medicinal causes have been excluded by means of appropriate 
investigations. Patients should be advised to report promptly any new or worsening 
respiratory symptoms. 
• 
Patients who develop radiological changes suggestive of non-infectious 
pneumonitis and have few or no symptoms may continue Everolimus therapy 
without dose alteration. 
 
Individuals participating in this trial will be routinely questioned as to the presence 
of new or changed pulmonary symptoms consistent with lung toxicity. In addition, 
pulmonary function tests (PFTs) can be conducted, if clinically indicated, to monitor 
for pneumonitis. If non-infectious pneumonitis develops, the guidelines in Table 4-
3 should be followed. Consultation with a pulmonologist is recommended for any 
case of pneumonitis that develops during the study. 
 


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Table 4-3 
Management of non-infectious pneumonitis 
Worst grade 
pneumonitis 
Required investigations 
Management of 
pneumonitis 
Everolimus dose adjustment 
Grade 1 
CT scans with lung windows. 
No specific 
therapy is 
required 
No dose adjustment required.  
Initiate appropriate monitoring. 
Grade 2 
CT scan with lung windows. 
Consider pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest. Consider a 
bronchoscopy with biopsy and/or 
BAL. Monitoring at each visit 
until return to ≤ grade 1. Return 
to initial monitoring frequency if 
no recurrence. 
Symptomatic 
only. Consider 
corticosteroids 
and/or other 
supportive 
therapy if 
symptoms are 
troublesome. 
Rule out infection and consider 
interruption of Everolimus until 
symptoms improve to Grade ≤ 
1. 
Re-initiate Everolimus at one 
dose level lower.  
Discontinue Everolimus if 
failure to recover within ≤ 28 
days. 
Grade 3 
CT scan with lung windows and 
pulmonary function testing 
includes: spirometry, DLCO, and 
room air O2 saturation at rest. 
Monitoring at each visit until 
return to ≤ grade 1. Return to 
initial monitoring frequency if no 
recurrence. Bronchoscopy with 
biopsy and/or BAL is 
recommended. 
Consider  
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated. 
Rule out infection and interrupt 
Everolimus until symptoms 
improve to Grade ≤ 1. 
Consider re-initiating 
Everolimus at one dose level 
lower.  
Discontinue Everolimus if 
failure to recover within ≤ 28 
days. 
Grade 4 
CT scan with lung windows and 
required pulmonary function 
testing, if possible, includes: 
spirometry, DLCO, and room air 
O2 saturation at rest. Monitoring 
at each visit until return to ≤ 
grade 1. Return to initial 
monitoring frequency if no 
recurrence. Bronchoscopy with 
biopsy and/or BAL is 
recommended if possible. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated. 
Rule out infection and 
discontinue Everolimus. 
4.5.9 
Management of hepatitis reactivation / flare 
 
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer 
receiving chemotherapy.32 Sporadic cases of Hepatitis B reactivation have also 
been seen in this setting with everolimus. Use of antivirals during anti-cancer 
therapy has been shown to reduce the risk of Hepatitis B virus reactivation and 
associated morbidity and mortality.33 A detailed assessment of Hepatitis B/C 
medical history and risk factors must be done for all patients at screening, with 
testing performed prior to the first dose of everolimus.  
 
4.5.10 Monitoring and prophylactic treatment for hepatitis B reactivation.  
 
Table 4-4 provides details for monitoring and prophylactic therapy according to the 
screening results of viral load and serologic markers testing. 


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Table 4-4 
Action to be taken based on screening hepatitis B results 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBsAb 
+ or - 
+ or - 
+ 
and no prior 
HBV vaccination 
+ or - 
- 
or + with prior 
HBV vaccination 
HBcAb 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendation 
Prophylaxis treatment 
should be started 1-2 
weeks prior to first dose of 
Everolimus 
 
Monitor HBV-DNA 
approximately every 4-8 
weeks 
 
 
No prophylaxis 
 
Monitor HBV-DNA 
approximately every 3-4 weeks  
No specific 
action 
 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of Everolimus. For HBV 
reactivation definition and management guidelines, see Table 4-5.  
 
Table 4-5 
Guidelines for the management of hepatitis B reactivation 
HBV reactivation (with or without clinical signs and symptoms)* 
For patients with baseline 
results:  
Positive HBV-DNA 
OR 
positive HBsAg 
-------------------------------------- 
reactivation is defined as: 
[Increase of 1 log in HBV-
DNA relative to baseline 
HBV-DNA value OR new 
appearance of measurable 
HBV-DNA] 
 
Treat: Start a second antiviral medication 
AND 
Interrupt Everolimus administration until resolution:  
• 
≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days, Everolimus should be re-started at 
one dose lower, if available. If the patient is already receiving the lowest 
dose of Everolimus according to the protocol, the patient should restart 
at the same dose after resolution. Both antiviral therapies should 
continue at least 4 weeks after last dose of Everolimus.  
If resolution occurs > 28 days Patients should discontinue Everolimus but 
continue both antiviral therapies at least 4 weeks after last dose of 
Everolimus. 
For patients with baseline 
results: 
Negative 
HBV-DNA 
and 
HBsAg 
AND 
[Positive HBsAb (with no 
prior history of vaccination 
against HBV), OR positive 
HBcAb] 
------------------------------------- 
Reactivation is defined as: 
New 
appearance 
of 
measurable HBV-DNA 
Treat : Start first antiviral medication 
AND 
Interrupt Everolimus administration until resolution: 
• 
≤ undetectable (negative) HBV-DNA levels 
If resolution occurs within ≤ 28 days, Everolimus should be re-started at 
one dose lower, if available . If the patient is already receiving the lowest 
dose of Everolimus according to the protocol, the patient should restart 
at the same dose after resolution. Antiviral therapy should continue at 
least 4 weeks after last dose of Everolimus. 
If resolution occurs > 28 days Patients should discontinue Everolimus 
but continue antiviral therapy at least 4 weeks after last dose of 
Everolimus. 
* All reactivations of HBV are to be recorded as grade 3 (e.g. CTCAE Version 4.03 - Investigations/Other: 
Viral Reactivation), unless considered life threatening by the investigator, in which case they should be 
recorded as grade 4. Date of viral reactivation is the date on which the rise or reappearance of HBV-
DNA was recorded. 


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4.5.11 Monitoring for hepatitis C flare 
The following two categories of patients should be monitored every 4–8 weeks 
for HCV flare: 
 
• 
Patients with detectable HCV RNA-PCR test at screening. 
• 
Patients known to have a history of HCV infection, despite a negative viral 
load test at screening (including those that were treated and are considered 
‘cured’) 
 
For definitions of HCV flare and actions to be taken in the event of a flare, please 
refer to  
Table 4-6. 
 
Table 4-6 
Guidelines for the management of hepatitis C flare 
Baseline results 
HCV flare definition* 
HCV flare management 
Detectable HCV-RNA 
 
> 2 log10 IU/mL increase in HCV-RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher. 
Discontinue Everolimus 
Knowledge of past hepatitis C 
infection with no detectable 
HCV-RNA 
New appearance of detectable HCV-RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher. 
Discontinue Everolimus 
* All flares of HCV are to be recorded as grade 3 (e.g. CTCAE Version 4.03 - Investigations - Other: 
Viral Flare), unless considered life threatening by the investigator; in which case they should be recorded 
as grade 4. Date of viral flare is the date on which both the clinical criteria described above were met. 
(e.g., for a patient whose HCV-RNA increased by 2 logs on 01 JAN 2011 and whose ALT reached > 5 
x ULN on 22 JAN 2011, the date of viral flare is 22 JAN 2011). 
4.6 
Concomitant Medications 
 
Patients must be instructed not to take any medications (over-the-counter or other 
products) during the protocol treatment period without prior consultation with the 
investigator. The investigator should instruct the patient to notify the study site about any 
new medications he/she takes after the start of study drug. All medications (other than 
study drug) and significant non-drug therapies (including physical therapy and blood 
transfusions) taken within 28 days of starting study treatment through the 30-day safety 
follow up visit should be reported on the CRF. 
 
4.6.1 
Permitted concomitant therapy: Other than study medications, patients may 
take other supportive therapies as prescribed by their treating physician. 
Treatment with systemic anticancer agents (chemotherapy, hormone therapy, 
targeted or biologic agents) other than the protocol treatment is not permitted.  
 
4.6.2 
Cytochrome 
P450 
and 
P-glycoprotein 
inhibitors/inducers/substrates: 
Everolimus is metabolized by CYP3A4 in the liver and to some extent in the 
intestinal wall. Therefore, the following are recommended: 
• 
Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, 
itraconazole, ritonavir) or P-glycoprotein (PgP) inhibitor should be avoided. 
• 
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, 
fluconazole) or PgP inhibitors should be used with caution. If a patient 
requires co-administration of moderate CYP3A4 inhibitors or PgP 
inhibitors, reduce the dose of everolimus . Additional dose reductions to 
every other day may be required to manage toxicities. If the inhibitor is 
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prior to initiation of the moderate CYP3A4/PgP inhibitor after a washout 
period of 2 to 3 days. 
• 
Grapefruit or citrus juices affect P450 and PgP activity. Concomitant use 
should be avoided. 
• 
Concommitant use of medications known to have inhibition or induction of 
CYP3A enzymes is strongly discouraged and should be discussed with 
the study chair. If patients begin therapy with strong CYP3A inducers (i.e., 
phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s 
wort), perform Everolimus trough concentration in 2 weeks. Enzyme 
induction usually occurs within 2 weeks.   
• 
For patients with low Everolimus trough concentrations (< 5 ng/ml), 
increase doses by 33% and repeat trough concentration in 2 weeks.   
• 
For patients with elevated Everolimus trough levels (>15 ng/ml), decrease 
dose by 25% and repeat trough concentration in 2 weeks. 
• 
Co-administration with strong inducers or inhibitors of CYP3A4 is strongly 
discouraged and should be discussed with the study chair. If a patient 
requires co-administration of strong CYP3A4 inducers (i.e., phenytoin, 
carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s wort), an 
increase in the dose of Everolimus may be necessary. Enzyme induction 
usually occurs within 2 weeks; therefore Everolimus dose should be 
increased by one increment 7 days after the start of the inducer therapy.  
If no safety concerns are seen within the next 7 days, the dose can be 
increased again one additional increment up to a maximum of twice the 
daily dose used prior to initiation of the strong CYP3A4 inducer. 
• 
This dose adjustment of Everolimus is intended to achieve similar AUC to 
the range observed without inducers. However, there are no clinical data 
with this dose adjustment in patients receiving strong CYP3A4 inducers. If 
the strong inducer is discontinued the Everolimus dose should be returned 
to the dose used prior to initiation of the strong CYP3A4/PgP inducer. 
Please refer to Table 4-7 listing relevant inducers and inhibitors of CYP3A 
and Table 4-8 for a list of relevant substrates, inducers, and inhibitors of 
PgP.  
 
Table 4-7 
Clinically relevant drug interactions: inducers, and inhibitors of 
isoenzyme CYP3A 
Inducers: 
carbamazepine, glucocorticoids, modafinil, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, 
rifabutin, rifampin, St. John’s wort, troglitazone, efavirenz, nevirapine, topiramate, avasimibe, 
bosentan, etravirine, nafcillin, ritonavir, talviraline (not available in US market), tipranavir, amprenavir, 
aprepitant, armodafinil (R-modafinil), dexamethasone, nevirapine, prednisone, pleconaril (not available 
in US market), rufinamide 
Inhibitors: 
Strong inhibitors: 
clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin, troleandamycin, voriconazole, tipranavir, elvitegravir, 
Posaconazole (Krishna et al 2009)  
Moderate inhibitors: 
aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, darunavir, diltiazem, erythromycin, 
fluconazole, grapefruit juice (citrus parasidi fruit juice), imatinib, tofisopam, verapamil, amprenavir, 
fosamprenavir, dronedarone 
 
 
 
 
 
 


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Table 4-8 
Clinically relevant drug interactions: substrates, inducers, inhibitors of PgP and 
PgP/CYP3A dual inhibitors 
Substrates: 
digoxin, fexofenadine, indinavir, vincristine, colchicine, topotecan, paclitaxel 
Inducers: 
rifampin, St John’s wort 
PgP Inhibitors and PgP/CYP3A Dual Inhibitors: 
amiodarone, captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, elacridar, 
erythromycin, felodipine, fexofenadine, ginkgo (ginkgo biloba), indinavir, itraconazole, , lopinavir, 
mibefradil, milk thistle (silybum marianum), nifedipine, nitrendipine, quercetin, quinidine, ranolazine, 
ritonavir, saquinavir, Schisandra chinensis, St John’s wort (hypericum perforatum), talinolol, telmisartan, 
tipranavir, valspodar, verapamil 
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Oct. 2, 2011, 
which summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug 
Interaction Studies”, the University of Washington’s Drug Interaction Database, and Indiana University 
School of Medicine's Drug Interaction Table. 
 
4.6.3 
Vaccinations: Immunosuppressants may affect the response to vaccination and 
vaccination during treatment with Everolimus may therefore be less effective. The 
use of live vaccines should be avoided during treatment with Everolimus Examples 
of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, 
BCG, yellow fever, varicella, and TY21a typhoid vaccines. 
4.6.4 
Wound healing complications: Impaired wound healing is a class effect of 
rapamycin derivatives, including everolimus. Caution should therefore be 
exercised with the use of Afinitor in the peri-surgical period.  
 
4.6.5 
Prohibited concomitant therapy Anti-neoplastic therapies: Treatment with 
systemic anticancer agents (chemotherapy, hormone therapy, targeted or biologic 
agents) other than the protocol treatment is not permitted until disease progression 
is documented per RECIST. Palliative radiotherapy or surgery is not allowed. 
4.7 
Toxicities and Dosing Delays/Dose Modifications 
 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
table. Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse 
Events (CTCAE), version 4.03. Dose adjustments should be made according to the system 
showing the greatest degree of toxicity.  
4.8 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue for 2 
years or until: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study, OR 
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 


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4.9 
Duration of Follow Up 
 
Patients will be followed after removal from treatment or until death, whichever occurs first. 
Follow-up for survival will occur by the treating oncologist and will be communicated to the 
PI or designee at 6-month intervals by phone or medical record review. Patients removed 
from treatment for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. 
4.10 
Removal of Patients from Protocol Therapy 
 
Patients will be removed from therapy when any of the criteria listed in Section 5.5 apply. 
Notify the Principal Investigator, and document the reason for study removal and the date 
the patient was removed in the Case Report Form. The patient should be followed-up per 
protocol.  
4.11 
Patient Replacement 
 
If a patient is withdrawn from the study prior to completing 1 course of therapy without 
experiencing a DLT prior to withdrawal, an additional patient may be added to that dose 
level.  
 
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before signed informed consent was obtained. 
 
5.1.1 
All screening procedures must be performed within 14 days prior to Course 1 Day 
1 unless otherwise stated.  
 
5.1.2 
Screening medical history, including complete medical and surgical history, history 
of infections, and MRI of the brain and spine 
 
5.1.3 
Demographics, including age, gender, race, ethnicity 
 
5.1.4 
Review subject eligibility criteria 
 
5.1.5 
Review previous and concomitant medications 
 
5.1.6 
Physical exam including vital signs (temperature, pulse, respirations, blood 
pressure, pulse oxygenation), height, weight, neurologic exam 
 
5.1.7 
Performance status, (Lansky Play Scale for children ≤ 10 years of age, Karnofsky 
Performance Level for patients > 10 years of age.) 
 
5.1.8 
Adverse event assessment: Baseline adverse events will be assessed. See 
section 6 for Adverse Event monitoring and reporting. 
 


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5.1.9 
Hematology: CBC with differential  
 
5.1.10 PT/PTT/INR 
 
5.1.11 Serum chemistries to include: alkaline phosphatase, ALT, AST, total bilirubin, 
calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting glucose, 
potassium, sodium, chloride, bicarbonate, uric acid, LDH, fasting lipid panel (LDL, 
total cholesterol, triglycerides) 
 
5.1.12 Hepatitis serology, including HBsAg, HBsAb, HBcAb, Hep C RNA for patients at 
risk of hepatitis as defined in Section 3.2.14. 
 
5.1.13 Pregnancy test (for females of child bearing potential), See section 3.2.13 for 
definition.  
 
5.1.14 Informed Consent 
 
5.1.15 Tumor assessment:  
5.1.15.1 Central Pathology Review 
5.1.15.2 Correlative biology studies (12 unstained FFPE slides) 
5.2 
Procedures During Treatment 
5.2.1 
Monthly (+/- 7 days): 
• Physical exam (including neurologic exam), vital signs, performance status 
• Pulse Oximetry 
• CBC with differential  
• Serum Chemistries to include: alkaline phosphatase, ALT, AST, total bilirubin, 
calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting glucose, 
potassium, sodium, chloride, bicarbonate, uric acid, LDH, fasting lipid panel 
(LDL, total cholesterol, triglycerides) 
• PT/PTT/INR 
• Urine pregnancy test for females of childbearing potential (Section 3.2.12) 
• AE Assessment  
• Review of Concomitant Medications 
• Drug Accountability Review 
• Everolimus trough levels will be tested 2 weeks after starting protocol therapy. 
Repeat testing may be required if there are dose adjustments or other 
parameters met as defined in Section 5.2.4. 
5.2.2 
Assessment of Tumor Response: 
• MRI of the brain and spine: MRI of the brain and spine should be performed 
every other month for the first year, every third month for the second year, and 
whenever clinically indicated.  Specifically, prior to courses 3, 5, 7, 9, 11, 13, 
16, 19, 22, and then at the end of treatment (after course 24).  Note: MRI should 
be completed within 7 days before the start of the indicated cycles. 
• Lumbar puncture for cytology: Not required, but to be performed as clinically 
indicated 
5.2.3 
Within 30 days after treatment termination: 
• Physical exam (including neurologic exam), vital signs, performance status 
• CBC with differential  
• Serum Chemistries to include: alkaline phosphatase, ALT, AST, total bilirubin, 
calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting glucose, 


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potassium, sodium, chloride, bicarbonate, uric acid, LDH, fasting lipid panel 
(LDL, total cholesterol, triglycerides). 
• PT/PTT/INR 
• Urine pregnancy test for females of childbearing potential (Section 3.2.12) 
• Hepatitis serology, including HBsAg, HBsAb, HBcAb, Hep C RNA for patients 
at risk of hepatitis as defined in Section 3.2.14. 
• AE Assessment  
• Review of Concomitant Medications  
• Drug Accountability Review 
 
 
5.2.4 
Pharmacokinetic Drug Monitoring and Adjustments:  
 
The target drug trough level of Everolimus is 5 – 15 ng/ml.  
• Everolimus trough levels will be assessed 2 weeks (+/- 4 days) after starting 
drug. If the level is outside of the target range, then the dose should be adjusted 
to achieve a trough level of 5 – 15 ng/ml.  Trough levels should be assessed 
within one hour before taking the daily dose. 
• Whenever any dose adjustment of Everolimus occurs, trough levels should be 
reassessed two weeks (+/- 4 days) following the adjustment to ensure that the 
new dose achieves the target drug trough level of 5-15 ng/ml. 
• Furthermore, Everolimus trough levels should be assessed 2 weeks (+/- 4 days) 
following the starting, ending, or changing of the dose of inducers or inhibitors 
of CYP3A4 or P-glycoprotein. 
5.3 
Follow-up Procedures  
 
Patients will be followed for survival after completion of (or early withdrawal from) study 
treatment or death. 
 
Adverse Events and concomitant medication monitoring should be continued for at least 
30 days following the last dose of study treatment.  
5.4 
Time and Events Table 
(See Appendix II) 
5.5 
Removal of Subjects from Study 
 
Patients can be taken off the study treatment and/or study at any time at their own request, 
or they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may 
include: 
 
5.5.1 
Patient voluntarily withdraws from treatment (follow-up permitted); 
5.5.2 
Patient withdraws consent (termination of treatment and follow-up); 
5.5.3 
Patient is unable to comply with protocol requirements; 
5.5.4 
Patient demonstrates disease progression (unless continued treatment with 
study drug is deemed appropriate at the discretion of the investigator); 
5.5.5 
Patient experiences toxicity that makes continuation in the protocol unsafe; 
5.5.6 
Treating physician judges continuation on the study would not be in the patient’s 
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5.5.7 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.5.8 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.5.9 
Lost to follow-up: If a research subject cannot be located to document survival 
after a period of 2 years, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the two years must be documented and 
approved by the Data Monitoring Committee. 
 
 
6.0 
MEASUREMENT OF EFFECT 
6.1 
Response Assessment 
6.1.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with study drug. 
 
Evaluable for objective response.  Only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for response. These 
patients will have their response classified according to the definitions stated 
below. (Note: Patients who exhibit objective disease progression prior to the end 
of cycle 1 will also be considered evaluable.) 
 
In this study, response and progression will be evaluated using the International 
Society of Pediatric Oncology Brain, Tumor Subcommittee for the Reporting of 
Trials criteria shown below with slight modification.34 Response will be assessed 
by magnetic resonance imaging (MRI) scan every 8 weeks (every 2 cycles) for 1 
year, then every 12 weeks. 
 
6.1.2 
Complete Response (CR):  
Complete disappearance on MRI of all enhancing tumor and mass effect, on a 
stable or decreasing dose of corticosteroids (or receiving only adrenal replacement 
doses), accompanied by a stable or improving neurologic examination and must 
be sustained for at least 4 weeks. If cerebral spinal fluid (CSF) evaluation was 
positive, it must become negative. CSF negativity has to be confirmed at least two 
times at consecutive samplings if the CSF was positive. 
 
6.1.3 
Partial Response (PR):  
Greater than or equal to 50% reduction in tumor size by bi-dimensional 
measurement on a stable or decreasing dose of corticosteroids, accompanied by 
a stable or improving neurologic examination and must be sustained for at least 4 
weeks. 
 
6.1.4 
Minor Response (MR):  
Greater than or equal to 25% to < 50% reduction in tumor size by bi-dimensional 
measurement on a stable or decreasing dose of corticosteroids, accompanied by 
a stable or improving neurologic examination and must be sustained for at least 4 
weeks. 
 


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6.1.5 
Stable Disease (SD):  
Neurologic examination is at least stable and maintenance corticosteroid dose is 
not increased, and MRI meets neither the criteria for MR nor the criteria for 
progressive disease and must be sustained for at least 8 weeks.  
 
6.1.6 
Stable Disease (SD):  
Neurologic examination is at least stable and maintenance corticosteroid dose is 
not increased, and MRI meets neither the criteria for MR nor the criteria for 
progressive disease and must be sustained for at least 8 weeks.  
 
6.1.6.1 Prolonged Stable Disease is defined as stable disease for at least 6 
months duration.  
 
6.1.7 
Progressive Disease (PD):  
Progressive neurologic abnormalities or worsening neurologic status not explained 
by causes unrelated to tumor progression (eg, anticonvulsant or corticosteroid 
toxicity, electrolyte disturbances, sepsis, hyperglycemia, etc), OR a greater than 
25% increase in the bi-dimensional measurement on MRI, OR the appearance of 
a new lesion or new CSF positivity, OR increasing doses of corticosteroids 
required to maintain stable neurologic status or imaging. 
 
All patients who have measurable disease according to the above response 
criteria, who received at least 1 cycle of therapy and who have their disease re-
evaluated will be evaluable for response. All sites of disease should be followed 
as either target or nontarget lesions, as categorized at baseline. All measurable 
lesions up to a maximum of 5 lesions should be identified as target lesions, while 
all other lesions (either additional measurable lesions or nonmeasurable lesions) 
should be classified as nontarget lesions. If possible, the same method, 
radiological or physical, should be employed and assessed by the same individual 
on each occasion. If possible, the same method should be employed and assessed 
by the same institution on each occasion. Ideally, any response should be 
confirmed by repeated evaluation at least 28 days after the first assessment where 
the response criteria were met. 
 
6.1.8 
Response Review 
Patients who have a confirmed response (CR, PR, MR, or prolonged SD) as 
deemed by the institution will have the response reviewed by an independent 
expert. Radiological images will be collected only for those patients who require 
central response review.  
 
6.1.9 
Central Review of Imaging: 
 
All required MRIs of the brain and spine with gadolinium contrast will be loaded 
onto a CD in DICOM format and sent to the address below for central review. 
Please send an e-mail notification (including tracking number) to the study PI at 
time of shipping. Note that central review is not required prior to starting therapy, 
but MRI’s should be submitted for central review concurrently with patient 
enrollment.  In the unlikely event that central review does not agree with the local 
read, the patient will immediately be removed from the protocol and discontinue 
study drug if study drug had been started.  Patients removed from protocol in this 
fashion will be replaced. 
 
 
 
Daniel C. Bowers, MD 
 
 
Department of Pediatrics 
 
 
5323 Harry Hines Blvd. 
 
 
UT Southwestern Medical Center 


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Dallas, TX, 75390-9063  
 
6.1.10 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). The patient's best response assignment will depend on the achievement 
of both measurement and confirmation criteria. 
 
 
 
Table 6-1 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Response for 
this Category Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. confirmation 
CR 
Non-CR/Non-
PD 
No 
PR 
 
>4 wks. confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least 
once >4 wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or 
CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be reported as “symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
Note: If subjects respond to treatment and are able to have their disease resected, the 
patient’s response will be assessed prior to the surgery. 
 
6.1.11 Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented.
 
 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started.  
 
6.1.12 Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression. 
 


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6.1.13 Event-Free Survival 
Event-Free Survival (EFS) is defined as the duration of time from start of treatment 
to: (1) disease progression; (2) second malignant neoplasm; (3) death regardless 
of cause; or (4) date of last contact, whichever comes first. 
6.2 
Safety/tolerability 
 
  
Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE version 4.03 (download: 
http://ctep.cancer.gov/reporting/ctc.html) for adverse event reporting. 
 
7.0 
ADVERSE EVENTS 
7.1 
Experimental Therapy 
 
 
7.1.1 
 
7.2 
Adverse Event Monitoring  
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial. Additionally, certain adverse events must be 
reported in an expedited manner to allow for optimal monitoring of the subject’s safety and 
care. Adverse events not requiring expedited reporting will be entered into the eCRF on a 
monthly basis. 
 
All subjects experiencing an adverse event, regardless of its relationship to study drug, will 
be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
 any abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 
 
7.2.1 
Definitions  
 
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam or laboratory finding), symptom, clinical event, or disease, temporarily 
associated with the subject’s participation in the research, whether or not it is considered 
related to the subject’s participation in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
can occur in the context of social and behavioral research. Adverse events may be 
expected or unexpected. 
Severity  


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Adverse events will be graded by a numerical score according to the defined NCI 
 
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) and Version 5.0. 
Adverse events not specifically defined in the NCI CTCAE will be scored on the Adverse 
Event log according to the general guidelines provided by the NCI CTCAE and as 
outlined below.   
• 
Grade 1: Mild  
• 
Grade 2: Moderate 
• 
Grade 3: Severe or medically significant but not immediately life threatening 
• 
Grade 4: Life threatening consequences 
• 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, 
occurring at any dose, which meets any of the following criteria:  
• 
Results in death   
• 
Immediately life-threatening  
• 
Results in inpatient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity  
• 
Results in a congenital anomaly/birth defect  
• 
Based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other outcomes 
listed in this definition. 
Note: A “Serious Adverse Event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 
adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring overnight hospitalization would be a serious adverse event for any 
research participant; likewise, in a study investigating end-stage cancer care, any 
hospitalization or death which occurs during the protocol-specified period of monitoring 
for adverse and serious adverse events would be a serious adverse event, even if the 
event observed is a primary clinical endpoint of the study. 
*Pre-planned hospitalizations or elective surgeries are not considered SAEs. Note: If 
events occur during a pre-planned hospitalization or surgery that prolongs the existing 
hospitalization, those events should be evaluated and/or reported as SAEs.  
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or 
other means, will be collected, recorded, and followed as appropriate.  
 
Adverse events that begin or worsen after informed consent should be recorded in the 
Adverse Events CRF. Conditions that were already present at the time of informed consent 
should be recorded in the patient’s eCRF. Adverse event monitoring should be continued 
for at least 30 days (or 5 half-lives, whichever is longer) following the last dose of study 
treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
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symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event. 
 
The occurrence of adverse events should be sought by non-directive questioning of the 
patient at each visit during the study. Adverse events also may be detected when they are 
volunteered by the patient during or between visits or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine: 
 
1. The severity grade (CTCAE Grade 1-4) 
2. Its duration (Start and end dates or if continuing at the Safety Follow-up Visit) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, 
Yes)  
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, hospitalized, unknown, not 
applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug 
therapy, concomitant medication/non-drug therapy) 
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Sections 
7.2.1 and 7.4.1. 
 
All adverse events should be treated appropriately. Such treatment may include changes 
in study drug treatment including possible interruption or discontinuation, starting or 
stopping concomitant treatments, changes in the frequency or nature of assessments, 
hospitalization, or any other medically required intervention. Once an adverse event is 
detected, it should be followed until its resolution, and assessment should be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the study drug, the interventions required to treat it, and the outcome. 
 
Information about common side effects already known about the investigational drug can 
be found in the Investigators’ Brochure. This information should be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
 
Adverse event monitoring should be continued for at least 30 days following the last dose 
of study treatment 
 
Laboratory Test Abnormalities 
 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation 
of the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record 
the lab/test result as an additional event.  
 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not 
be reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below 
and/or as per investigator’s discretion. A dose hold or medication for the lab abnormality 
may be required by the protocol and is still, by definition, an adverse event. 
 


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7.2.2     Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is found, but not 
defined in the regulations for the HHS regulations at 45 CFR 46, and the FDA regulations 
at 21 CFR 56. 108(b)(1) and 21 CRF 312.66. For device studies, part 812 uses the term 
unanticipated adverse device effect, which is defined in 21 CFR 812.3(s). Guidance from 
the regulatory agencies considers unanticipated problems to include any incident, 
experience, or outcome that meets ALL three (3) of the following criteria: 
• 
Unexpected in terms of nature, severity or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied;AND 
• 
Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research; AND  
• 
Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. Note: According to OHRP, if the adverse event is serious 
would always suggest a greater risk of harm.  
Follow-up  
All adverse events will be followed up according to good medical practices.  
 
7.2.3 
UTSW Reporting Requirements 
 
 
The UTSW IRB requires reporting of all UPIRSOs according to the guidance below. For 
participating centers other than UTSW, local IRB guidance should be followed for local 
reporting of serious adverse events. All SAEs occurring during the protocol-specified 
monitoring period should be submitted to the UTSW study team within 5 business days of 
the center learning of the event. 
7.2.3.1 UPIRSOs occurring on the study require expedited reporting, and are submitted to the 
UTSW IRB through the UTSW eIRB by the UTSW study team and to the SCCC DSMC 
Coordinator.  Hardcopies or electronic versions of the eIRB report; FDA Form #3500A 
forms, or other sponsor forms, if applicable; and/or any other supporting documentation 
available should be submitted to the UTSW study team and will be forwarded to the DSMC 
Coordinator.  The DSMC Coordinator forwards the information onto the DSMC Chairman 
who determines if immediate action is required.  Follow-up eIRB reports, and all 
subsequent SAE documentation that is available are also submitted to the DSMC Chair 
who determines if further action is required.  (See Appendix IV of the SCCC DSMC Plan 
for a template Serious Adverse Event Form which may be utilized when a sponsor form is 
unavailable and SAE submission to the eIRB is not required).  
  
 
All SAE/UPIRSOs at all sites, which occur in research participants on protocols for which 
the SCCC is the DSMC of record require reporting to the DSMC regardless of whether IRB 
reporting is required. All SAEs/UPIRSOs occurring during the protocol-specified monitoring 
period should be submitted to the SCCC DSMC within 5 business days of the PI or 
delegated study team members awareness of the event(s). In addition, for participating 
centers other than UTSW, local IRB guidance should be followed for local reporting of 
serious adverse events.  
 
The UTSW study team is responsible for submitting SAEs/UPIRSOs to the SCCC DSMC 
Coordinator. Hardcopies or electronic versions of the eIRB Reportable Event report; FDA 


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Form #3500A forms, or other sponsor forms, if applicable; and/or any other supporting 
documentation available should be submitted to the DSMC coordinator. The DSMC 
Coordinator forwards the information onto the DSMC Chairman who determines if 
immediate action is required. Follow-up eIRB reports, and all subsequent SAE/UPIRSO 
documentation hat is available area also submitted to the DSMC Chair who determines if 
further action is  required.  
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW, Simmons 
Cancer Center, the DOT Manager or lead coordinator ensures that all participating sites 
are notified of the event and resulting action, according to FDA guidance for expedited 
reporting. DSMC Chairperson reviews all SAEs/UPIRSOs upon receipt from the DSMC 
Coordinator.  The DSMC Chairperson determines whether action is required and either 
takes action immediately, convenes a special DSMC session (physical or electronic), or 
defers the action until a regularly scheduled DSMC meeting.  
 
 
 
 
  
Telephone reports to: 
Investigator: Daniel C. Bowers, MD  
214-648-8594 (business hours) or 214-456-7000 (nights and weekends) 
 
 
UTSW SCCC Data Safety Monitoring Committee Coordinator (if fax report is 
not available) within 5 working days to 214-648-7097. 
 
Written reports to: 
Investigator:  
Daniel C. Bowers, MD, Department of Pediatrics - Oncology 
5323 Harry Hines Blvd. 
Dallas, TX 75390 
Fax: 214-456-6151 
214-648-8594 (business hours) or 214-456-7000 (nights and weekends) 
RAD001C224T@childrens.com 
 
UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-7018 or deliver to NB 2.418 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation 
 
1. 
SAEs 
 
Serious adverse events occurring at sites other than UT Southwestern Medical Center will 
be promptly (less than 2 business days) reported to phone: 469-354-8137 and Dr. Daniel 
Bowers. These adverse events will be evaluated as whether or not they are related to study 
participation.  
 
Serious adverse events (SAEs) for studies where SCC DSMC is the DSMC of record 
require reporting to the DSMC coordinator within 5 working days of PI awareness, or as 
described in the protocol.   


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2. 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) 
Local Serious Adverse Event UPIRSOs require reporting to the UTSW IRB within 5 days 
of PI awareness of the event (life threatening or fatal events experienced by subjects 
enrolled by the investigator(s) under UTSW IRB jurisdiction).   
Local UPIRSOs (non-serious events experienced by subjects enrolled by the 
investigator(s) under UTSW IRB jurisdiction) require reporting to the UTSW IRB within 5 
business days of PI awareness.  
External UPIRSOs including those that occur as non-local events, require reporting to the 
UTSW IRB within 10 working days of PI awareness of the event. 
For further guidance for Investigators regarding safety reporting requirements for INDs 
and BA/BE studies, refer to FDA Draft Guidance document: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM227351.pdf 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v5).  
 
Step 2: Grade the adverse event using the NCI CTCAE v5. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- 
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 may NOT be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
 
Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the treatment. An adverse event is considered unexpected, for 
expedited reporting purposes only, when either the type of event or the severity of the 
event is not listed in: 
• 
the current known adverse events listed in the Agent Information Section of this 
protocol; 
• 
the drug package insert; 
• 
the current Investigator’s Brochure 
• 
the study agent’s background and associated known toxicities section of this 
protocol. 
 
7.4 
Serious Adverse Events 
 
 
7.4.1 Definitions 
A serious adverse event is an undesirable sign, symptom or medical condition 
which: 
• 
is fatal or life-threatening 


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• 
results in persistent or significant disability/incapacity 
• 
constitutes a congenital anomaly/birth defect 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is for: 
• 
routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition. 
• 
elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since the 
start of study drug 
• 
treatment on an emergency outpatient basis for an event not fulfilling any 
of the definitions of a SAE given above and not resulting in hospital 
admission 
• 
social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
• 
is medically significant, i.e., defined as an event that jeopardizes the patient 
or may require medical or surgical intervention to prevent one of the 
outcomes listed above 
 
 
7.4.2 Reporting Requirements 
 
The principal investigator, Dr. Bowers, has the obligation to report all serious adverse events 
to the FDA, IRB, and Novartis Pharmaceuticals Drug Safety and Epidemiology Department 
(DS&E). 
 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A 
(MedWatch Form).  
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring: 
• 
after the patient has provided informed consent and until at least 30 days after 
the patient has stopped study treatment/participation 
• 
after protocol-specified procedures begin and 30 days after the patient has 
stopped study treatment 
• 
after the start of any period in which the study protocol interferes with the 
standard medical treatment given to a patient (e.g., treatment withdrawal during 
washout period, change in treatment to a fixed dose of concomitant medication) 
and until 30 days after the patient has stopped study treatment  
 
must be reported to Novartis within 24 hours of learning of its occurrence (fax: 877-778-
9739)This includes serious, related, labeled (expected) and serious, related, unlabeled 
(unexpected) adverse experiences. All deaths during treatment or within 30 days following 
completion of active protocol therapy must be reported within 5 working days. 
 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. A SAE occurring 
at a different time interval or otherwise considered completely unrelated to a previously 
reported one should be reported separately as a new event.  The end date of the first event 
must be provided. 
 
The original copy of the SAE Report and the fax confirmation sheet must be kept within the 
Trial Master File at the study site. 
 
Follow-up information is sent to the same fax number as the original SAE Report Form was 
sent, using a new fax cover sheet, stating that this is a follow-up to the previously reported SAE, 
and giving the date of the original report. Each re-occurrence, complication, or progression of 


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the original event should be reported as a follow-up to that event regardless of when it occurs. 
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, and whether the patient continued or withdrew from study participation. 
 
If the SAE is not previously documented in the Everolimus Investigator Brochure or Package 
Insert (new occurrence) and is thought to be related to the Novartis study drug, a DS&E 
associate may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN), to inform all investigators 
involved in any study with the same drug that this SAE has been reported. Suspected 
Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC 
or as per national regulatory requirements in participating countries. 
 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the comparator drug company by the investigator. 
 
7.5 
Pregnancy 
Preclinical data regarding reproductive toxicity is described in the most recent Investigator 
Brochure. The potential reproductive risk for humans is unknown.  Women of childbearing 
potential should be advised to use highly effective contraception methods while they are 
receiving everolimus and up to 8 weeks after treatment has been stopped.   
 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. The newborn will be followed for at least 12 months. 
 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment and any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
7.6 
Stopping Rules 
 
Occurrence of >30% of patients requiring permanent discontinuation of Everolimus in this study 
(i.e., 4 of the first 10 patients or 6 of the first 16 patients) will lead to stopping this study.  A 
minimum of six patients will be treated. 
 
 
8.0 
CORRELATIVE STUDIES 
 
8.1 
FFPE 
 
Optional submission of tumor tissue, submitted as Formalin Fixed Paraffin Embedded 
(FFPE) tissue on 12 glass slides will be submitted to the study coordinating site within 28 
days of Course 1 Day 1. Slides will be identified by study participant number. 
8.2 
Immunohistochemistry 
 
Immunohistochemistry will be performed for biological markers of mTOR pathway 
activation, including phosphorylated S6235/236, phosphorylated S6240/244, phosphorylated 


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PRAS40 (pT246), phosphorylated 4EBP1, phosphorylated P70S6K, and PTEN 
expression. 
8.2.1 
Intensity of immunohistochemistry staining for each biomarker will be scored as 
Negative (-); weakly positive (+); moderately positive (++); and strongly positive 
(+++). 
8.2.2 
Results of intensity of immunohistochemistry staining will be described and 
correlated with tumor response to Everolimus. 
 
Send slides to the address below and clearly label package as CRAD001 study. Also, 
send an e-mail notification at time of shipping to the Study PI 
<Daniel.Bowers@UTSouthwestern.edu>, study coordinator 
<RAD001C224T@childrens.com>, and Dr. Rajaram <Veena.Rajaram@childrens.com> 
including tracking number. Central review is not required prior to starting therapy. 
 
 
Veena Rajaram, MD 
 
Department of Pathology 
 
Children’s Medical Center – Dallas 
 
1935 Medical District Drive 
 
Dallas, TX 75235 
 
8.2.3 
Immunohistochemistry will be performed on FFPE tumor tissue on slides for 
H3.K27me3 according to established methods. Based upon staining, tumors will 
be classified as Ependymoma Group A (negative – light staining) or Ependymoma 
Group B (positive staining). Descriptive results will be reported in the manuscript.  
 
9.0 
STATISTICAL CONSIDERATIONS  
9.1 
Study Design/Study Endpoints 
 
The study is a prospective single-arm multi-center phase II study that determines the 
objective response rate following treatment with everolimus for children with recurrent or 
progressive ependymomas. Given the relatively small study sample size, descriptive 
statistics will be used to report the results of the study. 
 
Study endpoints include the following: 
 
 
Objective Response Rate = Complete Response Rate + Partial Response Rate + 
Prolonged Stable Disease Rate. 
 
Duration of Response 
 
Progression Free Survival 
 
Overall Survival 
 
Dose-limiting toxicities 
 
Biological markers of mTOR pathway activation, including phosphorylated 
S6235/236, phosphorylated S6240/244, phosphorylated PRAS40 (pT246), 
phosphorylated 4EBP1, phosphorylated P70S6K, and PTEN expression. 
9.2 
Sample Size and Accrual 
 
Simon's two-stage optimal design35 is used to compute the number of patients to be 
recruited for this phase II trial. The null hypothesis that the true objective response rate 
(ORR) is 10% will be tested against a one-sided alternative. In the first stage, 7 patients 
will be accrued. If there is no ORR seen in these 7 patients, the study will be stopped. 


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Otherwise, 11 additional patients will be accrued for a total of 18 patients. The null 
hypothesis will be rejected if 4 or more ORRs are observed in 18 patients. This design 
yields a type I error rate of 10% and power of 80% when the true ORR is 30%. It is expected 
that the accrual will be completed in 2 years since 9 patients are expected to be recruited 
in a year.  
9.3 
Data Analyses Plans 
 
Objective response rate and the corresponding 95% confidence interval will be estimated 
using the exact binomial method. Kaplan-Meier method will be used to estimate the 
duration of response, progression free survival (PFS) and event free survival (EFS) 
following treatment with everolimus for children with recurrent or progressive 
ependymomas. The corresponding 95% confidence interval will be computed using 
Greenwood’s formula. Safety and tolerability of everolimus will be estimated using exact 
binomial method. Exploratory analysis will be conducted to investigate the correlation 
between response rate and biological markers of mTOR pathway activation, including 
phosphorylated S6235/236, phosphorylated S6240/244, phosphorylated PRAS40 (pT246), 
phosphorylated 4EBP1, phosphorylated P70S6K, and PTEN expression. 
10.0 
STUDY MANAGEMENT 
10.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the Conflict of Interest Office at their respective institution. All 
investigators will follow the University conflict of interest policy. 
10.2 
Institutional Review Board (IRB) Approval and Consent 
 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. Each 
consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient or their legally authorized representative and 
by the person who conducted the informed consent discussion. 
10.3 
Required Documentation (for multi-site studies) 
 
Before the study can be initiated at any site, the following documentation must be provided 
to the Clinical Research Office, Pauline Allen Gill Center for Cancer and Blood Disorders, 
Children’s Medical Center – Dallas. 


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• 
A copy of the official IRB approval letter for the protocol and informed consent 
• 
IRB membership list or Federal Wide Assurance letter 
• 
CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study 
• 
Form FDA 1572 appropriately filled out and signed with appropriate documentation 
(NOTE: this is required if this institution holds the IND. Otherwise, the affiliate 
Investigator’s signature on the protocol is sufficient to ensure compliance) 
• 
A copy of the IRB-approved consent form 
• 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
• 
Executed clinical research contract 
• 
Site Delegation Log 
10.4 
Registration Procedures 
 
All patients must be registered with the UT Southwestern Medical Center / Children’s 
Medical Center-Dallas (UTSW/CMC) Research Office before consenting to study 
participation. Prior to enrollment, eligibility criteria must be confirmed with the Clinical 
Research Office Study Coordinator at UTSW/CMC. To register a patient, call 214-456-
6167 Monday through Friday, 8:00AM-4:00PM CST. After hours, Daniel C. Bowers, MD 
(Study Principle Investigator) can be reached through the Children’s Medical Center paging 
operator at 214-456-7000. 
 
 
10.5 
Data Management and Monitoring / Auditing  
 
REDCap is the UTSW SCC institutional choice for electronic data capture of case report 
forms for this and all SCC investigator initiated trials. REDCap will be used for electronic 
data capture case report forms in accordance with Simmons Cancer Center requirements.  
 
Other institutions participating in this trial as sub-sites will be expected to enter data into 
REDCap and upload de-identified source materials as instructed by the study team to 
facilitate remote source to case report form verification.  
 
Trial monitoring will be conducted no less than annually and refers to a regular interval 
review of trial related activity and documentation performed by the DOT, which includes 
but is not limited to accuracy of case report forms, protocol compliance timelines and 
accuracy of Velos entries and AE/SAE management and reporting. Documentation of trial 
monitoring will be maintained along with other protocol related documents and will be 
reviewed during the internal audit.  
 
The UTSW Simmons Cancer Center (SCC) Data Safety Monitoring Committee (DSMC) is 
responsible for monitoring data quality and patient safety for all UTSW SCC clinical trials. 
As part of that responsibility, the DSMC reviews all local serious adverse events and 
unanticipated problems in real time as they are reported and reviews adverse events on a 
quarterly basis. The quality assurance activity for Clinical Research Office provides 
periodic auditing of clinical research documents to insure data integrity and regulatory 
compliance. A copy of the DSMC plan is available upon request.  
 
The SCC DSMC meets quarterly and conducts annual comprehensive reviews of ongoing 
clinical trials, for which it serves as the DSMC of record. The QAC works as part of the 
DSMC to conduct regular audits based on the level of risk. Audit findings are reviewed at 
the next available DSMC meeting. In this way frequency of DSMC monitoring is dependent 


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upon the level of risk. Risk level is determined by the DSMC Chairman and a number of 
factors such as the phase of the study, the type of investigational agent, device or 
intervention being studied, and monitoring required to ensure the safety of study subjects 
based on the associated risks of the study. Protocol specific DSMC plans must be 
consistent with these principles.  
 
 
 
 
 
10.6 
Adherence to the Protocol 
 
Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study patient requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol.  
10.6.1 Emergency Modifications 
 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, a IRB modification form must 
be completed within five (5) business days of making the change. 
10.6.2 Other Protocol Deviations/Violations 
 
All other planned deviations from the protocol must have prior approval by the 
Principal Investigator and the IRB. According to the IRB, a protocol deviation is 
any unplanned variance from an IRB approved protocol that:  
• 
Is generally noted or recognized after it occurs 
• 
Has no substantive effect on the risks to research participants 
• 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected  
• 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
• 
Has harmed or increased the risk of harm to one or more research participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal 
Investigator and IRB, please follow the guidelines below: 
 
Protocol Deviations: Personnel will report to any sponsor or data and safety 
monitoring committee in accordance with their policies. Deviations should be 
summarized and reported to the IRB at the time of continuing review. 
 
Protocol Violations: Study personnel should report violations within one (1) week 
of the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems.  


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10.7 
Amendments to the Protocol 
 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an amendment 
to the protocol substantially alters the study design or the potential risk to the patient, a 
revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
10.8 
Record Retention 
 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, 
signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator must 
retain all study documentation pertaining to the conduct of a clinical trial. In the case of a 
study with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
10.9 
Obligations of Investigators 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will require 
his/her final signature to verify the accuracy of the data. 
 
 


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Bjornsti MA, PJ H. The TOR pathway: A target for cancer therapy. Nat Rev Cancer 2004;4:335-
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22. 
Rogers HA, Mayne C, Chapman RJ, Kilday J-P, Coyle B, Grundy RG. PI3K Pathway Activation 
Provides a Novel Therapeutic Target for Pediatric Ependymoma and Is an Independent Marker of 
Progression-Free Survival. Clinical Cancer Research 2013;19:6450-60. 


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23. 
Franz DN, Leonard J, Tudor C, et al. Rapamycin causes regression of astrocytomas in tuberous 
sclerosis complex. Annals of Neurology 2006;59:490-8. 
24. 
Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal 
giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, 
placebo-controlled phase 3 trial. The Lancet 2013;381:125-32. 
25. 
Fouladi M, Laningham F, Wu J, et al. Phase I Study of Everolimus in Pediatric Patients With 
Refractory Solid Tumors. J Clin Oncol 2007;25:4806-12. 
26. 
Houghton PJ, Morton CL, Kolb EA, et al. Initial testing (stage 1) of the mTOR inhibitor rapamycin 
by the pediatric preclinical testing program. Pediatric Blood & Cancer 2008;50:799-805. 
27. 
Iwenofu OH, Lackman RD, Staddon AP, Goodwin DG, Haupt HM, Brooks JSJ. Phospho-S6 
ribosomal protein: a potential new predictive sarcoma marker for targeted mTOR therapy. Mod Pathol 
2007;21:231-7. 
28. 
Cho D, Signoretti S, Dabora S, et al. Potential Histologic and Molecular Predictors of Response to 
Temsirolimus in Patients with Advanced Renal Cell Carcinoma. Clinical Genitourinary Cancer 
2007;5:379-85. 
29. 
Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al. Clinical Activity of mTOR Inhibition With 
Sirolimus in Malignant Perivascular Epithelioid Cell Tumors: Targeting the Pathogenic Activation of 
mTORC1 in Tumors. J Clin Oncol 2010;28:835-40. 
30. 
Wolff N, Kabbani W, Bradley T, Raj G, Watumull L, Brugarolas J. Sirolimus and Temsirolimus for 
Epithelioid Angiomyolipoma. J Clin Oncol 2010;28:e65-8. 
31. 
Busaidy NL, Farooki A, Dowlati A, et al. Management of Metabolic Effects Associated With 
Anticancer Agents Targeting the PI3K-Akt-mTOR Pathway. Journal of Clinical Oncology 2012;30:2919-
28. 
32. 
Yeo W, Lam KC, Zee B, et al. Hepatitis B reactivation in patients with hepatocellular carcinoma 
undergoing systemic chemotherapy. Annals of Oncology 2004;15:1661-6. 
33. 
Loomba R, Rowley A, Wesley R, et al. Systematic review: the effect of preventive lamivudine on 
hepatitis B reactivation during chemotherapy. Annals of Internal Medicine 2008;148:519-28. 
34. 
Gnekow AK. Recommendations of the brain tumor subcommittee for the reporting of trials. 
Medical and Pediatric Oncology 1995;24:104-8. 
35. 
Simon R. Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled Clinical Trials 
1988;10:1-10. 
 
 
 


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APPENDIX I: Inclusion / Exclusion Checklist 
Inclusion Criteria—Complete each box with an “X” to confirm patient meets listed criteria 
 
Diagnosis and Age: Ependymoma (WHO grade II) or Anaplastic Ependymoma (WHO grade III) 
that has relapsed or become refractory to standard therapy. Patients must have had histologic 
verification of their malignancy at original diagnosis or time of recurrence. 
 
Age must be ≥ 2 years and ≤ 21 years of age at study entry. 
 
Performance status: Lansky ≥ 50% for patients ≤ 10 years of age or Karnofsky ≥ 50% for 
patients > 10 years of age. 
 
Adequate bone marrow function as shown by: ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3 and 
hemoglobin > 9.0 g/dL. (These values must be transfusion independent) 
 
Adequate liver function as shown by: Total serum bilirubin ≤ 2.0 mg/dL, ALT and AST ≤ 2.5x 
ULN, INR ≤ 2. 
 
Adequate renal function: serum creatinine ≤ 1.5x ULN. 
 
Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5x 
ULN (See protocol for exception). 
 
Signed informed consent obtained prior to any screening procedures 
 
Patients must have measurable residual disease, defined as tumor that is measurable in two 
diameters on MRI. Diffuse leptomeningeal disease is not considered measurable. 
 
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, 
immunotherapy, and radiotherapy prior to participating in this trial (see protocol for details). 
 
All patients must have an MRI of the brain and the complete spine that has measurable tumor 
(not only diffuse leptomeningeal tumor) within 14 days prior to study enrollment. 
 
If available, tumor tissue from either initial diagnosis or subsequent surgery will be submitted 
on Formalin Fixed Paraffin Embedded (FFPE) slides (n = 12) to the Pathology Laboratory at 
Children’s Medical Center-Dallas for correlative biological studies.  
Exclusion Criteria—Complete each box with “No” or “NA”, as appropriate, to confirm eligibility 
 
Known intolerance or hypersensitivity to Everolimus or other rapamycin analogs. 
 
Concomitant use of medications known to have inhibition or induction of CYP3A enzymes (see 
Table 4-7 and 4-8 for a list of prohibited medications). Note that systemic corticosteroids (e.g., 
dexamethasone is a CYP3A inducer) are not allowed. Inhaled corticosteroids are allowed. 
 
Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of oral Everolimus. 
 
Uncontrolled diabetes mellitus as defined by HbA1c > 8% despite adequate therapy. Patients 
with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, 
however blood glucose and antidiabetic treatment must be monitored closely throughout the 
trial and adjusted as necessary 
 
Patients who have any severe and/or uncontrolled medical conditions (see protocol) 
 
Patients with a known history of HIV sero-positivity 
 
Patients who have received live attenuated vaccines (see protocol for examples) within 1 week 
of start of Everolimus. 
 
Patients who have a history of another primary malignancy (see protocol for exceptions). 
 
Patients with a history of non-compliance to medical regimens or who are considered 
potentially unreliable or will not be able to complete the entire study. 
 
Patients who are currently part of or have participated in any clinical investigation with an 
investigational drug within 1 month prior to dosing. 
 
Pregnant or nursing (lactating) women. 
 
Women of child-bearing potential unless they are using highly effective methods of 
contraception (see protocol for details). 
 
Sexually active males unless they are using a condom (see protocol for details). 
 
Hepatitis screening must be completed if necessary (see protocols for details). 
 
I have reviewed the eligibility criteria and confirm the patient is eligible for enrollment. 
 
Physician Signature: _____________________________ 
Date: __________________


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APPENDIX II: Time and Events Table 
Period/Procedure 
Screening 
Course 1 
Courses 2-24 10 
End of Treatment Visit 
13 
Long Term 
Follow Up 
Study Day/Visit Day 
-14 to 1 
Day 14 
(+/- 4 days) 
Day 1 
(+/-7 days) 
Within 30 Days 
 
Informed Consent 
X 
 
 
 
 
Central Review of Pathology and MRI 
1 
X 
 
 
 
 
AE Assessment 
X 
 
X 
X14 
 
Concomitant Medications 
X 
 
X 
X14 
 
Drug Accountability 
 
 
X 
X 
 
Clinical procedures 
 
Physical Exam 
X 
 
X 
X 
 
Vital Signs 
X 
 
X 
X 
 
Medical History 
X 
 
 
 
 
Performance Status 
X 
 
X 
X 
 
Neurologic Exam 
X 
 
X 
X 
 
Pulse Oximetry 2 
X 
 
X 
 
 
Laboratory procedures 
 
CBC w/ Diff 3 
X 
 
X 
X 
 
Blood Chemistry 4 
X 
 
X 
X 
 
Coagulation 5 
X 
 
X 
X 
 
Pregnancy Test (HCG) 6 
X 
 
X 
X 
 
Hepatitis (If Required) 7,8 
X 
 
 
X 
 
Everolimus PK Test 9 
 
X 
 
 
 
Disease Assessment & Outcomes 
 
Imaging (MRI) 11 
X 
 
X* 11 
X 
 
Lumbar Puncture (optional) 12 
X 
 
X 
X 
 
Survival Follow Up & Other 
Treatment 
 
 
 
 
X15 
 
 


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1 Central review of pathology/MRI should be completed concurrently with registration, but is not required before starting therapy. 
2 If pulse oximetry is less than 93% on room air patient should get a CXR monthly until pulse oximetry is >93%. 
3 Including CBC with differential  
4 Including alkaline phosphatase, ALT. AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, glucose, potassium, 
sodium, chloride, bicarbonate, uric acid, LDH, and lipid panel (LDL, total cholesterol, triglycerides) 
5 Including PT/PTT/INR 
6 For females of child bearing potential, urine or serum pregnancy test as per your institutional guidelines. See Section 3.1.12 for further 
details. 
7 Including HBsAg, HBsAb, HBcAb, Hep C RNA.  See Protocol Section 3.2.14 for details. 
8 Patients who test positive for hepatitis B antibodies without receiving prior vaccination will be monitored for HBsAg every 4 weeks. 
9 PK testing should also be performed 2 weeks post any Everolimus dose adjustment or any CYP3A4 concomitant medication 
administration/dose adjustment.  See Protocol Section 5.2.4 for details. 
10 Courses are 28 days in length.  Each subsequent course following course 1 should begin within 7 days of the end of the prior course. 
11 MRI of the brain and spine will be performed at the beginning of courses 3, 5, 7, 9, 11, 13, 16, 19, 22, and at the end of treatment visit (after 
course 24).  This assessment should be performed on day 1 of these courses as possible, but may be performed up to 7 days prior to 
starting these courses if necessary. 
12 Lumbar puncture for cytology is optional but may be performed if clinically indicated. 
13 The End of Treatment Visit should be completed within 30 days of treatment termination. 
14 Adverse event and concomitant medication monitoring should be continued for at least 30 days following the last dose of study treatment 
15 Survival follow up will be completed by phone or medical record review. 


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APPENDIX III:  Patient Drug Diary 
 
 
 

ICF_003.pdf: 
 
INFORMED CONSENT FORM 
 
 
Official title: PHASE II STUDY OF EVEROLIMUS (RAD001, AFINITOR®) 
FOR CHILDREN WITH RECURRENT OR PROGRESSIVE EPENDYMOMA 
NCT number: NCT02155920 
IRB Approved Document date: 9/26/2017 


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The University of Texas Southwestern Medical Center at Dallas
Parkland Health & Hospital System
Children’s Medical Center
Retina Foundation of the Southwest
Texas Scottish Rite Hospital for Children
Texas Health Presbyterian Hospital of Dallas
CONSENT TO PARTICIPATE IN RESEARCH
Title of Research:
Phase II Study of Everolimus (RAD001, AFINITOR®) for 
Children with Recurrent or Progressive Ependymoma
Funding Agency/Sponsor:
UT Southwestern Medical Center
Novartis Pharmaceuticals Corporation
Study Doctor:
Daniel C. Bowers, MD 
You may call the study doctor or research personnel during regular office hours at 214-456-
2382.  At other times, you may call them at 214-456-7000.
Note: If you are a parent or legal guardian of a child who may take part in this study, 
permission from you is required.  The assent (agreement) of your child may also be required.  
When we say “you” in this consent form, we mean you or your child; “we” means the doctors 
and other staff.
Instructions:
Please read this consent form carefully and take your time making a decision about whether 
to participate.  As the researchers discuss this consent form with you, please ask him/her to 
explain any words or information that you do not clearly understand.  The purpose of the 
study, risks, inconveniences, discomforts, and other important information about the study 
are listed below.  If you decide to participate, you will be given a copy of this form to keep.
Why is this study being done?
This study is being done to find out if the investigational drug Everolimus (Afinitor®) is safe 
and has beneficial effects for children who have a recurrent or progressive brain tumor called 
an ependymoma. At present, there are no standard-of-care medications or medications 
approved by the U.S. Food and Drug Administration (FDA) for children with recurrent 
ependymomas. 
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The goals of this study are to:

Determine the response rate of children with recurrent or progressive ependymoma 
following treatment with Everolimus (Afinitor®) for children with recurrent or 
progressive ependymomas.

Determine the duration of response of children with recurrent or progressive 
ependymoma following treatment with Everolimus (Afinitor®) for children with 
recurrent or progressive ependymomas.

Determine safety and tolerability of Everolimus (Afinitor®) among children with 
recurrent or progressive ependymomas.

Examine whether certain proteins present on ependymoma tumor tissue is 
associated with a tumor’s response to Everolimus (Afinitor®).
Why is this considered research? 
This is a research study because Everolimus (Afinitor®) is investigational and has not been 
approved by the U.S. Food and Drug Administration (FDA) for the treatment of recurrent or 
progressive Ependymomas.
The following definitions may help you understand this study: 

Standard medical care means the regular care you would receive from your personal 
doctor if you choose not to participate in this research.

Researchers means the study doctor and research personnel at the University of 
Texas Southwestern Medical Center at Dallas and its affiliated hospitals.
Why am I being asked to take part in this research study?
You are being asked to take part in this study because you have a recurrent or progressive 
ependymoma.  Ependymomas are types of childhood brain tumors that have historically 
been considered resistant to standard chemotherapy drugs.  There is no standard treatment 
for children with recurrent or progressive ependymomas.
Do I have to take part in this research study?
No.  You have the right to choose whether you want to take part in this research study.  If 
you decide to participate and later change your mind, you are free to stop participation at 
any time.
If you decide not to take part in this research study it will not change your legal rights or the 
quality of health care that you receive at this center.
It is important for you to know why this study is being done before you decide to take part in 
this research study.  This consent will tell you about the study.  This consent will also tell 
you about risks and side effects that might happen to you if you take part in this study.  You 
also need to know you do not have to take part in this study.  You can talk to your doctor 
about other cancer treatments.  Taking part in this study is voluntary.
Please read this consent form carefully and take your time to make your decision.  Discuss 
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it with your friends and family.  We encourage you to include your child in the discussion 
and decision to the extent that he or she is able to understand and take part.
How many people will take part in this study?
About 10 people will take part in this study at UT Southwestern or Children’s Medical Center.  
This study also is taking place at a number of other medical facilities around the country.  
There will be a total of 18 people participating in this research study throughout the United 
States.
What is involved in the study?
If you choose to take part in this research study, you will be asked to sign this consent form 
and will have the following tests and procedures.  Some of the procedures may be part of 
your standard medical care, but others are being done solely for the purpose of this study.
Screening Procedures
You will need to have the following exams, tests or procedures to find out if you can be in 
the study.  These exams, tests or procedures are part of regular cancer care and may be 
done even if you do not join the study.  If you have had some of them recently, they may not 
need to be repeated.  This will be up to your study doctor.  

A medical history and demographic information (age, sex, ethnic origin)

Review of medications you are currently taking and have taken in the past 
including herbal medications 

Physical exam, including a neurological exam

You will be asked about the symptoms you are having from your disease and 
evaluated to determine your performance status

Vital signs (blood pressure, respirations, heart rate, temperature, weight, height, 
and body surface area)

Blood tests

Pulse oximetry (test to evaluate the amount of oxygen in your blood)

Pregnancy test (if you are a female who could have children)

MRI of brain and spine*

Baseline adverse event assessment

Any other studies or tests your treating doctor thinks are necessary in order to 
give you the best care 

If a lumbar puncture (spinal tap) is performed as part of your clinical care, the 
results of that test will also be used for this research. However, a lumbar puncture 
is not done separately for this research study. 
*Magnetic Resonance Imaging or MRI is a scan that provides multiple detailed pictures of 
the inside of the body.  MRI does not use radiation.  In order to better view some structures 
in the body, including tumors, a special dye or contrast agent will be injected intravenously 
(through a vein). 
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If you are female and have the potential to become pregnant, you will be tested to see if you 
are pregnant with a urine pregnancy test prior to your first dose of study medication.  All 
participants of reproductive potential must use an effective method of birth control 
throughout the study and for at least 8 weeks following termination of treatment.  Your doctor 
will discuss appropriate means of birth control with you if required. 
In addition, it is also important to inform your study doctor if you:

Have had hepatitis B and/or hepatitis C;

Have had blood transfusions(s) before 1990;

Are now or have been an intravenous drug user;

Are having or have had dialysis;

Have someone in your household who has hepatitis B or C;

Are having or have had high-risk sexual activity;

Have had body piercing or tattoos;

Have a mother who had hepatitis B.
Tests will be done for hepatitis B and/or C if:

You have a risk of having hepatitis B and/or C or;

You live in or have lived in Asia, Africa, Central and South America, Eastern Europe 
and Spain, Portugal or Greece;

Your study doctor thinks it is appropriate.
If you test positive for hepatitis B, your study doctor will inform you if you need to take an 
anti-viral drug.  An anti-viral drug is used to treat infections caused by viruses.  You will not 
be able to participate in this study.  If you test negative for hepatitis B, the study doctor may 
continue to monitor your blood for the genetic material of the hepatitis B virus and to see if 
your liver is damaged or inflamed.  If the amount of the genetic material and your liver test 
increases, then your study doctor will inform you of the treatment.  This may mean that you 
are given an anti-viral drug and also, you will need to stop taking the study drug.
If you test positive for hepatitis C, you will not be allowed to participate in the study.  If you 
test positive for hepatitis C while you are taking the study drug, you will need to stop taking 
the study drug because the treatment for hepatitis C has serious side effects.
Biology Studies-
We would like to use tumor tissue that was removed during surgery (either when you were 
first diagnosed or at a subsequent surgery) to determine if proteins present in your tumor 
are associated with response to everolimus.  Participating in these extra tests will not require 
that you undergo any additional procedures.  These tests use tumor tissue left over after 
diagnostic tests are completed.  These extra tests will help us learn about predicting 
outcomes of children with ependymoma, but they will not directly help you. 
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Study Medication/Intervention
If you decide to participate in this study, you will take Everolimus (Afinitor®) by mouth at a 
starting dose that will be determined by your weight and height.  Each Course of therapy will 
last for 28 days.
Procedures and Evaluations during the Research
You will have the following tests and/or evaluations:
Prior to each Course of treatment (every 28 days):

Medical history and physical exam, including neurological exam;

Vital signs

Drug diary review

Adverse event assessment

Review of medications you are currently taking and have taken in the past including 
herbal medications

Blood tests to evaluate bone marrow, blood clotting, kidney and liver function;

If you are a female who could become pregnant, you will have a pregnancy test.

Pulse oximetry (test to evaluate the amount of oxygen in your blood)
o If oxygen levels are low, then a chest x-ray will be done monthly until oxygen 
levels in the blood are appropriate.

If a lumbar puncture (spinal tap) is performed as part of your clinical care, the results 
of that test will also be used for this research. However, a lumbar puncture is not 
done separately for this research study 

You will be given a medication diary to complete daily.

Prescription for medication will be dispensed. 
Two weeks after you receive the first dose of Everolimus: 

Blood test (about ½ a teaspoon) to evaluate the level of study drug in your blood.  If 
the dose is outside of the target range, the dose will be adjusted to achieve an 
appropriate level.  Study drug levels will be repeated two weeks after any change in 
dose of Everolimus or changes to other medications that could affect the study drug.
Prior to Courses 3, 5, 7, 9, 11 and 13, then prior to Courses 16, 19, 22, and after Course 24:

MRI of the brain and spine to reassess tumor response to treatment.
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End of Treatment Visit
Within 30 days of completing course 24, you will have the following tests and/or evaluations:

Physical exam, including neurological exam;

Vital signs

Drug diary review

Adverse event assessment

Review of medications you are currently taking and have taken in the past including 
herbal medications

Blood tests to evaluate bone marrow, blood clotting, kidney and liver function;

If you are a female who could become pregnant, you will have a pregnancy test.

MRI of the brain and spine to reassess tumor response to treatment.

If a lumbar puncture (spinal tap) is performed as part of your clinical care, the results 
of that test will also be used for this research. However, a lumbar puncture is not 
done separately for this research study
How long can I expect to be in this study?
You may be in the study for up to two years if you are responding to therapy and not having 
side effects that are dangerous for you.  After you are taken off treatment or after you have 
completed your treatment, your treating doctor will ask you to return for follow up exams and 
tests to ensure that you are not having dangerous side effects.  Please continue to follow 
these instructions to ensure your safety.
After completing 24 courses of Everolimus (Afinitor®), if your tumor is responding favorably 
to Everolimus (Afinitor®) and you are tolerating the drug, you can discuss with your treating 
physician whether you should continue taking Everolimus outside of the clinical trial.
After you have completed study treatment, we would like to continue to follow-up with you 
(about every six months) by phone or at regularly scheduled clinic visits regarding your 
medical condition.  
What are the risks of the study?
Because of your participation in this study, you are at risk for the following side effects.  You 
should discuss these with the researchers and your regular health care provider. 
Everolimus (Afinitor®) may cause some, all or none of the side-effects listed below. 
Most Likely (more than 50% of subjects experienced these side effects):

Stomatitis: Mouth lining changes such as redness, soreness, swelling in the mouth or 
mouth ulcers.  To help avoid these effects, you should brush your teeth with a very soft 
toothbrush and if your gums bleed, rub your teeth with gauze instead. Use an alcohol-
free mouthwash up to 3 times a day. Eat soft, bland foods like puddings, milkshakes, 
and cream soups, and avoid spicy, crunchy, acidic and very hot foods. 
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Likely (more than 10% of subjects experienced these side effects) :

Infections

Anemia

Decreased appetite

Hyperglycemia – high blood glucose

Hypercholesterolemia – high 
cholesterol

Dysgeusia – change in taste

Pneumonitis

Epistaxis

Diarrhea

Nausea

Rash

Pruritis

Fatigue

Peripheral edema

Asthenia - weakness

Weight decreased
Unlikely (more than 5% of subjects experienced these side effects):

Vomiting

Cough

Skin or nail changes (including acne, 
rash, redness, itching, dryness or 
irritation)

Hypertension 

Pyrexia 

Dyspnea 

Headache

Hemorrhage

AST and ALT increased

Hypertriglyceridemia 

Thrombocytopenia – low platelet 
count

Neutropenia – low number of 
neutrophils in blood that help to 
fight infections.
Rare (Less than 5% of subjects experienced these side effects):

Leukopenia

Lymphopenia

Diabetes mellitus

Hypophosphatemia – low phosphate 
level in blood

Hyperlipidemia – high level of fats in 
the blood

Dehydration

Insomnia

Dry mouth

Abdominal pain

Dyspepsia – stomach pain

Acne

Erythema

Hand-foot syndrome

Arthralgia

Proteinuria – high protein in urine

Menstruation irregular

Mucosal inflammation

Blood creatinine increased
Very Rare (Less than 1% of subjects experienced these side effects):

Pancytopenia – too few red and white 
blood cells, and platelets

Pure red cell aplasia

Hypersensitivity – allergic reactions

Ageusia

Congestive cardiac failure

Deep vein thrombosis

Haemoptysis – coughing up blood

Pulmonary embolism – blood clot in 
the lung

Acute respiratory distress syndrome

Angioedema – swelling beneath skin 
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surface

Increased daytime urination

Acute renal failure

Amenorrhea – absence of 
menstruation

Non-cardiac chest pain

Impaired wound healing
Drugs like Everolimus can cause the patient’s immune system to not work as well.  A patient 
with hepatitis B or hepatitis C who takes Everolimus could be susceptible to the virus 
becoming more active.  If you had or have hepatitis B or C, you will not be allowed into the 
study.
Changes to the levels of blood sugar (glucose), which could lead to diabetes, could occur 
while taking Everolimus, so your blood sugar levels will be checked regularly throughout the 
study.  Another diabetes test (Hemoglobin A1c) will be checked at the beginning of the study.  
The levels of cholesterol and triglycerides or liver enzymes (transaminases) in your blood 
could increase (increased levels of cholesterol are an important factor of risk of heart 
disease), so your blood cholesterol and triglyceride levels will be regularly checked in this 
study, as well as your liver enzymes.  There could also be an increase in a waste product 
of your liver (bilirubin), which could mean that your liver is not working as well.  In addition 
there could be a lowering of electrolytes (potassium, phosphate). 
Everolimus may cause toxicity to your kidneys and cause the levels of creatinine in your 
blood and protein in your urine to increase.  In very rare cases, this toxicity could lead to 
kidney failure.  Therefore, your blood creatinine levels and urine protein levels (and other 
urine tests) will be regularly monitored in this study.
This research study may involve unpredictable risks.  Problems or side effects that are not 
now known could also occur.  You will be given any new information that may affect your 
willingness to start or continue in the study.
All problems or side effects need to be reported to the study doctors or study nurses looking 
after you either by phone or at the next visit. 
For more information about risks and side effects, you should feel free to ask your study 
doctor.  If you are concerned about your health between visits due to participating in this 
trial, please call the emergency telephone numbers provided at the end of this document.
Risks to Sperm, Embryo, Fetus or Breast-fed Infant
Males: Being in this research may damage your sperm, which could cause harm to a child 
that you may father while on this study.  If you take part in this study and are sexually active, 
you must agree to use a medically-acceptable form of birth control.  Medically-acceptable 
forms of birth control include:
(1) surgical sterilization (vasectomy) with use of a condom, or
(2) a condom used with a spermicide (a substance that kills sperm).
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In case you father a child while in this study you are asked to report the pregnancy to the 
Study Doctor.  Consent from your partner will be needed to allow your Study Doctor to 
medically follow this pregnancy until delivery to monitor the mother`s and child`s safety.
Females: If you are part of this study while pregnant or breast-feeding an infant, it is possible 
that you may expose the unborn child or infant to risks.  For that reason, pregnant and 
breast-feeding females cannot participate in the study.  If you can become pregnant, a blood 
pregnancy test will be done (using 1 teaspoon of blood drawn from a vein by needle-stick), 
and it must be negative before you participate in this study.  If you take part in this study and 
you are sexually active, you and any person that you have sex with must use medically-
acceptable birth control (contraceptives) during the study and for at least 8 weeks after 
completion of study treatment.  Medically-acceptable birth control (contraceptives) includes:
(1) surgical sterilization (such as hysterectomy or “tubes tied”),
(2) approved hormonal contraceptives ( such as birth control pills, patch or ring; 
Depo-Provera, Implanon),
(3) barrier methods (such as condom or diaphragm) used with a spermicide (a 
substance that kills sperm), or 
(4) an intrauterine device (IUD).
If you become pregnant or suspect being pregnant during study treatment, you must inform 
the study doctor immediately and you have to stop ongoing study treatment immediately.  
You will not be allowed to continue study treatment if you are pregnant.  Your study doctor 
will medically follow your pregnancy until delivery to monitor you and your child`s safety.  .
Pregnancy tests performed during the early stages of pregnancy do not always reveal 
pregnancy.  Therefore, radiation exposure that includes the reproductive organs will be 
limited to the first ten days after a woman who can become pregnant (age 10-50 years) has 
begun her most recent menstrual period.  This is standard policy in clinics and hospitals 
within UT Southwestern.  This policy applies unless there is an important medical reason 
requiring radiation outside this time frame
Radiation Risks
The radiation dose that you will get from diagnostic tests is medically indicated for your 
condition and it is the same that you would get if you were not involved in this research 
study.
Risks of MRI
There are no known risks from exposure to magnetic fields.  You may experience 
nervousness and/or anxiety due to the loud banging made by the machine while it is taking 
pictures and from confinement in a tight space (claustrophobia).  If you become anxious, 
you can stop the procedure at any time
You may also experience some discomfort and fatigue from lying still during imaging.
If you have any metal clips or plates in your body, you should tell the investigator.  MRI may 
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not be appropriate if you are pregnant or are trying to become pregnant.  MRI may not be 
appropriate if you have permanent eyeliner or eyebrows or any pieces of metal in your body, 
such as the following:
heart pacemaker, heart valve replacement, or aortic clips
metal fragments in your eyes, skin, or elsewhere in your body
brain clips or pieces of metal used in aneurysm surgery or intercranial bypass
venous umbrella
pieces of metal in the body resulting from work as a sheet-metal worker or welder
clips placed in an internal organ
prosthetic devices, such as middle ear, eye, joint, or penile implants
joint replacement.
hearing aid that cannot be removed
neurostimulator
insulin pump
intrauterine device (IUD)
shunts or stents
metal mesh or coil implants
metal plate, pin, screws, or wires, or any other metal implants.
Gadolinium Contrast: 
A risk associated with the use of MRI contrast material has been identified recently.  
Because some of the procedures used in this study include the administration of MRI 
contrast, you should read and understand the following information before deciding to 
continue in the study:
Special Note: In June 2006, the FDA released a public advisory regarding contrast agents 
containing gadolinium.  They are investigating the potential relationship between gadolinium 
and the development of Nephrogenic System Fibrosis/Nephrogenic Fibrosing Dermopath 
(NSF/NFD) in patients with renal (kidney) failure.  A rare condition termed NSF, or 
nephrogenic systemic fibrosis, has been reported in patients receiving gadolinium in the 
setting of acute or chronic kidney failure or in the period of time surrounding liver 
transplantation.  This condition can result in fibrosis of the skin, muscles, heart and lung.  
There have been a few fatalities.  In the cases reported, symptoms began from 2 weeks to 
up to 18 months after receiving the contrast material.  Approximately 90% of the cases of 
NSF occurred after the use of specific brands of contrast material (Omniscan and Optimark).  
These brands are NOT used in this study.  No cases have been reported in people with 
normal or mildly impaired kidney function.  We perform a simple blood test (serum 
creatinine) to ensure the kidney function is normal prior to administering the gadolinium.  If 
kidney function is abnormal, we will inform you and will not proceed with this aspect of 
testing.
A small percentage of patients (less than 5%) have experienced temporary headaches after 
the MRI contrast (gadolinium) is injected and a small number (less than 5%) have 
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experienced nausea.  Severe allergic reactions are exceedingly rare (1/100,000).  Patients 
with a prior allergic reaction to gadolinium should not participate in this study.  
Risks of Blood Drawing
Risks associated with drawing blood from your arm include minimal discomfort and/or 
bruising.  Infection, excess bleeding, clotting, and/or fainting also are possible, although 
unlikely.  Blood will be taken at every visit during the study and approximately 2.5 mL (1/2 
teaspoon) of blood will be collected each time.  The blood pressure cuff may also cause 
discomfort or bruising to the upper arm.
Before the start of study drug (screening visit), approximately 10 milliliters (2 teaspoons) of 
blood may be collected to assess the baseline for Hepatitis B and Hepatitis C.  A monitoring 
test for Hepatitis B might be performed every 4-8 weeks depending on the result of your 
screening test.  A monitoring test for Hepatitis C might be performed every 4-8 weeks if you 
have a history of past infection.  Your study doctor will inform you if you need these tests to 
be performed and about the frequency of the monitoring tests.
Loss of Confidentiality
Any time information is collected; there is a potential risk for loss of confidentiality.  Every 
effort will be made to keep your information confidential; however, this cannot be 
guaranteed. 
Other Risks
There may possibly be other side effects that are unknown at this time.  If you are concerned 
about other, unknown side effects, please discuss this with the researchers.
How will risks be minimized or prevented?  
Potential risks and discomforts will be minimized and/or prevented by the researchers, who 
will perform routine physical exams, laboratory tests, imaging studies and provide supportive 
care when needed during your clinic and/or inpatient visits.  Also, the researchers will be 
informed if any unexpected events occur on the study that requires changes to the study 
procedures.
What will my responsibilities be during the study?  
During your participation in this study, the researchers will follow you closely to determine 
whether there are problems that need medical care.  It is your responsibility to do the 
following:

Ask questions about anything you do not understand.

Keep your appointments.

Follow the researchers’ instructions.

Let the researchers know if your telephone number or address changes.

Store study materials and study medications in a secure place at home away from 
anyone who is unable to read and understand labels, especially children.
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
Tell the researchers before you take any new medication, even if it is prescribed by 
another doctor for a different medical problem or something purchased over the 
counter.

Tell your regular doctor about your participation in this study.

Carry information about the research in your purse or wallet.

Report to the researchers immediately any injury or illnesses while you are on study, 
even if you do not think it is related. 
If I agree to take part in this research study, will I be told of any new risks that may be 
found during the course of the study?
Yes.  You will be told if any new information becomes available during the study that could 
cause you to change your mind about continuing to participate or that is important to your 
health or safety.
What should I do if I think I am having problems?
If you have unusual symptoms, pain, or any other problems while you are in the study, you 
should report them to the researchers right away.  Telephone numbers where they can be 
reached are listed on the first page of this consent form.
If you have a sudden, serious problem, like difficulty breathing or severe pain, go to the 
nearest hospital emergency room, or call 911 (or the correct emergency telephone number 
in your area).  Tell emergency personnel about being in this study.  Ask them to call the 
researchers immediately. 
What are the possible benefits of this study?
We hope that you will get personal medical benefit from taking part in this clinical trial, but 
we cannot be certain.  You may not get any benefits by taking part in this study.
We expect that the information learned from this study will benefit other patients in the future.
  
What options are available if I decide not to take part in this research study?
Your other choices may include:

Treatment with other chemotherapy drugs that have been previously tried with your 
type of brain tumor.

Other types of investigational trial (if available).

No further treatment and comfort care only.
Please discuss these options with your treating doctor as well as other trusted persons or 
family members.
Will I be paid if I take part in this research study?
No.  You will not be paid to take part in this research study.  There are no funds available to 
pay for parking expenses, transportation to and from the research center, lost time away 
from work and other activities, lost wages, or child care expenses.
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Will my insurance provider or I be charged for the costs of any part of this research 
study?
Yes.  The costs related to standard medical care for your ependymoma (which includes the 
exams and procedures outlined in this consent form) will be billed to you or your insurance 
provider.  Some health plans will not pay the costs for people taking part in studies.  Taking 
part in this study may or may not cost your insurance provider or government program more 
than the cost of getting regular cancer care. 
The pharmaceutical company which makes Everolimus (Afinitor®) will provide the 
Everolimus (Afinitor®) at no charge while you take part in the study.  You will not be charged 
for the biology studies that are being done for research purposes only.
For more information on clinical trials and insurance coverage, you can visit the National 
Cancer Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-
coverage/.  You can print a copy of the “Clinical Trials and Insurance Coverage” information 
from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask 
them to send you a free copy.
What will happen if I am harmed as a result of taking part in this study?
It is important that you report any illness or injury to the research team listed at the top of 
this form immediately.
Compensation for an injury resulting from your participation in this research is not available 
from the University of Texas Southwestern Medical Center at Dallas, Children’s Medical 
Center, or the drug supplier.
You retain your legal rights during your participation in this research.
Can I stop taking part in this research study?
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about 
stopping or decide to stop.  He or she will tell you how to stop safely.  It is important to tell 
the study doctor if you are thinking about stopping so any risks from Everolimus (Afinitor®) 
can be evaluated by your doctor.  Another reason to tell your doctor that you are thinking 
about stopping is to discuss what follow-up care and testing could be most helpful for you.  
The study doctor may stop you from taking part in this study at any time if he/she believes 
it is in your best interest; if you do not follow the study rules; or if the study is stopped. 
If I agree to take part in this research study, can I be removed from the study without 
my consent?
Yes.  The researchers may decide to take you off this study if:

The side effects of Everolimus (Afinitor®) are too harmful for you

You need a treatment that is not allowed on this study
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
Your tumor has grown back or become larger despite receiving Everolimus (Afinitor®)

You are not able to follow study-related treatment instructions

New information becomes available

The study is not in your best interest

The study is stopped because there is no benefit for your type of brain tumor
Will my information be kept confidential?
Information about you that is collected for this research study will remain confidential unless 
you give your permission to share it with others, or if we are required by law to release it.  
We will do our best to make sure that the personal information in your medical record will 
be kept private.  However, we cannot guarantee total privacy.  Your personal information 
may be revealed if required by law.  If information from this study is published or presented 
at scientific meetings, your name and other personal information will not be used.
Your medical records are available to those caring for you at this hospital.  Organizations 
that may look at and/or copy your medical records for research, quality assurance, and data 
analysis include:

Novartis, the drug supplier, and its authorized agents

The FDA, the National Cancer Institute (NCI), or other governmental agencies 
involved in keeping research studies safe for children, and governmental agencies in 
other countries where the study drug may be considered for approval.

The Institutional Review Board of your hospital
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required 
by the U.S. Law.  This Web site will not include information that can identify you.  At most, 
the Web site will include a summary of the results.  You can search this Web site at any 
time.
In addition to this consent form, you will be asked to sign an "Authorization for Use and 
Disclosure of Protected Health Information."  This authorization will give more details about 
how your information will be used for this research study, and who may see and/or get 
copies of your information.
Are there procedures I should follow after stopping participation in this research?
Yes.  If you, the researchers, or the sponsor stops your participation in the research, you 
may be asked to do the following:

Let the researchers know immediately that you wish to withdraw from the research.

Return to the research center for tests that may be needed for your safety.

Return any unused study materials, including empty containers.

Discuss your future medical care, if any, with the researchers and/or your personal 
doctor.
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Is there anything else I should know before I decide? 
Dr. Laetsch has financial interests in the sponsor and maker of a drug used in this study. 
You should feel free to ask questions about this. 
Whom do I call if I have questions or problems?
For questions about the study, contact Dr. Daniel Bowers at 214-456-2382 during regular 
business hours and at 214-456-7000 after hours and on weekends and holidays.  
For questions about your rights as a research participant, contact the UT Southwestern 
Institutional Review Board (IRB) Office at 214-648-3060.
Where can I get more information?
If you are in the United States, you may call the National Cancer Institute's Cancer 
Information Service at: 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615
You may also visit the NCI Web site at http://cancer.gov/

For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/

For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form.  You will be given a copy of the protocol (full study plan) 
upon request.  
YOU WILL BE GIVEN A COPY OF THIS CONSENT FORM TO KEEP.
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Your signature below certifies the following:

You have read (or been read) the information provided above.

You have received answers to all of your questions and have been told who to call if 
you have any more questions.

You have freely decided to participate in this research.

You understand that you are not giving up any of your legal rights.

You understand that a copy of this signed consent document, information about this 
study and the results of any test or procedure done may be included in your medical 
record and this information may be available to health care providers and authorized 
persons including your insurance company.
__________________________________________________
Participant’s name
__________________________________________________       
Participant’s signature
_______________
Date
__________      __________AM / PM
Date                    Time
__________________________________________________
Parent or Legally authorized representative’s name (printed) 
__________________________________________________       
Parent or Legally authorized representative’s Signature           
__________      __________AM / PM
Date                    Time
__________________________________________________
Name (printed) of person obtaining Consent
__________________________________________________
Signature of person obtaining consent
__________      __________AM / PM
Date                    Time
ASSENT OF A MINOR:
I have discussed this research study with my parent or legal guardian and the researchers, and I 
agree to participate.
__________________________________________________
Signature of participant (age 10 through 17)
__________      __________AM / PM
Date                    Time
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INTERPRETER/WITNESS STATEMENT:
I have interpreted this consent form into a language understandable to the participant and the 
participant has agreed to participate as indicated by their signature above.
__________________________________
Name of Interpreter (printed)
__________________________________
Signature of Interpreter
_________      __________AM / PM
Date                    Time
WITNESS [Needed when the interpreter is not physically present, i.e. a language line is 
used]:
I attest that the information in the consent form was accurately explained to, and 
apparently understood by the subject or the subject's legal authorized representative, and 
that informed consent was freely given by the subject or the subject’s legal authorized 
representative.
____________________________
         ________     _______AM / PM
Name of Witness (Printed)
Date
Time
____________________________                                       ________     _______AM / PM
Signature of Witness                                                                Date                Time
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