Conditions: Pediatric Recurrent Progressive Low-grade Gliomas Pediatric Progressive Low-grade Gliomas
Keywords: pediatric recurrent progressive low-grade gliomas pediatric progressive low-grade gliomas everolimus mTOR inhibition
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 65
Healthy volunteers: no

Brief summary:
This is an open label study of everolimus in children with recurrent or progressive low-grade glioma.

Detailed description:
This is an open label study of everolimus in children with recurrent or progressive low-grade glioma. All patients will receive everolimus at a dose of 5 mg/m2/dose daily. An adaptive Simon two-stage design for phase 2 studies of targeted therapies will be used to assess the efficacy primary objective. The proposed treatment with everolimus will be deemed not worthy of further investigation in this patient population if the true PFS at 6-months (PFS6) is less than 50%. If in the first stage, with a combined sample size of 25, there is preliminary evidence to suggest efficacy of everolimus is restricted to patients with PI3K/AKT/mTOR activation as measured by p-S6 positivity, a total of 45 patients will be enrolled and the design will have 81% statistical power to detect a true disease stabilization rate ≥70%. If in the first stage there is preliminary evidence to suggest efficacy of everolimus is independent of PI3K/AKT/mTOR activation, a total of 65 patients will be enrolled and the design will have \>95% statistical power to detect a true disease stabilization rate ≥70%.

Arms:
arm 1: Everolimus tablet will be taken daily by mouth with water. Twenty-eight days will constitute one course and subsequent courses will immediately follow with no break in the administration of the drug. Dosing is based on the body surface area (BSA) calculated at the beginning of each course of therapy. Patients will also be provided with a drug diary for everolimus. The maximum time on study is 24-months, but if there is no disease progression or adverse events, the patient may speak with a doctor about continuing the treatment off-study.

Interventions: intervention 1: Everolimus
Intervention descriptions: intervention 1: Everolimus tablet will be taken daily by mouth with water. All patients will be given a dose of 5 mg/m2/dose daily.

Protocol document:
Prot_SAP_000.pdf: 
Proprietary and Confidential
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws.  Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed.
Phase II Study of everolimus for recurrent or progressive low-grade gliomas in children
Protocol Number:  CC #120817
Study Drug:  Everolimus
Version Number: 11.1
Version Date:  01-07-19
IND Number:  116,730 (Exempt)
Study Chair (Sponsor-Investigator)
Daphne Haas-Kogan, MD
Harvard University Dana-Farber Institute
Study Co-Chair (Sponsor-Investigator)
Sabine Mueller, MD, PhD, MAS
University of California San Francisco
Research Coordinating Center
Pacific Pediatric Neuro-Oncology Consortium
Project Co-Leader
Michael Prados, MD
University of California, San Francisco
Statistician
Annette Molinaro, PHD
Revision History
Version 11.1
01-07-19
Version 11.0
02-13-18
Version 10.1
08-08-17
Version 10.0
06-26-17
NCT#  01734512


 
Version 9.0
Version 8.0
09-29-16
09-03-15
Version 7.0
04-29-15
Version 6.0
Version 5.0
Version 4.0
Version 3.0
Version 2.0
04-08-15
09-05-14
11-06-13
01-11-13
09-28-12
Version 1.0
07-12-12


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Protocol PNOC 001 / CC#: 120817
Phase 2 – Everolimus
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 Pacific Pediatric Neuro-Oncology Consortium Institutions 
Benioff Children’s Hospital 
University of California, San Francisco 
PI:  Sabine Mueller, MD, PhD, MAS
Co-PI: Cassie Kline, MD, MAS
 
University of Minnesota/Children’s Minnesota
PI: Christopher Moertel MD
Co-PI: Anne Bendel, MD
  
 
Children’s Hospital Los Angeles
PI:   Ashley Margol, MD
Co-PI:   Girish Dhall, MD
  
University of Utah
PI:  Nicholas Whipple, MD, MPH
Co-PI: Carol Bruggers MD
 
University of Florida
PI: Sridharan Gururangan, FRCP
Co-PI: Duane Mitchell, MD, PhD
 
Seattle Children’s Hospital
University of Washington, Seattle
PI:  Sarah Leary, MD
Co-PI:  Nick Vitanza, MD
  
Doernbecher Children’s Hospital 
Oregon Health & Science University
PI:  Kellie Nazemi, MD
Co-PI:  Rebecca Loret De Mola, DO, MCR
Rady Children’s Hospital
University of California, San Diego 
PI: John Crawford, MD, MS
Co-PI: Jennifer Elster, MD
  
The Children’s Hospital of Philadelphia
PI:  Jane Minturn, MD, PhD
Co-PI:  Angela Waanders, MD, MPH
  
Children’s National Medical Center
PI:  Lindsay Kilburn, MD
Co-PI:  Roger Packer, MD 
St. Jude Children’s Research Hospital
PI: Amar Gajjar, MD
Co-PI: Christopher Tinkle, MD, PhD
 
Nationwide Children’s Hospital
PI:.Mohamed AbdelBaki, MD,
Co-PI:  Jonathan L. Finlay, M.B., Ch.B., F.R.C.P.
 


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Washington University in St. Louis
PI: Karen Gauvain, MD, MSPH
Co-PI: Josh Rubin, MD, PhD
Telephone: (314) 286-2790
Ann & Robert H. Lurie Children’s Hospital of 
Chicago
PI: Stewart Goldman, MD
Co-PI:  Natasha Pillay Smiley, DO
Harvard University Dana-Farber Institute
PI: Susan Chi, MD 
Co-PI: Daphne Haas-Kogan, MD 
The Hospital for Sick Children 
PI: Eric Bouffet MD FRCP(C)
Co-PI: Annie Huang, MD, PhD
Texas Children’s Hospital
PI: Patty Baxter, MD
Co-PI: Will D. Parsons, MD, PhD
Johns Hopkins Hospital
PI: Kenneth J. Cohen, MD, MBA
Co-PI: Eric H. Raabe, MD, PhD
Participating Sites:
Massachusetts General Hospital (in connection with DFCI)
PI: David Ebb, MD
UCSF Benioff Children’s Hospital Oakland (in connection with UCSF Benioff San Francisco)
PI: Tabitha Cooney, MD 
Mattel Children’s Hospital University of California, Los Angeles
PI:  Tom Belle Davidson, MD
Please refer to the PNOC SOP: Study Chair and Co-Chair Responsibilities for a description of PNOC Study 
Chair/Co-Chair responsibilities.  This document can be found in the PNOC Members SharePoint website documents 
area
Please refer to the PNOC Constitution for a description of PNOC Investigator responsibilities.  This document can be 
found in the PNOC Members SharePoint website documents area 


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Phase 2 – Everolimus
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Protocol Signature Page
Protocol No.: PNOC 001/ CC #120817
Version Date: 01-07-2019
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Institutional Review Board (IRB), and Data Safety Monitoring Committee (DSMC). 
I will conduct the study in accordance with applicable IRB requirements, Federal regulations, 
and state and local laws to maintain the protection of the rights and welfare of study 
participants. 
I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol. 
I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in 
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the 
Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In 
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the 
www.clinicaltrials.gov website. 
I agree to maintain adequate and accurate records in accordance with IRB policies, Federal, 
state and local laws and regulations.
UCSF Principal Investigator / Study Chair
Printed Name
Signature
Date
Participating Site(s): Pacific Pediatric Neuro-Oncology Consortium Institutions
Principal Investigator
Site
Printed Name
Institution
Signature
Date


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Abstract
Title
Phase II Study of everolimus for recurrent or progressive low-grade gliomas 
in children
Patient 
population
Children with recurrent or progressive low-grade gliomas
Rationale for 
Study
This study is driven by two hypotheses—first that mTOR inhibition will 
be efficacious for pediatric LGGs and second that PI3K/AKT activation will 
be associated with response to mTOR inhibition.  This study is unique 
among all pediatric brain tumor trials in its hypothesis-driven biological 
approach and it fulfills an unmet need for a pediatric population for whom 
few other therapeutic options exist.
Primary 
Objective
Efficacy: Estimate the Progression Free Survival (PFS) rate at 6-months 
associated with everolimus therapy for symptomatic, progressive or 
recurrent pediatric low-grade glioma patients with measureable disease 
with the aim of determining whether everolimus warrants additional study 
only in patients with activated PI3K/Akt/mTOR pathway as measured by 
positivity of p-S6 status or in the entire population.
Secondary 
Objectives
 
Estimate PFS and OS distributions as well as objective response 
(CR+PR) rates associated with everolimus treatment in recurrent 
pediatric LGGs.

Explore associations between activation of the PI3K pathway as 
measured by expression of phospho-AKT, phospho-PRAS40, and 
phospho-4EBP1 and outcome as measured by the 6-month 
disease stabilization rates (a dichotomous variable; see section 
7.1.2.2) as well as PFS for progressive or recurrent pediatric low-
grade glioma patients with measureable disease treated with 
everolimus.

Collect tissue from all enrolled patients and prospectively analyze 
key molecular features including activation of the PI3K, mTOR and 
MAPK pathways, aberrations in PTEN, p53, PDGFRA 
amplification, CDKN2A loss, and activating mutations in BRAF 
(KIAA1549-BRAF fusion and BRAFV600E missense BRAF 
mutation). In addition to the targeted approaches described above 
that examine previously reported alterations additional genomic 
profiling studies will be performed including targeted sequencing, 
RNA sequencing, and/or exome (plus) next generation sequencing 
if sufficient tissue is available.  Such studies will include but are not 
limited to molecular analyses of DNA, RNA and protein in tumor 
biopsy specimens and blood samples.  When possible and/or 
sufficient blood/tissue is provided, sample will be used to establish 
tumor cell cultures, cell lines and/or transplantation models. These 
studies will be carried out in collaboration with Dr. Adam Resnick, 
Children’s Hospital of Philadelphia.

Explore MR quantitative measures of relative cerebral blood 
volume, permeability and apparent diffusion coefficient within the 


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region of hyper-intensity on T2-weighted images as markers of 
disease response and/or progression in comparison to institutional 
evaluation of disease response and/or progression and quantitative 
measures of tumor response as determined by central review 
(based upon both area and volumetric measures.
Study Design
This is an open label study of everolimus in children with recurrent or 
progressive low-grade glioma. All patients will receive everolimus at a 
dose of 5 mg/m2/dose daily.  An adaptive Simon two-stage design for 
phase 2 studies of targeted therapies will be used to assess the efficacy 
primary objective. The proposed treatment with everolimus will be deemed 
not worthy of further investigation in this patient population if the true PFS 
at 6-months (PFS6) is less than 50%. If in the first stage, with a combined 
sample size of 25, there is preliminary evidence to suggest efficacy of 
everolimus is restricted to patients with PI3K/AKT/mTOR activation as 
measured by p-S6 positivity, a total of 45 patients will be enrolled and the 
design will have 81% statistical power to detect a true disease stabilization 
rate ≥70%. If in the first stage there is preliminary evidence to suggest 
efficacy of everolimus is independent of PI3K/AKT/mTOR activation, a 
total of 65 patients will be enrolled and the design will have >95% 
statistical power to detect a true disease stabilization rate ≥70%.
Number of 
patients
Up to 65 patients
Duration of 
Therapy
Patients may continue treatment for 24 cycles from the time of study entry. 
Duration of 
Follow up
Patients will be followed after removal from protocol therapy for five years 
from initiating protocol therapy or until death, whichever occurs first.
Duration of 
study
The study will reach completion approximately 8 years from the time the 
study opens to collection of last data point.
Study Drugs
Everolimus
Safety 
Assessments
Analyses will be performed for all patients having received at least one 
dose of study drug.  The study will use the NCI CTCAE v4.0.
Efficacy 
Assessments
The primary goal of this study is to evaluate efficacy as determined using 
6-month progression free survival. Response will be determined by the bi-
dimensional diameters.  However, RECIST criteria will be collected and
used for secondary evaluation.  Patients will have brain MRI scans with
and without gadolinium performed prior to therapy, before every odd cycle
(3, 5, 7, 9, and 11) in the first year, and before every third cycle in the
second year (13, 16,19, and 22), and at the End of Treatment visit (if not
done within prior 3 months). Spine MRIs should be performed prior to
therapy and at the same time points as standard brain MRIs if clinically
indicated.


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Unique 
Aspects of 
this Study
This study is unique in several critical respects: (i) the requirement for 
available tumor tissue as an eligibility criterion in order to accomplish the 
important objective of exploring associations between activation of specific 
signaling cascades and response to everolimus; (ii) the incorporation of 
metabolic and physiologic imaging analyses that may be critical to future 
assessments of tumor responses in trials that increasingly test inhibitors 
that are cytostatic rather than cytotoxic.


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List of Abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical (Classification System)
AUC
area under the curve
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CR
complete response
CRC
Clinical Research Coordinator
CRF
case report form
CSF
cerebral spinal fluid
CTCEA
Common Terminology Criteria for Adverse Events
CTMS
Clinical Trial Management System
DLT
dose limiting toxicity
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECOG
Eastern Cooperative Oncology Group
FCBP
female of childbearing potential
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HBeAg
Hepatitis B “e” antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HGB
hemoglobin
HIV
human immunodeficiency virus
ICH
International Conference on Harmonization
IND
investigational new drug application
IRB
Institutional Review Board
IV
intravenous
LDH
lactate dehydrogenase
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities


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List of Abbreviations
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
ORR
overall response rate
PD
disease progression
PO
Per os (by mouth, orally)
PR
partial response
PRC
Protocol Review Committee (UCSF)
RBC
red blood cell (count)
SD
stable disease
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
ULN
upper limit of normal
WBC
white blood cell (count)


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Table of Contents
Abstract.......................................................................................................................................6
List of Abbreviations..................................................................................................................9
Table of Contents .....................................................................................................................11
1
Introduction.......................................................................................................................15
1.1
Pediatric Low Grade Gliomas (LGG) .......................................................................15
1.2
Everolimus.................................................................................................................15
1.2.1
mTOR pathway and mechanism of action....................................................15
1.2.2
Preclinical studies .........................................................................................16
1.2.3
Preclinical safety...........................................................................................18
1.2.4
Everolimus pharmacokinetics.......................................................................18
1.2.5
Everolimus pharmacodynamic studies .........................................................19
1.2.6
Clinical Experience.......................................................................................20
1.3
Rationale for the Proposed Study..............................................................................21
1.3.1
Rationale for targeting mTOR in low-grade gliomas ...................................21
1.3.2
Rationale for everolimus in pediatric central nervous system malignancies23
1.4
Correlative Studies ....................................................................................................25
1.4.1
Rationale for additional radiographic imaging as an exploratory aim..........25
1.4.2
Rationale for molecular profiling studies .....................................................26
2
Objectives of the Study.....................................................................................................26
2.1
Primary ......................................................................................................................26
2.2
Secondary ..................................................................................................................27
3
Study Design ......................................................................................................................27
3.1
Characteristics ...........................................................................................................27
3.2
Number of Subjects ...................................................................................................27
3.3
Eligibility Criteria......................................................................................................28
3.3.1
Inclusion Criteria ..........................................................................................28
3.3.2
Exclusion Criteria .........................................................................................30
3.4
Registration Procedures.............................................................................................31
3.4.1
General Guidelines........................................................................................31
3.4.2
Reservation and Registration Process...........................................................31
3.5
Duration of Therapy ..................................................................................................32
3.6
Duration of Follow Up ..............................................................................................32
3.7
Study Timeline ..........................................................................................................32
3.7.1
Interim Analysis............................................................................................32
3.7.2
Primary Completion......................................................................................32
3.7.3
Study Completion .........................................................................................33
4
Study Drugs .......................................................................................................................33
4.1
Description, Supply and Storage of Everolimus .......................................................33
4.2
Drug Accountability ..................................................................................................33
4.3
Drug Ordering ...........................................................................................................33
4.4
Packaging and Labeling of Study Drugs...................................................................33
5
Study Procedures and Observations ...............................................................................33
5.1
Pre-Treatment Period.................................................................................................37


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5.1.1
Screening Assessments .................................................................................37
5.2
Treatment Period .......................................................................................................37
5.2.1
Study Procedures, Cycle 1, Day 1 ................................................................38
5.2.2
Study Procedures, Cycle 1, Day 15 ..............................................................38
5.2.3
Study Procedures, Cycle 2, Day 1 ................................................................38
5.2.4
Study Procedures, Cycle 2, Day 15 ..............................................................39
5.2.5
Study Procedures, Cycle 3, 5, 7, 9, 11, 13, 16, 19, 22, Day 1 ......................39
5.2.6
Study Procedures, Cycles 4, 6, 8, 10, 12, 14, 15, 17, 18, 20, 21, 23, and 24, 
Day 1 39
5.2.7
Study Procedures, End-of-Treatment............................................................40
5.2.8
Study Procedures, Long Term/Survival Follow-up Procedures ...................40
5.3
Interruption or discontinuation of treatment..............................................................41
5.3.1
Monitoring of everolimus suspected toxicities.............................................43
5.3.2
Known Undesirable Side Effects of everolimus...........................................43
5.3.3
Management of Hepatitis reactivation/flare..................................................44
5.3.4
Management of stomatitis/oral mucositis/mouth ulcers ...............................45
5.3.5
Management of hyperlipidemia and hyperglycemia.....................................45
5.3.6
Management of non-infectious pneumonitis ................................................45
5.3.7
Febrile neutropenia .......................................................................................47
5.3.8
Diarrhea.........................................................................................................48
5.3.9
Neurosurgical Procedures .............................................................................48
5.4
Treatment Plan...........................................................................................................48
5.4.1
Everolimus Administration...........................................................................48
5.4.2
Concomitant therapy.....................................................................................49
5.5
Reasons to Withdraw a Subject.................................................................................52
5.6
Off Treatment Criteria...............................................................................................52
5.7
Off Study Criteria......................................................................................................52
6
Correlative Studies and Pathology Review.....................................................................53
6.1
Obtaining tissue and blood samples ..........................................................................53
6.2
Preparation of tissue samples ....................................................................................53
6.3
Review of FFPE tissue samples ................................................................................53
6.4
Immunohistochemical and molecular assays ............................................................53
7
Reporting and Documentation of Results.......................................................................55
7.1
Evaluation of Efficacy (or Activity)..........................................................................55
7.1.1
Definitions.....................................................................................................55
7.1.2
Disease Parameters .......................................................................................56
7.2
Definitions of Adverse Events...................................................................................59
7.2.1
Adverse Event...............................................................................................59
7.2.2
Adverse reaction ...........................................................................................59
7.3
Recording of an Adverse Event.................................................................................60
7.4
Follow-up of Adverse Events....................................................................................61
7.5
Adverse Events Monitoring.......................................................................................61
7.6
Expedited Reporting..................................................................................................62
8
Statistical Considerations and Evaluation of Results ....................................................64
8.1
Study Endpoints.........................................................................................................64


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8.2
Determination of Sample Size and Accrual Rate......................................................64
8.2.1
Sample Size and Power Estimate..................................................................64
8.2.2
Accrual estimates..........................................................................................65
8.3
Interim Analyses and Stopping Rules .......................................................................66
8.4
Analysis Plans ...........................................................................................................66
8.4.1
Analysis Population ......................................................................................66
8.4.2
Primary Analysis (or Analysis of Primary Endpoints) .................................66
8.4.3
Secondary Analysis (or Analysis of Secondary Endpoints) .........................67
8.5
Evaluation of Safety ..................................................................................................69
8.6
Study Results.............................................................................................................69
9
Study Management ...........................................................................................................69
9.1
Pre-study Documentation ..........................................................................................69
9.2
Institutional Review Board Approval........................................................................69
9.3
Informed Consent ......................................................................................................69
9.4
Changes in the Protocol.............................................................................................70
9.5
Handling and Documentation of Clinical Supplies...................................................70
9.6
Case Report Forms (CRFs) .......................................................................................70
9.7
Oversight and Monitoring Plan .................................................................................71
9.8
Multicenter Communication......................................................................................71
9.9
Record Keeping and Record Retention .....................................................................71
9.10
Coordinating Center Documentation of Distribution ..............................................72
9.11
Regulatory Documentation ......................................................................................72
10 References..........................................................................................................................73
11 Appendices.........................................................................................................................77
Appendix 1
BSA Adjusted Daily Dose for RAD001.........................................................77
Appendix 2
Performance Status Criteria..........................................................................80
Appendix 3
PNOC001 Archival Tissue Confirmation Form ..........................................81
Appendix 4
Imaging Guidelines.........................................................................................82
Appendix 5
PNOC Data Safety and Monitoring..............................................................85
Appendix 6
PNOC Institutions Required Regulatory Documents .................................88
Appendix 7
Required Data and Time Table for Submission ..........................................89
Appendix 8 PNOC Specimen Collection and Shipping ........................................................90
List of Tables
Table 5.1   
Schedule of Assessments** .................................................................................35
Table 5.2   
Everolimus dose level modification guidelines ...................................................41
Table 5.3
Criteria for dose-modification in case of suspected everolimus toxicity and re-
initiation of everolimus treatment ..............................................................................................41
Table 5.4
Management of non-infectious pneumonitis........................................................47


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Table 5.5        Weight Specific Guidelines for Therapeutic Use of Loperamide.......................48
Table 5.6
Clinically relevant drug interactions: substrates, inducers, and inhibitors of 
isoenzyme CYP3A .....................................................................................................................49
Table 5.7   
Clinically relevant drug interactions mediated by PgP ........................................51
Table 6.1   
Summary of Assays to evaluate activation of the PI3K/AKT/mTOR pathway...54


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1
Introduction
1.1
Pediatric Low Grade Gliomas (LGG)
Astrocytomas are the most common childhood central nervous system (CNS) tumor 
representing 40-50% of all pediatric tumors. The 5- and 10-year overall survival (OS) rates for 
children with low-grade gliomas (LGGs) are relatively high; however, progression free survival 
(PFS) after subtotal resection remains disappointing (1). Patients with high-risk features such as 
hypothalamic location and young age at diagnosis have overall survival rates as low as 60% at 
10 years despite multimodality treatment (1). Therapies for inoperable, residual or recurrent 
disease remain controversial and may include observation, second surgery, radiation and/or 
chemotherapy. Since patients with low-grade gliomas have relatively long survival times these 
patients may be considered as having a chronic disease and treatment strategies should focus 
not only on cure but also on reducing treatment related morbidity (1).
1.2
Everolimus
Everolimus has been in clinical development since 1996 as an immunosuppressant in solid 
organ transplantation and has obtained marketing authorization (Certican®) for prophylaxis of 
rejection in renal and cardiac transplantation in a number of countries, including the majority of 
the European Union. Everolimus has been in development for patients with various 
malignancies since 2002 (2). Everolimus 5 mg and 10 mg tablets were recently approved under 
the trade name Afinitor® for patients with advanced renal cell carcinoma (RCC) after failure of 
treatment with Sutent® (sunitinib) or Nexavar® (sorafenib) in the US, EU and several other 
countries and is undergoing registration in other regions worldwide (RAD001/Everolimus 
Investigator’s Brochure. Novartis Pharma AG. Edition 11, release date 15-Nov-2012).
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 (3);
Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (through potent 
inhibition of tumor cell HIF-1 activity, VEGF production and VEGF-induced proliferation of 
endothelial cells). The role of angiogenesis in the maintenance of solid tumor growth is well 
established, and the mTOR pathway has been implicated in the regulation of tumor production 
of pro-angiogenic factors as well as modulation of VEGFR signaling in endothelial cells (4-7).
1.2.1
mTOR pathway and mechanism of action
At cellular and molecular levels, everolimus acts as a signal transduction inhibitor. Everolimus 
selectively inhibits mTOR (mammalian target of rapamycin), a key and highly conservative 
serine-threonine kinase, which is present in all cells and is a central regulator of protein 
synthesis and ultimately cell growth, cell proliferation, angiogenesis and cell survival. mTOR is 
the only currently known target of everolimus [Reviewed in (3)].
mTOR signals downstream within the PI3K/AKT pathway, a pathway known to be dysregulated 
in a wide spectrum of human cancers (e.g. through loss/mutation of the PTEN negative 
regulator; PI3K mutation/amplification; AKT/PKB overexpression/overactivation; modulation of 
TSC1/TSC2 tumor suppressors). In addition, activation of the PI3K/AKT/mTOR pathway is 
frequently a characteristic of worsening prognosis through increased aggressiveness, 
resistance to treatment and progression (8). 
The main known functions of mTOR include the following (3, 9):


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
mTOR functions as a sensor of mitogens, growth factors and energy and nutrient levels,
facilitating cell-cycle progression from G1 to S phase in appropriate growth conditions.

The PI3K-mTOR pathway itself is frequently activated in many human cancers, and
oncogenic transformation may sensitize tumor cells to mTOR inhibitors.

Through inactivating eukaryotic initiation factor 4E binding proteins (4E-BP1) and
activating the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates translation of
important messages, including those encoding the HIF-1 proteins, c-myc, ornithine
decarboxylase, and cyclin D1, as well as ribosomal proteins themselves.

The activation of mTOR pathway leads to increased production of pro-angiogenic factors
(i.e., VEGF) in tumors and to cell growth and proliferation of tumor, endothelial, and
smooth muscle cells.

The regulation of mTOR signaling is complex and involves positive regulators, such as
AKT that phosphorylate and inactivate negative regulators such as the Tuberous
Sclerosis Complex (TSC1/TSC2).
mTOR is represented by two structurally and functionally distinct multiprotein signaling 
complexes, mTORC1 (mTOR complex 1, rapamycin sensitive) and mTORC2 (mTOR complex 
2, rapamycin insensitive) (10). 
mTORC1 is mainly activated via the PI3-kinase pathway through AKT (also known as PKB, 
protein kinase B) and the tuberous sclerosis complex (TSC1/TSC2) (9). Activated AKT 
phosphorylates TSC2, which leads to the dissociation of TSC1/TSC2 complex, thus inhibiting 
the ability of TSC2 to act as a GTPase activating protein. This allows Rheb, a small G-protein, 
to remain in a GTP bound state and to activate mTORC1. AKT can also activate mTORC1 by 
PRAS40 phosphorylation, thereby relieving the PRAS40-mediated inhibition of mTORC1 (11, 
12). 
mTORC2 (mTOR complex 2) is activated through a currently unknown mechanism, possibly by 
receptor tyrosine kinase (RTK) signaling (12). It has been suggested that mTORC2 
phosphorylates and activates a different pool of AKT that is not upstream of mTORC1. PHLPP 
phosphatase plays a role of a negative regulator. mTORC2 is rapamycin insensitive and is 
required for the organization of the actin cytoskeleton (10). 
mTORC1-mediated signaling is subject to modulation by the macrocyclic lactone rapamycin and 
its derivatives, such as everolimus. Once these agents bind to the 12 kDa cytosolic FK506-
binding protein immunophilin FKBP12, the resulting rapamycin-FKBP12 complexes bind to a 
specific site near the catalytic domain of mTORC1 and inhibit phosphorylation of mTOR 
substrates. As a consequence, downstream signaling events involved in regulation of the G1 to 
S-phase transition are inhibited. This mechanism is thought to be responsible for the
immunosuppressive effects of rapamycin as well as its putative antineoplastic activity [Reviewed
in (13)]. As many cancers are characterized by dysregulation of G1 transit (for example,
overexpression of cyclin or cyclin-dependent kinases), inhibition of mTOR becomes an
intriguing target for inducing cytostasis (9).
1.2.2
Preclinical studies
Everolimus acts as an inhibitor of interleukin and growth-factor-dependent proliferation of cells. 
The only currently known target of everolimus is mTOR, a key regulatory protein affecting cell 
growth (3). Everolimus exerts its activity through high affinity interaction with an intracellular 
receptor protein, the immunophilin FKBP12. The FKBP12/everolimus complex subsequently 
interacts with the mTOR protein kinase, inhibiting downstream signaling events involved in 
regulation of the G1 to S-phase transition. 


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The main known functions of mTOR include:
• Function as a sensor of mitogens, growth factors, energy and nutrient levels, facilitating cell-
cycle progression from G1 - S phase in appropriate growth conditions.
• Regulation of protein synthesis important for tumor cell proliferation and angiogenesis through
inactivating eukaryotic initiation factor 4E binding proteins and activating the 40S ribosomal S6
kinases (e.g. p70S6K1). For example, activation of the mTOR pathway leads to a) increased
production of pro-angiogenic factors (e.g. VEGF) in tumors b) tumor, endothelial and smooth
muscle cell growth and proliferation.
The PI3K-mTOR pathway itself is frequently activated in many human cancers, and oncogenic 
transformation may sensitize tumor cells to mTOR inhibitors. The regulation of mTOR signaling 
is complex and involves positive regulators such as AKT that phosphorylate and inactivate 
negative regulators such as the Tuberous Sclerosis Complex (TSC1/TSC2). In summary, 
mTOR has pleiotropic functions; hence, the activities of everolimus may vary depending upon 
cell type.
The mTOR inhibitory activities presumably contribute to the antiproliferative activity of 
everolimus against tumor cell lines. However, everolimus may also exert an antitumor effect 
through the inhibition of angiogenesis. Indeed, both rapamycin and everolimus potently inhibit 
proliferation of endothelial cells (5, 7, 14) and have antiangiogenic activity in vivo (4-6, 15). 
Exactly which molecular determinants predict responsiveness of tumor cells to everolimus is still 
unclear. Currently, the activation status of the PI3K/AKT/mTOR/p70S6K pathway may be 
indicative of responsiveness to rapamycins. For example, preclinically, loss of PTEN or 
constitutive/hyper-activation of AKT has been suggested to sensitize tumors to the effects of 
inhibition of mTOR [Reviewed in (3, 6). Also, clinically, it has been suggested that high p70S6K 
activation in baseline GBM tumor samples may predict a patient population more likely to derive 
benefit from mTOR inhibition (16).
Everolimus is a highly specific inhibitor of mTOR, which is afforded by high-affinity binding to the 
protein FKBP-12 (IC50 of 5.3 nM) similar to that of rapamycin. Similar potency of rapamycin and 
everolimus was also demonstrated at forming the mTOR / FKBP-12 tertiary complex in vitro. 
Specificity was demonstrated by a lack of inhibitory activity against 10 other protein kinases at 
concentrations up to 10 μM.
The anti-proliferative effects of everolimus were investigated in a mixed panel of 48 different 
tumor cell lines (including breast, colon, epidermoid, glioblastoma, lung, melanoma, prostate 
and renal). The majority of tumor cell lines were highly sensitive to the anti-proliferative effects 
of everolimus while a few others appeared intrinsically insensitive, or ‘resistant’ (IC50 range 0.2 
to 4125 nM) (17). The median IC50 value of the 48 cell lines was 0.5 nM. Similar findings have 
been observed for rapamycin (2). Everolimus was also shown to have activity in human 
pancreatic neuroendocrine cells, where induction of apoptosis was reported (18), as well as in 
acute myeloid leukemia cells (19), mantle cell lymphoma cells (20), adult T-cell leukemia cells 
(21), diffuse large B cell lymphoma cells (22), pancreatic tumor cells (23), ovarian cancer cells 
(6, 24) and hepatocellular carcinoma cells (25).
Everolimus was also evaluated in a clonogenic assay using cells derived from 81 patient 
derived tumor xenografts never cultured in vitro (11 human tumor types with 3 to 24 tumors 
each: bladder, colon, gastric, NSCLC, SCLC, breast, ovary, pancreatic, renal, melanoma, and 
pleuramesothelioma). Everolimus inhibited colony formation in a concentration-dependent 
manner (mean IC50: 175 nM). In addition, normal hematopoetic stem cells were found to be 
relatively insensitive to everolimus, with an IC50 about 15 fold higher than the tumor lines 


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(RAD001/Everolimus Investigator’s Brochure. Novartis Pharma AG. Edition 11, release date 15-
Nov-2012).
Everolimus was effective and well tolerated against subcutaneous tumors established from a 
variety of tumor cell lines of diverse histotypes (NSCLC, pancreatic, colon, melanoma, 
epidermoid), including a PgP170-overexpressing, multi-drug resistant tumor line. Typically, the 
antitumor activity of everolimus was that of reduction of tumor growth rates rather than 
producing regressions or stable disease although, in the case of A549 and NCI-H596 lung and 
ARJ42 pancreatic tumors, regressions could be obtained. These effects occurred within the 
dose range of 2.5 to 10 mg/kg, p.o., once per day. The change in tumor volume of the treated 
mice divided by the change in tumor volume of control mice (T/C) typically ranged from 
approximately 15 to 50% at optimal doses. A marked loss of antitumor activity occurred when 
tumor-bearing mice were treated with everolimus once per week, but improved moderately with 
twice per week dosing (RAD001/Everolimus Investigator’s Brochure. Novartis Pharma AG. 
Edition 11, release date 15-Nov-2012). Antitumor activity of everolimus has also been 
demonstrated in mouse models of ovarian (6), breast (26, 27), and gastrointestinal stromal 
tumors (28). 
1.2.3
Preclinical safety
In safety pharmacology studies, everolimus was devoid of relevant effects on vital organ 
functions including the cardiovascular, respiratory and nervous systems. Everolimus had no 
effects on QT interval. Furthermore, everolimus showed no antigenic potential. Although 
everolimus passes the blood-brain barrier, there was no indication of relevant changes in the 
behavior of rodents, even after single oral doses up to 2000 mg/kg or after repeated 
administration at up to 40 mg/kg/day (RAD001/Everolimus Investigator’s Brochure. Novartis 
Pharma AG. Edition 11, release date 15-Nov-2012).
The preclinical safety profile of everolimus was assessed in mice, rats, minipigs, monkeys, and 
rabbits. The major target organs were male and female reproductive systems (testicular tubular 
degeneration, reduced sperm content in epididymides and uterine atrophy) in several species; 
lungs (increased alveolar macrophages) in rats and mice; and eyes (lenticular anterior suture 
line opacities) in rats only. Minor kidney changes were seen in the rat (exacerbation of age-
related lipofuscin in tubular epithelium, increases in hydronephrosis) and mouse (exacerbation 
of background lesions). There was no indication of kidney toxicity in monkeys or minipigs 
(RAD001/Everolimus Investigator’s Brochure. Novartis Pharma AG. Edition 11, release date 15-
Nov-2012.
Genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of 
clastogenic or mutagenic activity. Administration of everolimus for up to 2 years did not indicate 
any oncogenic potential in mice and rats up to the highest doses, corresponding respectively to 
4.2 and 0.2 times the estimated clinical exposure. In reproduction studies, everolimus was toxic 
to the conceptus in rats and rabbits, and was considered potentially teratogenic in rats. It is 
therefore recommended that females of childbearing potential should use effective 
contraceptive measures during the entire treatment period and for 8 weeks thereafter.
More pre-clinical information is provided in the RAD001/Everolimus Investigator’s Brochure. 
Novartis Pharma AG. Edition 11, release date 15-Nov-2012.
1.2.4
Everolimus pharmacokinetics
Everolimus is rapidly absorbed with a median tmax of 1-2 hours. The steady-state AUC0-τ is 
dose-proportional over the dose range between 5 to 70 mg in the weekly regimen and 5 and 10 
mg in the daily regimen. Steady state was achieved within two weeks with the daily dosing 


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regimen. Cmax is dose-proportional between 5 and 10 mg for both the weekly and daily 
regimens. At doses of 20 mg/week and higher, the increase in Cmax is less than dose 
proportional. In healthy subjects, high fat meals reduced systemic exposure to everolimus 10 
mg (as measured by AUC) by 22% and the peak plasma concentration Cmax by 54%. Light fat 
meals reduced AUC by 32% and Cmax by 42%. Food, however, had no apparent effect on the 
post absorption phase concentration-time profile.
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 
to 5,000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is 
approximately 20% at blood concentrations observed in cancer patients given everolimus 10 
mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients 
with moderate hepatic impairment. 
Everolimus is a substrate of CYP3A4 and a substrate and moderate inhibitor of PgP. Following 
oral administration everolimus is the main circulating component in human blood and is 
considered to contribute the majority of the overall pharmacologic activity.  No specific excretion 
studies have been undertaken in cancer patients; however, data available from the 
transplantation setting found the drug to be mainly eliminated through the feces. There was a 
significant correlation between AUC0-τ and pre-dose trough concentration at steady state on the 
daily regimen. The mean elimination half-life of everolimus is approximately 30 hours.
Please refer to Section 5.4.2 for more information on the concomitant use of CYP3A4 
inhibitors/inducers and other medications.
More information on RAD001 pharmacokinetics is provided in the RAD001/Everolimus 
Investigator’s Brochure. Novartis Pharma AG. Edition 11, release date 15-Nov-2012.
1.2.5
Everolimus pharmacodynamic studies
Pharmacokinetic/pharmacodynamic modeling based on inhibition of the biomarker p70S6 
kinase 1 in peripheral blood mononuclear cells (PBMC) suggests that 5-10 mg daily should be 
an adequate dose to produce a high-degree of sustained target inhibition (Study C2101 / Study 
2102). In molecular changes in tumor were evaluated through serial biopsies before and during 
treatment. Biopsy on treatment took place at week 4 (pharmacokinetic steady-state). All patients 
underwent a 24-hour post-dose biopsy. Patients following the weekly regimen had a further 
biopsy on Day 4 or 5 of the same week. Molecular activity was measured by 
immunohistochemistry. In the absence of a reliable technique for measuring mTOR 
phosphorylation, the phosphorylation status of downstream markers S6 and eIF4G, for which 
reliable antibodies exist, was selected as reflecting the immediate pharmacodynamic effect of 
everolimus. Also measured were changes in the phosphorylation status of upstream AKT and 
the proliferation index Ki67. Fifty-five patients were treated and the results revealed a dose and 
schedule dependent inhibition of the mTOR pathway with a near complete inhibition of pS6 and 
pelF-4G at the 10 mg/day and 50 mg/wk schedules. In addition, pAKT was upregulated in 50% 
of the treated tumors. In the daily schedule, there was a correlation between everolimus plasma 
trough concentrations and inhibition of peIF4G and p4E-BP1. There was good concordance of 
mTOR pathway inhibition between skin and tumor [(Study C2107), (29)].
More information is provided in the RAD001/Everolimus Investigator’s Brochure. Novartis 
Pharma AG. Edition 11, release date 15-Nov-2012.


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1.2.6
Clinical Experience
Everolimus has been in clinical development since 1996 as an immunosuppressant in solid 
organ transplantation and was approved in Europe in 2003 under the trade name Certican®, for 
the prevention of organ rejection in patients with renal and cardiac transplantation. Approval 
was granted in the United States in 2010 under the trade name of Zortress® for the prevention 
of organ rejection in adults receiving kidney transplants who are at a low to moderate 
immunologic risk.
Additional non-oncologic indications currently being explored are wet age-related macular 
degeneration (AMD) and autosomal dominant polycystic kidney disease (ADPKD). Clinical 
experience of everolimus in the transplant indication is summarized in a separate Investigator’s 
Brochure version 11. 
In oncology, everolimus has been in clinical development since 2002 for patients with various 
hematologic and non-hematologic malignancies as a single agent or in combination with 
antitumor agents. Malignancies that are currently being evaluated in Novartis sponsored studies 
include the following: metastatic renal cell carcinoma (mRCC), breast cancer, 
gastroenteropancreatic neuroendocrine tumors (NET), mantle cell lymphoma (MCL) and diffuse 
large B cell lymphoma (DLBCL), hepatocellular cancer (HCC), gastric cancer, and lung cancer. 
In addition, treatment of patients with Tuberous Sclerosis Complex (TSC) associated 
subependymal giant cell astrocytoma (SEGA) and Angiomyolipoma are also being evaluated. 
Colorectal cancer (CRC) and lung cancer are no longer being evaluated. As of 30- Sep-2011, 
there are a total of 11 Phase III trials ongoing in mRCC (1), advanced NET (2), breast cancer 
(3), TSC (2), DLBCL (1), gastric cancer (1), and hepatocellular carcinoma (1) 
(RAD001/Everolimus Investigator’s Brochure. Novartis Pharma AG. Edition 11, release date 15-
Nov-2012).
Everolimus 5mg and 10mg tablets were recently approved under the trade name Afinitor® for 
patients with advanced renal cell carcinoma in the US, EU and several other countries and are 
undergoing registration in other regions worldwide. Everolimus has been evaluated as a single 
agent and in combination with other antitumor agents, including cytotoxic chemotherapeutic 
agents, targeted therapies, antibodies and hormonal agents.  Phase I dose escalating studies, 
exploratory Phase I/II studies with everolimus as single agent or in combination with other anti-
cancer agents, Phase II/III studies of everolimus in indications, and Phase III double-blind 
studies are contributing to the extensive database. Approximately 18,730 patients, (excluding 
those patients who received marketed Afinitor®/Votubia® have been treated with everolimus as 
of 30-Sep-2011:

9,528 patients in Novartis-sponsored clinical trials

2,559 patients in the individual patient supply program

6,638 in investigator-sponsored studies.
In addition, healthy volunteer subjects and non-oncology hepatically impaired subjects have 
participated in the clinical pharmacology studies.
Recent approvals of everolimus (Afinitor®) were based upon a Phase III, international, 
multicenter randomized, double-blind, placebo-controlled study [C2240] in patients with 
metastatic renal cell carcinoma (mRCC) whose disease had progressed despite prior treatment 
with VEGFR-TKI (vascular endothelial growth factor receptor tyrosine kinase inhibitor) therapy. 
Progression-free survival (PFS) assessed via a blinded, independent central review, was the 
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In the pivotal, Phase III study [C2240], which included patients with advanced renal cell 
carcinoma, the most common adverse reactions (incidence ≥10%) were stomatitis, rash, 
fatigue, asthenia, diarrhea, anorexia, nausea, mucosal inflammation, vomiting, pneumonitis, 
cough, peripheral edema, infections, dry skin, epistaxis, pruritus, and dyspnea. The most 
common grade 3-4 adverse reactions (incidence ≥2%) were infections, stomatitis, fatigue, and 
pneumonitis. Non-infectious pneumonitis is a class effect of rapamycin derivatives, including 
Everolimus and some of these cases have been severe and on rare occasions, fatal outcomes 
have been observed. Everolimus has immunosuppressive properties and may predispose 
patients to bacterial, fungal, viral or protozoan 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
The most common laboratory abnormalities (incidence ≥50%) were anemia, 
hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased 
creatinine. The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were 
lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths 
due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were 
observed on the everolimus arm. The rates of treatment-emergent adverse reactions resulting in 
permanent discontinuation were 7% and 0% for the everolimus and placebo treatment groups, 
respectively. 
Overall, safety data available from completed, controlled and uncontrolled studies are consistent 
with the aforementioned findings of the Phase III trial. Everolimus is generally well tolerated at 
weekly and daily dose schedules. The safety profile is characterized by manageable adverse 
events (AEs). These AEs are generally reversible and non-cumulative.
Further detailed information regarding RAD001 clinical development, safety and efficacy is 
provided in the RAD001/Everolimus Investigator’s Brochure. Novartis Pharma AG. Edition 11, 
release date 15-Nov-2012.
1.3
Rationale for the Proposed Study
1.3.1
Rationale for targeting mTOR in low-grade gliomas
This study is driven by two hypotheses—first that mTOR inhibition will be efficacious for 
pediatric LGGs and second that PI3K/AKT activation will be associated with response to mTOR 
inhibition.  This study is unique among all pediatric brain tumor trials in its hypothesis-driven 
biological approach and it fulfills an unmet need for a pediatric population for whom few other 
therapeutic options exist.
A compelling rationale exists for targeting mTOR in LGGs. Activation of PI3K/AKT leads to 
increased susceptibility of tumors to inhibition of mTOR in pre-clinical and clinical studies (30).  
And in a recent report we document that over half of adult LGGs display activation of the 
PI3K/AKT/mTOR pathway, likely due to methylation of the PTEN promoter (31). With this 
rationale as a foundation we initiated a phase II trial of everolimus (RAD001) for adults with 
recurrent LGGs. Of the 36 enrolled patients, 11 patients continue on active therapy, 15 patients 
had stable disease for over a year, and 4 had stable disease for over 2 years, all despite 
multiple prior recurrences. Although accrual continues towards the planned 60 patients, 
preliminary analyses of molecular parameters and imaging studies have yielded provocative 
results. Imaging studies in the first 17 accrued patients, demonstrated that compared to patients 
who progressed on everolimus, those who did not progress (n=13) demonstrated statistically 


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significant decreases in tumor vascular properties, as measured by size of contrast-enhancing 
lesions, capillary density, and vascular permeability. Perfusion parameters may thus represent 
an early marker of treatment response of LGGs to everolimus and to our knowledge this is the 
first demonstration of anti-angiogenic effects of an mTOR inhibitor in a clinical setting. We plan 
on incorporating these imaging parameters into our trial of everolimus for PLGGs in order to 
determine whether early changes in angiogenic and vascular properties will predict responses 
of PLGGs to everolimus. Preliminary analyses of molecular features of the first 23 patients on 
study have also yielded provocative results.  Whereas in a cohort of newly diagnosed adult 
LGGs who were not treated with signaling inhibitors, PI3K/AKT/mTOR activation as measured 
by positive p-S6 and p-PRAS40 staining, was associated with worse progression-free survival 
(PFS), in our cohort of recurrent adult LGGs treated with everolimus PI3K/AKT/mTOR activation 
was associated with improved PFS. The “reversal” of the association of PI3K/AKT/mTOR 
activation with PFS when everolimus is administered supports our central hypothesis that 
PI3K/AKT/mTOR pathway activation acts as a predictive marker of response to mTOR 
inhibition. We plan on testing this hypothesis in the current PLGG trial.
We have extended our pre-clinical studies and biologic analyses to pediatric gliomas.  
Approximately half of pediatric LGGs displayed PI3K/AKT/mTOR activation and methylation of 
the PTEN promoter. Specifically, pediatric LGGs demonstrated PI3K/Akt/mTOR pathway 
activation in 14/32 (43.8%) tumors by phosphorylated-S6 and 16/32 (50%) tumors by 
phosphorylated-4EBP1. Over 50% of grade I (6/11) and almost all grade II tumors (6/7) showed 
PTEN promoter methylation.  In addition, an inverse association was found between PTEN 
promoter methylation and PTEN protein expression (32). As for the adult study described 
above, these findings, in combination with the link between response to mTOR inhibition and 
PI3K/AKT activation provide the pre-clinical rationale for treating pediatric LGGs with an mTOR 
inhibitor.  In this proposed study, molecular features, including PTEN status and activation of the 
PI3K/mTOR pathway, will be assessed prospectively to investigate possible associations 
between these molecular characteristics and response to mTOR inhibition.
Everolimus is an orally bioavailable derivative of the macrolide rapamycin. By inhibiting its 
intracellular target, mTOR, everolimus arrests cell proliferation, induces apoptosis in selected 
models, and inhibits angiogenesis, all with limited normal tissue toxicity. Cell lines derived from 
childhood tumors including glioblastoma demonstrate marked sensitivity to everolimus. The 
Pediatric Preclinical Testing Program (PPTP) has completed testing of pediatric solid tumors in 
in vitro and in vivo models and reported intermediate activity for 3 of 4 GBM xenografts.  Studies 
investigating the determinants of sensitivity to mTOR inhibition suggest that tumor cells 
sensitive to mTOR inhibition are the tumors with aberrant signaling through PI3K/Akt such as 
those with activating mutations and/or amplification of growth factor receptors, PI3K, Akt, or 
through loss of PTEN or TSC1/2 (30).
This is an open label study of everolimus in children with recurrent or progressive low-grade 
glioma. All patients will receive everolimus at a dose of 5 mg/m2/dose daily.  An adaptive Simon 
two-stage design for phase 2 studies of targeted therapies will be used to assess the efficacy 
primary objective. The proposed treatment with everolimus will be deemed not worthy of further 
investigation in this patient population if the true PFS at 6-months (PFS6) is less than 50%. If in 
the first stage, with a combined sample size of 25, there is preliminary evidence to suggest 
efficacy of everolimus is restricted to patients with PI3K/AKT/mTOR activation, a total of 45 
patients will be enrolled and the design will have 81% statistical power to detect a true disease 
stabilization rate ≥70%. If in the first stage there is preliminary evidence to suggest efficacy of 
everolimus is independent of PI3K/AKT/mTOR activation, a total of 65 patients will be enrolled 
and the design will have >95% statistical power to detect a true disease stabilization rate ≥70%.


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This will be a multi-institutional study.  The study will be carried out under the auspices of the 
newly formed Pacific Pediatric Neuro-Oncology Consortium (PNOC). It must be emphasized 
that there is a glaring lack of current studies for this patient population.  Such a study within a 
multi-institutional environment provides children with recurrent LGGs access to a much-needed 
therapeutic treatment in a geographic region in which many children have no other options.
This study is unique in several critical respects: (i) the requirement for available tumor tissue as 
an eligibility criterion in order to accomplish the important objective of exploring associations 
between activation of specific signaling cascades and response to everolimus; (ii) the 
incorporation of metabolic and physiologic imaging analyses that may be critical to future 
assessments of tumor responses in trials that increasingly test inhibitors that are cytostatic 
rather than cytotoxic.  Overall, the current proposed study is distinct from other pediatric studies 
in that it steps beyond response-driven approaches and attempts to define which patients are 
most likely to respond to a specific signaling inhibitor.  Clearly, only a subgroup of pediatric 
LGGs is likely to respond to a given signaling inhibitor and as future studies attempt to design 
rational combinations of novel agents, it is critical to explore potential predictive molecular 
features of individual tumors.  Future rationale approaches will include combining everolimus 
with a BRAFV600E-, a PDGFR-, or a MEK-inhibitor, among others. Completion of this trial will 
allow progression to the next generation of clinical trials for children with gliomas in which 
rational drug combinations are designed and guided by molecular features of individual tumors.
1.3.2
Rationale for everolimus in pediatric central nervous system malignancies
Everolimus (RAD001) is an orally bioavailable derivative of the macrolide rapamycin. It has the 
same intracellular target as rapamycin, mTOR (mammalian target of rapamycin) a serine 
threonine kinase implicated in the control of cellular proliferation of activated T-lymphocytes and 
neoplastic cells (RAD001/Everolimus Investigator’s Brochure. Novartis Pharma AG. Edition 11, 
release date 15-Nov-2012). mTOR is a ubiquitous protein kinase implicated in cell cycle control 
and specifically in the progression of cells from G1 to S phase. mTOR function is modulated by 
numerous interleukins and growth factors. 
Rapamycin inhibits interleukin and growth factor dependent proliferation of cells, exerting its 
activity through a high affinity interaction with an intracellular receptor protein, the immunophilin 
FKBP -12 (13).  This complex inhibits downstream signaling pathways involved in the regulation 
of the G1 to S transition (33).  The primary downstream targets of mTOR, eIF4E binding protein 
(4EBP1) (34, 35) and p70S6 kinase (36, 37), play key roles in the translation regulation of 
mRNA encoding proteins involved in G1 phase progression (RAD001/Everolimus Investigator’s 
Brochure. Novartis Pharma AG. Edition 11, release date 15-Nov-2012). Thus, through inhibition 
of mTOR function rapamycin blocks these essential translational events resulting in inhibition of 
G1 progression. 
Rapamycin also indirectly blocks phosphorylation and inactivation of pRb, a G1 suppressor 
protein (38), as well as rRNA synthesis (39, 40), PKCα phosphorylation (41) and the activity of 
steroid receptor-regulated genes (39). Finally, rapamycin is a potent inhibitor of vascular 
endothelial cells (7, 14) and has antiangiogenic activity in vivo (4) possibly through inhibiting 
translation of Hypoxia Inducible Factor (HIF)-1α mRNA. P70s6k mediated protein synthesis is 
important in endothelial cell proliferation (7).
In vitro data demonstrate that everolimus inhibits the proliferation of a range of human tumor cell 
lines, including lung, breast, colon, melanoma, and glioblastoma with IC50 values ranging from 
0.7 nM to 4.1 μM. Relative sensitivity to everolimus in vitro often correlates with the degree of 
activation of the Akt/PKB protein kinase pathway (e.g. in glioblastoma).  Treatment with 20 nM 
of everolimus for 30 minutes potently inhibits the mTOR signaling pathway for 96-120 hr. 
Rapamycin and its other analogue, CCI 779, have also shown in vitro activity in 


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medulloblastomas/PNET and glioblastoma cell lines. Georger et al. reported that rapamycin 
inhibits PNET/medulloblastoma cell lines at IC50 values <10ng/ml (42).
In vitro, everolimus exhibits antiangiogenic properties, inhibiting the proliferation of HUVECS 
with IC50 values in the picomolar range for VEGF (120 ± 22 pM) and βFGF (841 ± 396 pM).  
Tumor cell lines that were relatively sensitive to everolimus had higher phospho-AKT levels than 
lines that were more resistant to everolimus. PTEN status was not generally predictive of 
sensitivity to everolimus, although in glioblastoma PTEN-/- lines exhibited a trend towards 
increased sensitivity to everolimus (RAD001/Everolimus Investigator’s Brochure. Novartis 
Pharma AG. Edition 11, release date 15-Nov-2012). Cell lines derived from childhood tumors 
including glioblastoma demonstrate marked sensitivity to everolimus (43).
Recently, the PPTP has completed testing of pediatric solid tumors in in vitro and in vivo models 
and reported intermediate activity for 3 of 4 GBM xenografts (44).  Several studies have 
reported that PTEN loss correlates with rapamycin sensitivity; however, Houghton et al. noted a 
poor correlation between in vitro and in vivo sensitivity in solid tumor xenograft models and 
hypothesized that the activity of rapamycin in vivo for these xenografts was primarily due to anti-
angiogenic effects (44).  Thus, the fact that Pollack et al. have recently demonstrated the low 
incidence of PTEN loss in pediatric gliomas does not diminish the justification for the use of 
mTOR inhibitors in these tumors, as the primary mechanism of activity in high-grade glioma 
models is rapamycin’s antiangiogenic function (45).  
A further rationale for evaluating rapamycin and its analogues in pediatric high-grade gliomas is 
the potential for these agents to inhibit signaling downstream of the type I insulin-like growth 
factor receptor. These drugs may block the autocrine growth or paracrine stimulation found 
frequently in glioblastoma (46-48).
In one Phase II study of CCI779 in adults with recurrent high grade gliomas, Chang et al. 
demonstrated 17% objective response rate in patients not on EIACD (49).  Galanis et al. 
reported no objective responses in another phase II trial in patients with recurrent GBM (16).  
Everolimus penetration into brain tissue has been evaluated in mice and rats (50).  Non-tumor 
bearing BALB/c mice were administered everolimus once at 5 mg/kg orally or 1 mg/kg 
intravenously, and blood and tissues were obtained at specified times after drug administration.  
The extent of penetration (AUCbrain/AUCblood) was 1.8% and 5.2% after oral and intravenous 
administration, respectively.  Despite the relatively low penetration, everolimus brain tissue 
concentrations (69 ng/g after oral; 8 ng/g after intravenous) are within range of the IC50 values 
for glioblastomas for 2-9 hours (RAD001/Everolimus Investigator’s Brochure. Novartis Pharma 
AG. Edition 11, release date 15-Nov-2012).
Phase I studies in children with recurrent solid tumors have established the MTD of everolimus 
at 5 mg/m2 daily continuously with mucositis, diarrhea, and liver dysfunction as the major 
toxicities. Preliminary correlative studies revealed that target inhibition in peripheral 
mononuclear cells was achieved in patients at higher dose levels.  Although no PRs or CRs 
were noted, 1 patient with medulloblastoma remained on therapy for 4 courses, 1 patient with 
ependymoma continued on therapy for 4 courses, 1 patient with AA continued on therapy for 4 
courses and developed dose limiting toxicity and was removed from study, 1 patient with a BSG 
continued on therapy for 5 courses and a patient with gliomatosis cereberi continues on therapy 
after 12+ courses. One patient with osteosarcoma continues on therapy for 7+ courses. Serum 
concentrations achieved exceeded the IC50 values in in vitro studies (16).
Everolimus (RAD001) has been investigated as a component of multi-drug immunosuppression 
in solid organ transplantation since 1996.   Because of its potent antiproliferative effects against 
a variety of tumor types and evidence that it synergizes with chemotherapy in pre-clinical 
models, more recently it has been investigated as an anti-tumor agent (47).  Phase I clinical 


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trials in 147 advanced cancer patients, utilizing various dosing regimens and schedules have 
been investigated (including weekly schedule of 5-70 mg and daily schedules of 5-10 mg).  
Common toxicities included rash or erythema (46%), stomatitis/mucositis (40%), fatigue (30%), 
headache (14%), diarrhea (16%), nausea (16%), pruritis, infection and constipation (10% each) 
(46, 48).  Efficacy has been noted in clinical trials at various doses on both the weekly and daily 
schedules in patients with non-small cell lung cancer, breast, renal, rectal cancer and 
mesothelioma (51).
The Pediatric Oncology Experimental Therapeutics Investigators' Consortium (POETIC) has 
initiated a Phase II study of everolimus (RAD001) for children with chemotherapy refractory 
and/or progressive or recurrent low-grade gliomas (Protocol 10-047).  The stated objective of 
the study is to assess “the safety and effectiveness of everolimus (RAD001) in children with low-
grade gliomas that have either not responded to treatment or have come back after treatment.”  
This is a standard phase II response-driven trial in which the investigators also propose to 
examine mTOR inhibition in peripheral blood mononuclear cells (PBMCs) and limited 
pharmacokinetic studies as well as standard neuroimaging analyses.  The study proposed 
herein is distinct from the POETIC trial in several critical respects: (i) the PNOC study requires 
the availability of tumor tissue as an eligibility criterion in order to accomplish the important 
Primary Objective of exploring associations between activation of specific signaling cascades 
and response to everolimus; (ii) the proposed PNOC study prospectively incorporates metabolic 
and physiologic imaging analyses that may be critical to future assessments of tumor responses 
in trials that increasingly test inhibitors that are cytostatic rather than cytotoxic.  Overall, the 
current proposed study is distinct from the POETIC trial in that recent biological studies of 
pediatric LGGs have allowed our PNOC consortium to step beyond the response-driven 
approach of other pediatric trials and incorporate important Secondary Objectives that may shed 
light on which patients are most likely to respond to a specific signaling inhibitor.  Clearly, only a 
subgroup of pediatric LGGs is likely to respond to a given signaling inhibitor and as future 
studies attempt to design rational combinations of novel agents, it is critical to explore potential 
predictive molecular features of individual tumors.
Specific hypothesis: mTOR inhibition will be efficacious for pediatric low-grade gliomas.
1.4
Correlative Studies
1.4.1
Rationale for additional radiographic imaging as an exploratory aim
Standard anatomic MRI in conjunction with clinical evaluation such as neurologic status and 
corticosteroid use remains the key determinant of response to therapy and the evaluation of 
tumor recurrence for LGG (52, 53). Increase in contrast enhancement, worsening cerebral 
edema, and mass effect are universal traits of malignant transformation. Acquiring tissue 
samples to confirm tumor upgrade, although considered the “gold standard” for determining the 
presence of viable tumor, can result in both false positives and negatives that relate to sampling 
error (54, 55). Recent studies using MR spectroscopic imaging (MRSI) suggest that in vivo 
levels of metabolites such as choline, creatine, N-acetylaspartate, lactate and lipids provide 
more-reliable measures of the presence of recurrent tumor. Perfusion-weighted imaging (PWI) 
and diffusion-weighted imaging (DWI) have been explored for patients with newly diagnosed 
glioma, but only on a limited basis for patients with recurrent LGG. Techniques to characterize 
the molecular morphology of pre-specified areas in addition to neuroimaging parameters may 
better define the biologic behavior of such lesions.
Many of the newer drugs being studied in neuro-oncology target specific aberrant pathways and 
are cytostatic rather than cytotoxic. Examples include anti-invasive and anti-angiogenic agents. 
These agents may cause stability of the tumor rather than regression, and surrogate biomarkers 
are important in the assessment of these types of agents.  Pending funding availability, we will 


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prospectively incorporate metabolic and physiologic imaging to this trial to allow us to assess 
the ability of the key parameters to predict clinically relevant endpoints such as treatment 
related radiographic response, time to progression and survival.
We are eager to incorporate these imaging aims into this pediatric study because preliminary 
analysis of our institutional study of everolimus for adult LGGs has resulted in the first clinical 
demonstration of anti-angiogenic effects of an mTOR inhibitor and we are eager to extend these 
analyses to the pediatric population. Specifically, the phase II trial of everolimus (RAD001) for 
adults with recurrent LGGs includes a critical imaging objective that incorporates MR 
spectroscopy, perfusion-weighted, and diffusion-weighted imaging to predict clinically relevant 
endpoints. Early analyses reveal that capillary density and vascular permeability measured 4 
and 6 months after start of everolimus decreased significantly in patients with stable disease but 
not in those with progressive disease, suggesting that decreased angiogenesis may represent 
an early marker of response to treatment.  
1.4.2
Rationale for molecular profiling studies
Only patients for whom tumor tissue is available for molecular analyses will be eligible for this 
study. This will be the only pediatric LGG cohort for which tissue will be collected prospectively 
from every enrolled child, thus providing critical data on the prevalence of genetic aberrations 
among pediatric LGGs. These molecular analyses will be determined using tissue samples from 
prior surgeries.
The correlative studies aim to address the following specific goals:
(i) To explore associations between pS6 positivity and outcome as measured by the 6-month 
disease stabilization rates (a dichotomous variable, see section 7.1.2.2) as well as PFS for 
progressive or recurrent pediatric low-grade glioma patients with measureable disease treated 
with everolimus.
(ii) To collect tissue from all enrolled patients and prospectively analyze key molecular features 
including activation of the PI3K, mTOR and MAPK pathways, aberrations in PTEN, IDH1, and 
IDH2, and activating mutations in BRAF (KIAA1549-BRAF fusion and BRAFV600E missense 
BRAF mutation).  
(iii) In addition to the targeted approaches described above that examine previously reported 
alterations additional genomic profiling studies will be performed including targeted sequencing, 
RNA sequencing, and/or exome(plus) next generation sequencing if sufficient tissue is available 
including fresh frozen tissue.  Such studies will include but are not limited to molecular analyses 
of DNA, RNA and protein in tumor biopsy specimens using blood as control.  When possible 
and/or sufficient blood/tissue is provided, sample will be used to establish tumor cell cultures, 
cell lines and/or transplantation models. These studies will be carried out in collaboration with 
Dr. Adam Resnick, Children’s Hospital of Philadelphia. 
2
Objectives of the Study
2.1
Primary
Efficacy: Estimate the Progression Free Survival (PFS) rate at 6-months associated with 
everolimus therapy for symptomatic, progressive or recurrent pediatric low-grade glioma 
patients with measureable disease with the aim of determining whether everolimus warrants 
additional study only in patients with activated PI3K/Akt/mTOR pathway or in the entire 
population.


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2.2
Secondary

Estimate PFS and OS distributions as well as objective response (CR+PR) rates 
associated with everolimus treatment in recurrent pediatric LGGs.

Explore associations between pS6 positivity and outcome as measured by the 6-month 
disease stabilization rates (a dichotomous variable; see section 7.1.2.2) as well as PFS 
for progressive or recurrent pediatric low-grade glioma patients with measureable 
disease treated with everolimus.

Collect tissue from all enrolled patients and prospectively analyze key molecular features 
including activation of the PI3K, mTOR and MAPK pathways, aberrations in PTEN, 
IDH1, and IDH2, and activating mutations in BRAF (KIAA1549-BRAF fusion and 
BRAFV600E missense BRAF mutation).  In addition to the targeted approaches 
described above that examine previously reported alterations additional genomic 
profiling studies will be performed including targeted sequencing, RNA sequencing, 
and/or exome(plus) next generation sequencing if sufficient tissue including fresh frozen 
tissue is available.  Such studies will include but are not limited to molecular analyses of 
DNA, RNA and protein in tumor biopsy specimens and blood samples.  When possible 
and/or sufficient blood/tissue is provided, sample will be used to establish tumor cell 
cultures, cell lines and/or transplantation models. These studies will be carried out in 
collaboration with Dr. Adam Resnick, Children’s Hospital of Philadelphia.

Explore MR quantitative measures of relative cerebral blood volume, permeability and 
apparent diffusion coefficient within the region of hyper-intensity on T2-weighted images 
as markers of disease response and/or progression in comparison to institutional 
evaluation of disease response and/or progression and quantitative measures of tumor 
response as determined by central review (based upon both area and volumetric 
measures.
3
Study Design
3.1
Characteristics
This is a nonrandomized, open label Phase 2 study evaluating the efficacy of everolimus 
therapy for symptomatic, progressive or recurrent pediatric low-grade glioma patients.  Patients 
will receive everolimus once daily by mouth.  Twenty-eight (28) days will constitute one cycle 
and subsequent cycles will immediately follow, with no break in the administration of the drug. 
Dosing is based on the BSA calculated at the beginning of each cycle of therapy. The dose 
prescribed should be rounded to the nearest deliverable dose based on the BSA adjustment 
and the available pill sizes. Dosing Tables that reflect this approach are available in Appendix 1. 
Patients will be provided with a drug diary for everolimus instructed in its use, and asked to 
bring the diary with them to each appointment. The total length on study is 24 cycles. If disease 
remains stable or improved and there are no significant side effects, the patient might be able 
receive the medication off study based on patient’s preference, treating physician’s 
recommendation and availability of everolimus (RAD001) outside the clinical trial. Monitoring 
should be guided per best clinical practice based on the treating physician’s recommendation.
3.2
Number of Subjects
With the anticipated accrual numbers provided by the eight PNOC institutions, we anticipate that 
25-30 patients/year may be available. If we assume that 50% of these would be eligible for the 
biology objective, i.e. would have measureable disease and would have tissue available from 
prior surgeries, we can expect that the interim analysis will take place within 2.5-3.5 years from 


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initiation of accrual, including the 6-month disease evaluation window. Hence at the time of the 
interim analysis we expect to have accrued 25 patients. 
If preliminary evidence in the first stage (at the interim analysis) suggests efficacy of everolimus 
is limited to the patients with pathway activation, an additional 20 pathway activated patients will 
be recruited. Assuming 50% of the eligible patients have pathway activation, we can expect 6-7 
patients per year for a full accrual in 5.5-6.5 years from initiation of accrual. If preliminary 
evidence in the first stage (interim analysis) suggests efficacy of everolimus is not limited to the 
patients with pathway activation, an additional 40 patients will be recruited regardless of their 
activation status. We can then expect 13-15 patients per year for a full accrual in 5.5-6.5 years 
from initiation of accrual.
3.3
Eligibility Criteria
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria.  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 written 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.
3.3.1
Inclusion Criteria

Patients must have progressive or recurrent confirmed low-grade glioma (WHO grade I
or II) that was confirmed histologically.

Tissue from the initial diagnosis or recurrence must be made available for correlative
testing. Appendix 3 or an email from the pathology department may be used to confirm
tissue availability at the time of enrollment.

Depending on the stage of the protocol, pathway activation based on p-S6 will need to
be done in real time to assess if patient is eligible. As of April 2017, pathway activation
does not need to be performed in real time to access eligibility.

Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least two dimensions on MRI.  See Section 7.1.2.2 for the
evaluation of measurable disease.

Patients may have had treatment (chemotherapy and/or radiotherapy) or no treatment
for any number of relapses prior to this recurrence.
o
Patients must have received their last dose of myelosuppressive anticancer
chemotherapy at least three (3) weeks prior to study registration or at least six (6)
weeks of nitrosourea.
o
Patients must have received their last dose of other investigational or biological
agent > 7 days prior to study entry.
 
For agents that have known adverse events occurring beyond 7 days 
after administration, this period should be extended beyond the time 
during which adverse events are known to occur. This should be 
discussed with the study chair.
o
If patients received prior monoclonal antibody treatment, at least three half-lives
must be elapsed by the time of treatment initiation. These patients should also be
discussed with the study chair.


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o
Patients must have received their last fraction of craniospinal or focal radiation to
primary tumor or other sites >12 weeks (3 months) prior to registration.

Age ≥3 and ≤21 years.
o
Because no dosing or adverse event data are currently available on the use of
everolimus in patients <3 years of age, these young children are excluded from
this study.

Patient must have a Karnofsky (if ≥ 16 years of age) or Lansky Performance score (if ≤
15 years of age) of ≥50 by the time of registration. Patients who are unable to walk
because of paralysis, but who are up in a wheelchair, will be considered ambulatory for
the purpose of assessing the performance score.

Patients must have adequate bone marrow function (ANC ≥ 1,000/mm3, platelet count of
≥ 100,000/mm3, and hemoglobin ≥ 9 gm/dL) before starting therapy. Eligibility level for
hemoglobin may be reached by transfusion.

Patients must have adequate liver function (SGPT/ALT ≤ 2.5 times ULN and bilirubin ≤
1.5 times ULN) before starting therapy.

Patients must have adequate renal function, defined as:
o
Creatinine clearance or radioisotope GFR   70mL/min/1.73 m2 or
o
A serum creatinine based on age/gender as follows:
Age
Maximum Serum
Creatinine (mg/dL)
Male
Female
3 to < 6 years
0.8
0.8
6 to < 10 years
1
1
10 to < 13 years
1.2
1.2
13 to < 16 years
1.5
1.4
≥ 16 years
1.7
1.4
The threshold creatinine values in this table were derived from the Schwartz 
formula for estimating GFR utilizing child length and stature data published 
by the CDC.

Patients must have cholesterol level <350 mg/dL and triglycerides < 400 mg/dL before
starting therapy.  In case one or both of these are exceeded, the patient can only be
included after initiation of appropriate lipid lowering medication and documentation of
cholesterol < 350mg/dL and triglycerides < 400mg/dl before start of therapy.

Patients must have normal pulmonary function testing for age based on pulse oximetry.

The effects of everolimus on the developing human fetus at the recommended
therapeutic dose are unknown.  For this reason and because everolimus are known to
be teratogenic, female patients of child-bearing potential and men must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation.  Should a female patient become
pregnant or suspect she is pregnant while participating in this study, she should inform
her treating physician immediately.


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
Female patients of child bearing potential must not be breastfeeding or pregnant as 
evidenced by a negative pregnancy test.
3.3.2
Exclusion Criteria

Patients with primary spinal cord tumors

Patients receiving concomitant medication that may interfere with study outcome. For 
example, patients cannot be on enzyme inducing anticonvulsants like phenytoin. For a 
complete list please refer to section 5.4.2.

Patients should not receive immunization with attenuated live vaccines within one week 
of study entry or during study period. Close contact with those who have received 
attenuated live vaccines should be avoided during treatment with everolimus. Examples 
of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, 
yellow fever, varicella and TY21a typhoid vaccines.

HBsAg and HCVAb blood test must be done at screening for all patients. Patients who 
test positive for Hepatitis C antibodies or the Hepatitis B antigen are ineligible.

A known history of HIV seropositivity. HIV-positive patients on combination antiretroviral 
therapy are ineligible because of the potential for pharmacokinetic interactions with 
everolimus.  In addition, these patients are at increased risk of lethal infections when 
treated with marrow-suppressive therapy.  

Patients receiving chronic, systemic treatment with corticosteroids or another 
immunosuppressive agent. Note: Patients that are currently using inhaled, intranasal, 
ocular, topical or other non-oral or non-IV steroids are not necessarily excluded from the 
study but need to be discussed with the study chair. 

Patients may not have therapy for this recurrence (including radiation). 

Patients who do not have measurable disease on MRI.

Patients who have been previously treated with an mTOR inhibitor.

Patients with a known hypersensitivity to everolimus or other rapamycins (e.g. sirolimus, 
temsirolimus).

Patients receiving any other concurrent anticancer or investigational therapy.

Patients with any clinically significant unrelated systemic illness that would compromise 
the patient’s ability to tolerate protocol therapy.

Impairment of gastrointestinal function or gastrointestinal disease that may significantly 
alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome or small bowel resection.

Patients with inability to return for follow-up visits to assess toxicity to therapy.

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 


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
Patients with a history of any other cancer (except non-melanoma skin cancer or 
carcinoma in situ of the cervix), unless in complete remission and off of all therapy for 
that disease for a minimum of 3 years. 
Important note: The eligibility criteria listed above are interpreted literally and cannot be 
waived.
3.4
Registration Procedures
3.4.1
General Guidelines
Patients must meet all inclusion criteria and no exclusion criteria should apply. The patient must 
have signed and dated an approved, current version of all applicable consent forms.  To allow 
non-English speaking patients to participate in this study, bilingual health services will be 
provided in the appropriate language when feasible.
Registration materials will be submitted to the PNOC operations office as described below.  The 
PNOC operations office will check the registration materials for completeness and contact the 
site with any discrepancies. 
The PNOC operations office will forward eligibility checklist including source documentation to 
the Study Chair or Co-Chair as well as the project leader or co-project leader of PNOC for 
review of eligibility and sign off. 
Eligible patients will be registered using the UCSF OnCore® database that is used for all PNOC 
trials.  Treatment on protocol therapy cannot be initiated prior to receiving registration 
confirmation email from the PNOC operations office.
3.4.2
Reservation and Registration Process
The wait-list for study slots will be maintained by the PNOC Operations Office.  Investigators 
can view updated information about slot availability on the PNOC Member’s SharePoint website 
using their secure login and password, or by emailing a request to 
. 
To place a patient on the waitlist, please send an email to 
 and 
include the following information in the email: Study name, Patient initials, Patient age, Consent 
signed date (or estimate), and Expected start date (if found eligible).
To register a patient for the study, the patient demographics along with a signed consent form 
and HIPAA authorization should be emailed to the PNOC Operations Office at 
 The patient will be given the status of consented in OnCore®.


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When the eligibility checklist has been completed the member institution PI and/or Coordinator 
will upload the completed eligibility checklist along with copies of any supporting documents into 
the patient’s OnCore® record.
Once the necessary documents have been received and the patient eligibility has been 
confirmed, the PNOC Operations Office will send a confirmation e-mail to the site PI(s) and 
research coordinator(s) with the patient’s study ID and dose information. 
Detailed patient screening and registration instructions can also be found on the PNOC 
Member’s SharePoint Wiki. 
To allow non-English speaking patients to participate in this study, bilingual health services will 
be provided in the appropriate language when feasible.
Patients must begin treatment within 10 business days of study registration. Registration and 
informed consent must be completed prior to beginning of everolimus (RAD001).
3.5
Duration of Therapy
In the absence of treatment delays due to adverse events, treatment may continue for 24 cycles 
or until a “off treatment” criterion is met (see section 5.6)
Note – after 24 cycles of therapy, if patients continue to show benefit from therapy, treatment 
may be extended “off study” at the investigator’s discretion but will not be supported by Novartis.
3.6
Duration of Follow Up
 Patients who are off protocol therapy must be followed for up to five years from the start of 
therapy or until an “Off Study Criterion” is met, whichever occurs first (see section 5.7).  Any 
patient removed from protocol therapy for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.
3.7
Study Timeline
3.7.1
Interim Analysis
Based on the expected accrual as outlined above the first analysis will take place 2.5-3.5 years 
from initiation of accrual, including the 6-month disease evaluation window. Hence at the time of 
the interim analysis we expect to have accrued 25 patients. 
3.7.2
Primary Completion
If preliminary evidence in the first stage (at the interim analysis) suggests efficacy of everolimus 
is limited to the patients with pathway activation, an additional 20 pathway activated patients will 
be recruited. Assuming 50% of the eligible patients have pathway activation, we can expect 6-7 
patients per year for a full accrual in 5.5-6.5 years from initiation of accrual. If preliminary 
evidence in the first stage (interim analysis) suggests efficacy of everolimus is not limited to the 
patients with pathway activation, an additional 40 patients will be recruited regardless of their 
activation status. We can then expect 13-15 patients per year for a full accrual in 5.5-6.5 years 
from initiation of accrual.


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3.7.3 Study Completion
The study will reach completion approximately 8 years from the time the study opens to accrual 
to the final date on which all data are expected to be collected.  
4
Study Drugs
4.1
Description, Supply and Storage of Everolimus
[Refer to the package insert(s) for complete information].
Everolimus (RAD001, Afinitor®) is an investigational agent and will be supplied by Novartis 
Pharmaceuticals Corporation.
Formulation
Everolimus is formulated as tablets of 2.5 mg, 5 mg, and 10 mg strength.
Storage
Everolimus is blister-packed under aluminum foil in units of 10 tablets that should be opened 
only at the time of administration as drug is both hygroscopic and light sensitive. Storage must 
be at temperatures below 30°C and in the original blister packs. Shelf life will be described on 
the medication label.
Administration
Everolimus may be taken with or without food. The tablets should be swallowed whole with a 
glass of water and should not be chewed or crushed. For patients unable to swallow tablets, the 
tablet(s) should be dispersed completely in a glass of water (containing approximately 30 mL) by 
gently stirring, immediately prior to drinking. The glass should be rinsed with the same volume of 
water and the rinse completely swallowed to ensure the entire dose is administered.
Side Effects
See section 5.3.2.  Complete and updated adverse event information is available in the 
Investigational Drug Brochure and/or product package insert. 
4.2
 Drug Accountability
Novartis will directly distribute study drug to PNOC institutions. Each PNOC institution will be 
responsible for reconciling the drug supply at their site.
4.3
Drug Ordering
Each PNOC institution will be responsible for requesting their own drug supply directly from 
Novartis. The PNOC001 drug request form can be found on the SharePoint member website 
under the documents tab. 
4.4
Packaging and Labeling of Study Drugs
Drugs will be packaged and labeled per institutional standards, adhering to applicable local and 
federal laws.
5
Study Procedures and Observations
The study-specific assessments are outlined in Table 5.1 and are detailed below.  Imaging 
evaluations necessary to establish eligibility for study entry must be done within 21 days prior to 
the start of therapy.  All other evaluations except laboratory parameters necessary to establish 


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eligibility for study entry must be done within 14 days prior to the start of therapy.  Patients must 
start therapy within 10 business days of registration. If a test that is repeated after registration 
and prior to therapy is outside the limits for eligibility, it must be rechecked 48 hours prior to the 
start of therapy. If the recheck is still outside the limits for eligibility, the patient may not receive 
protocol therapy. All patients must meet the following inclusion and exclusion criteria. 
All on-study visit procedures are allowed a window of ± 3 days unless otherwise noted.
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the consent form will be given to the subject and filed in 
the medical record. A copy of the consent must also be uploaded into OnCore® as part of the 
registration process. The original will be kept on file with the study records.  
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system is 
password protected and meets HIPAA requirements.
 Refer to section 3.4 for registration procedures. 


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Table 5.1   
Schedule of Assessments**
All on-study visit procedures are allowed a window of ±3 days unless otherwise noted.
Period/
Procedure
Screenin
g
Cycl
e 1
Cycl
e 1
Cycl
e 2
Cycl
e 2
Cycle 3, 5, 7, 
9,11,13,16,19
, 22 
Cycle 4, 6, 8, 
10, 12, 14, 15, 
17, 18, 20, 21, 
23, 24
Study 
Day/Visit 
Day
-14 to 0
Day 
1
Day 
15
Day 
1
Day 
15
Day 1
Day 1
 End of 
Treatment 
visit1
30 Day 
Tox 
Check2
Follow 
up3
Informed 
consent
X
AE 
assessment
X
X
X
X
X
Concomitan
t 
medications
X
X
X
X
X
X
Tumor 
Tissue 
Collection 
X
Treatment Administration
Everolimus
Daily, oral, self-administration
Clinical procedures
Physical 
exam
X
X
X
X
X
Vital signs
X
X
X
X
X
Medical 
history
X
Performanc
e Status
X
X
X
X
X
Neurologic 
exam
X
X
X
X
X
Pulse 
oximetry
X
X
X
X
X
Survival
X
Laboratory procedures
CBC w/ Diff 
X
X
X
X
X
X
X
X
Blood 
chemistry 4
X
X
X
X
X
X
X
X
Coagulation 
X
X
X
Hepatitis 
X
Pregnancy 
test (HCG)5
X
X
X
X
X
X
Correlative 
Studies 
X
Imaging procedures 


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Period/
Procedure
Screenin
g
Cycl
e 1
Cycl
e 1
Cycl
e 2
Cycl
e 2
Cycle 3, 5, 7, 
9,11,13,16,19
, 22 
Cycle 4, 6, 8, 
10, 12, 14, 15, 
17, 18, 20, 21, 
23, 24
Study 
Day/Visit 
Day
-14 to 0
Day 
1
Day 
15
Day 
1
Day 
15
Day 1
Day 1
 End of 
Treatment 
visit1
30 Day 
Tox 
Check2
Follow 
up3
Imaging 
(MRI) 6
X
X
X
X
Chest X-
Ray 7
X
X
X
X
X
ECG/EKG8 
X
**Please refer to sections 5.1 and 5.2 for complete information about screening assessments and study procedures
1 To be completed when one of the off-treatment criteria is met. 
2 The toxicity check can be done via phone at 30 days after the last dose (+7 days). All study drug related 
adverse events must continue to be followed until resolution or return to baseline. Review of concomitant 
medications.
3 Patients who are off-treatment will be followed for up to 5 years after discontinuing drug or until one of 
the off-study criteria is met, to collect required follow-up information (see Long Term/Survival Follow-up 
Procedures). 
4 Including: Sodium, potassium, chloride, bicarbonate, calcium, fasting glucose, albumin, total protein, 
BUN, serum creatinine, total bilirubin, AST, ALT, alkaline phosphatase, uric acid, phosphorus,  and 
fasting serum lipid profile. 
5For females of childbearing age; pregnancy test should be done.
6 Brain MRI scans are due prior to therapy, before every odd cycle (3, 5, 7, 9, and 11) in the first year (+/-
7 days), and before every third cycle in the second year (13, 16, 19, and 22) (+/- 7 days). Spine MRIs 
should be performed if clinically indicated.  
7 Chest X-Ray to be performed as clinically indicated.
8 EKG to be performed at screening and then as clinically indicated.


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5.1
Pre-Treatment Period
5.1.1 Screening Assessments
The Screening procedures and assessments must be completed within 14 days of Cycle 1, Day 
1 visit except brain MRI.

Physical examination

Vital signs (Height, pulse, blood pressure, respiration rate, temperature and weight)

Complete medical history, including current medications and baseline conditions

Performance status (Karnofsky Performance Status or Lansky Performance score)

Neurologic exam

Pulse oximetry

Laboratory assessments
o
Complete Blood Count (CBC) with differential and platelet count
o
Blood chemistry assessment, including:

Sodium, potassium, chloride, bicarbonate, calcium, fasting glucose, albumin,
total protein, BUN, serum creatinine.

Total bilirubin, AST, ALT, alkaline phosphatase, uric acid, phosphorus,

Fasting serum lipid profile (total cholesterol, triglycerides, HDL and LDL)
o
Coagulation assessment, including prothrombin time, partial thromboplastin time,
international normalized ratio (PT/PTT/INR)
o
Hepatitis B and C screening (including HBsAg and HCVAb). Should be done at
screening and then as clinically indicated.
o
Serum or urine pregnancy test - Only if participant is a female of child bearing age;
pregnancy test should be done at screening and monthly thereafter (± 3 days within
Day 1 of each cycle).

Imaging (Magnetic Resonance Imaging) of brain with gadolinium and echoplanar
diffusion for tumor/lesion assessment.  Spine MRIs should be performed if clinically
indicated.  Screening scans may be done within 21 days of beginning study treatment.
See Imaging Guidelines (Appendix 4) for specifics.

Electrocardiogram (ECG) – to be performed at screening and then as clinically indicated

Chest X-Ray - If clinically indicated.  If pulse oximetry is less than 93% on room air
patient should get a CXR monthly until pulse oximetry is >93. May be done within 21
days of beginning study treatment

Archival tumor tissue collection –tumor samples from a prior surgery will be used to test
for molecular analyses. Appendix 3 or an email from the pathology department may be
used to confirm tissue availability at the time of enrollment. The tissue itself must be
submitted within 90 days of registration (see appendix 8).
5.2
Treatment Period
Clinical assessments will be required after the first and second cycle, and then every 2 cycles 
through cycle 13, and finally every 3 cycles until end of treatment unless more frequent 
monitoring is clinically indicated. After 4 weeks of treatment, a toxicity check will be performed 
as outlined in Table 5.1. Whenever possible, all assessments at each scheduled time-point will 


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be completed in a single clinic visit.  Evaluations can be obtained within ± 3 days from a 
scheduled time point unless otherwise noted. 
All relevant information regarding drug doses, concomitant medications and doses, evaluable 
lesions with measurements, tumor response, laboratory examinations, and treatment-related 
toxicities shall be documented in the patient’s medical record and flow sheets. Patients will 
maintain a treatment diary while on therapy. The Treatment Diary will be initiated on Day 1 of 
therapy and continue throughout treatment. Treatment Diaries will be collected from the patient 
during clinical follow up per study calendar until the patient discontinues therapy.
5.2.1
Study Procedures, Cycle 1, Day 1 
Day 1 procedures do not need to be repeated if done within 14 days prior during screening 
assessments.  MRI does not need to be repeated if done within 21 days prior.

Physical examination

Evaluation of adverse events

Concomitant medications

Vital signs 

Performance status

Neurologic exam 

Laboratory assessments
o
Complete Blood Count (CBC) with differential and platelet count
o
Blood chemistry assessment (see Screening Assessments for complete list)
o
Coagulation assessment
o
Pregnancy test- if a female of childbearing age

Pulse oximetry

Chest X-ray – if clinically indicated

Brain MRI –does not need to be repeated if done within 21 days prior during screening

Spinal MRI – if clinically indicated

Research blood (required) and Fresh Frozen Tissue (optional, if available) for genomic 
DNA isolation within (+90) days of registration for genomic profiling studies (see 
Appendix 8).
5.2.2 Study Procedures, Cycle 1, Day 15

Laboratory assessments
o
Complete Blood Count (CBC) with differential and platelet count
o
Blood chemistry assessment (see Screening Assessments for complete list)
5.2.3 Study Procedures, Cycle 2, Day 1 

Physical examination

Evaluation of adverse events

Concomitant medications


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
Vital signs 

Performance status

Neurologic exam 

Laboratory assessments
o
Complete Blood Count (CBC) with differential and platelet count
o
Blood chemistry assessment (see Screening Assessments for complete list)
o
Pregnancy test – if a female of childbearing age

Pulse oximetry

Chest X-ray – if clinically indicated
5.2.4 Study Procedures, Cycle 2, Day 15

Laboratory assessments
o
Complete Blood Count (CBC) with differential and platelet count
o
Blood chemistry assessment (see Screening Assessments for complete list)
5.2.5 Study Procedures, Cycle 3, 5, 7, 9, 11, 13, 16, 19, 22, Day 1

Physical examination

Evaluation of adverse events

Concomitant medications

Vital signs 

Performance status

Neurologic exam 

Laboratory assessments
o
Complete Blood Count (CBC) with differential and platelet count
o
Blood chemistry assessment (see Screening Assessments for complete list)
o
Pregnancy test – if a female of childbearing age

Pulse oximetry

Chest X-ray – if clinically indicated

Brain MRI (+/- 7 days)

Spinal MRI – if clinically indicated
5.2.6 Study Procedures, Cycles 4, 6, 8, 10, 12, 14, 15, 17, 18, 20, 21, 23, and 24, 
Day 1 

Laboratory assessments
o
Complete Blood Count (CBC) with differential and platelet count
o
Blood chemistry assessment (see Screening Assessments for complete list)
o
Pregnancy test – if a female of childbearing age


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5.2.7
Study Procedures, End-of-Treatment 
After 24 cycles of treatment with everolimus, patients will have completed the protocol-defined 
treatment period and will be considered “off-treatment”. Patients may continue on treatment with 
everolimus, based on the recommendation of the treating physician; however, Novartis will not 
sponsor these efforts.  
The following assessments must be performed within 30 days after the last dose unless these 
have been evaluated within 14 days prior to the last dose. 

Physical examination

Evaluation of adverse events

Concomitant medications

Vital signs

Performance Status

Neurologic exam

Laboratory procedures -
o
Complete Blood Count (CBC) with differential and platelet count
o
Blood chemistry assessment (see Screening Assessments for complete list)
o
Coagulation assessment (see Screening Assessments for complete list)
o
Pregnancy test – if a female of childbearing age

Pulse oximetry

Chest X-ray – if clinically indicated

MRI if not performed within the past 12 weeks.
In addition to assessments due at the End of Treatment, a separate 30-day Toxicity Check is 
required for all patients. The toxicity check can be done via phone at 30 days after the last dose 
(+7 days). 

Evaluation of adverse events (All study drug related adverse events must continue to be
followed until resolution or return to baseline).

Review of concomitant medications
Patients removed from protocol therapy for unacceptable adverse events while on treatment 
and/or within 30 days of the last administration of study drug will be followed until resolution or 
return to baseline of the adverse event.
5.2.8
Study Procedures, Long Term/Survival Follow-up Procedures
Patients off protocol therapy will continue to be followed for PFS, OS and start of new treatment 
for up to five years after initiation of protocol therapy or patient death, whichever is earlier. 
All patients will be followed until resolution (or return to baseline) of all adverse events occurring 
while on treatment and/or within 30 days of the last administration of study drug. Toxicities that 
are related to study therapy and are ongoing at the end of day 30 after last treatment date will 
be followed until resolution or return to baseline. Patients who are Off-treatment will be followed 
to collect any adverse events that are possibly, probably or definitely related to the study drug 


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as well as the date of progression, date of last contact and date of death. Post treatment the 
patient’s status is to be reported every follow-up visit for neuroimaging and/or clinical evaluation. 
The requested follow-up data is to be collected every three months (+/- 30 days) from the date 
the patient went off treatment. Please refer to Appendix 7 for submission deadlines.
The following elements are captured during the long-term follow-up: 

Patient Status 

Date of progression and associated disease assessments 

Date of last contact 

Date of death 
5.3
Interruption or discontinuation of treatment
For patients who are unable to tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted in order to keep the patient on study drug. If administration of everolimus must be 
interrupted because of unacceptable toxicity, drug dosing will be interrupted or modified according 
to rules described in Table 5.3. Toxicity will be assessed using the NIH-NCI Common Terminology 
Criteria for Adverse Events, version 4.0 (CTCAEv4.0, If a patient requires a dose delay of ≥ 3 
weeks from the intended day of the next scheduled dose, then the patient must be discontinued 
from treatment.
All interruptions or changes to study drug administration must be recorded.
It will be documented within OnCore® whether or not each patient completed the clinical study. If 
for any patient either study treatment or observations were discontinued the reason will be 
recorded in OnCore® and a deviation report will be submitted if applicable. 
Table 5.2   
Everolimus dose level modification guidelines
Dose level
Dose and schedule
0 (starting dose)
5 mg/m2 daily
-1
2.5 mg/m2 daily
-2
2.5 mg/m2 mg every other day
Table 5.3
Criteria for dose-modification in case of suspected everolimus toxicity and 
re-initiation of everolimus treatment 
Toxicity
Actions
Non-hematological toxicity
Grade 2 
(except pneumonitis – refer to Table 5.4)
If the toxicity is tolerable to the patient, 
maintain the same dose. If the toxicity is 
intolerable to patient, interrupt 
everolimus until recovery to grade  1. 
Then reintroduce everolimus at same 
dose.
If event returns to intolerable grade 2, 
then interrupt everolimus until recovery 


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to grade 1. Then reintroduce 
everolimus at the lower dose level. 
Grade 3
(except hyperlipidemia*)
(except pneumonitis – refer to Table 5.4)
Interrupt everolimus until recovery to 
grade 1. Then reintroduce everolimus 
at the lower dose level. For pneumonitis 
consider the use of a short course of 
corticosteroids.
Grade 4
Discontinue everolimus.
Hematological toxicity
Grade 2 Thrombocytopenia (platelets <75, ≥ 
50x109/L) 
Interrupt everolimus until recovery to 
grade 1 (>75 x109/L). Then reintroduce 
everolimus at initial dose.
If thrombocytopenia again returns to 
grade 2, interrupt everolimus until 
recovery to grade 1. Then reintroduce 
everolimus at the lower dose level. 
Grade 3 Thrombocytopenia (platelets <50, ≥ 25 x109/L)
Interrupt everolimus until recovery to 
grade ≤1 (platelets ≥ 75 x109/L).  Then 
resume everolimus at one dose level 
lower.  If grade 3 thrombocytopenia 
recurs, discontinue everolimus.
Grade 4 Thrombocytopenia (platelets < 25 
x109/L)
Discontinue everolimus.
Grade 3 Neutropenia (neutrophils <1, ≥0.5 
x109/L)
Interrupt everolimus until recovery to 
grade 1 (neutrophils ≥ 1.5 x 109/L). 
Then resume everolimus at the initial 
dose.  If ANC again returns to Grade 3, 
hold everolimus until the ANC ≥ 1.5 x 
109/L.  Then resume everolimus dosing 
at the lower dose level.  Discontinue 
patient from study therapy for a third 
episode of grade 3 neutropenia.
Grade 4 Neutropenia (neutrophils < 0.5 x109/L)
Interrupt everolimus until recovery to 
grade  1  (neutrophils ≥ 1.5 x 109/L). 
Then resume everolimus at the lower 
dose level. If grade 3 or grade 4 
neutropenia occurs despite this dose 
reduction, discontinue everolimus.
Grade 3 febrile neutropenia (not life-threatening)
Interrupt everolimus until resolution of 
fever and neutropenia to grade ≤ 1. Hold 
further everolimus until the ANC ≥ 
1,500/mm3 and fever has resolved. Then 
resume everolimus at the lower dose 


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level. If febrile neutropenia recurs, 
discontinue everolimus.
Grade 4 febrile neutropenia (life-threatening)
Discontinue everolimus.
Any hematological or non-hematological toxicity 
requiring interruption for ≥ 3 weeks
Discontinue everolimus
*Grade 3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should be 
managed using medical therapies (see Sec. 5.3.5).
5.3.1 Monitoring of everolimus suspected toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
abnormal laboratory value suspected to be related to everolimus must be followed at least weekly 
until the adverse event or abnormal laboratory resolves or returns to grade 1. If a patient requires 
a dose delay of ≥ 3 weeks from the intended day of the next scheduled dose, then the patient 
must be discontinued from the study.
5.3.2 Known Undesirable Side Effects of everolimus
The data described below reflect exposure to everolimus (n=274) and placebo (n=137) in a 
randomized phase III study for the treatment of metastatic renal cell carcinoma. In total, 165 
patients were exposed to everolimus 10 mg/day for ≥4 months. The median age of patients was 
61 years (range 27 to 85). The most common adverse reactions (incidence ≥10%) were stomatitis, 
rash, fatigue, asthenia, diarrhea, anorexia, nausea, mucosal inflammation, vomiting, cough, 
peripheral edema, infections, dry skin, epistaxis, pruritus, and dyspnea. The most common grade 
3-4 adverse reactions (incidence ≥2%) were infections, stomatitis, fatigue, and pneumonitis. 
Amenorrhea has been observed in two phase 3 studies of patients with TSC, Amenorrhea 
occurred in 17% of AFINITOR-treated females aged 10 to 55 years (3 of 18) and none of the 
females in the placebo group in one trial. For this same group of AFINITOR-treated females, the 
following menstrual abnormalities were reported: dysmenorrhea (6%), menorrhagia (6%), 
metrorrhagia (6%), and unspecified menstrual irregularity (6%). In a second trial, Amenorrhea 
occurred in 15% of AFINITOR-treated females (8 of 52) and 4% (1 of 26) of females in the placebo 
group. Other adverse reactions involving the female reproductive system were menorrhagia 
(10%), menstrual irregularities (10%), and vaginal hemorrhage (8%). (RAD001/Everolimus 
Investigator’s Brochure. Novartis Pharma AG. Edition 11, release date 15-Nov-2012).
The median duration of blinded study treatment was 141 days (range 19 to 451) for patients 
receiving everolimus and 60 days (range 21 to 295) for those receiving placebo. The rates of 
treatment-emergent adverse reactions resulting in permanent discontinuation were 7% and 0% 
for the everolimus and placebo treatment groups, respectively. Most treatment-emergent adverse 
reactions were grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were 
reported in 39% versus 7% of patients receiving everolimus and placebo, respectively. Deaths 
due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were 
observed on the everolimus arm.
Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, 
viral or protozoan 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.


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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.
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving 
chemotherapy (56). 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 (57). 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. Testing includes HBsAg 
and HCVAb at screening and then as clinically indicated. 
Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, 
dyspnea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or 
without respiratory impairment) have been observed with everolimus.
Hyperglycemia has been reported in clinical trials. Monitoring of fasting serum glucose is 
recommended prior to the start of everolimus therapy and periodically thereafter. Optimal 
glycemic control should be achieved before starting a patient on everolimus. Mouth ulcers, 
stomatitis and oral mucositis have been seen in patients treated with everolimus. In such cases 
topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should 
be avoided as they may exacerbate the condition. Antifungal agents should not be used unless 
fungal infection has been diagnosed.
Elevations of serum creatinine, usually mild, have been reported in clinical trials. Monitoring of 
renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, is 
recommended prior to the start of everolimus therapy and periodically thereafter.
Decreased hemoglobin, lymphocytes, platelets and neutrophils have been reported in clinical 
trials. Monitoring of complete blood count is recommended prior to the start of everolimus therapy 
and periodically thereafter.
Everolimus is not recommended in patients with severe hepatic impairment, (Child-Pugh class 
C).
The use of live vaccines and close contact with those who have received live vaccines should be 
avoided during treatment with everolimus.
Hypophosphatemia, hypomagnesemia, hyponatremia and hypocalcemia have been reported as 
serious adverse reactions. Electrolytes should be monitored in patients treated with everolimus.
Table 5.4 provides general recommendations for the management of patients, with suspected 
drug toxicities while on treatment with everolimus as single-agent therapy.
More detailed information regarding everolimus reported suspected toxicities and individual cases 
is provided in the RAD001/Everolimus Investigator’s Brochure. Novartis Pharma AG. Edition 11, 
release date 15-Nov-2012.
5.3.3 Management of Hepatitis reactivation/flare
In cancer patients with hepatitis B, whether carriers or in chronic state, use of antivirals during 
anticancer therapy has been shown to reduce the risk of hepatitis B virus (HBV) reactivation and 
associated HBV morbidity and mortality (57).


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Monitoring and prophylactic treatment for hepatitis B reactivation should occur based on the 
institutional standard for pediatric patients and in consultation with a pediatric gastrointestinal 
specialist and/or pediatric infectious disease.
5.3.4 Management of stomatitis/oral mucositis/mouth ulcers
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%) mouthwash 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 hydrogen peroxide, iodine, and thyme derivatives may tend to worsen
mouth ulcers. It is preferable to avoid these agents.
4. Antifungal agents must 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 their strong inhibition of everolimus metabolism, thereby
leading to higher everolimus exposures. Therefore, topical antifungal agents are preferred if
an infection is diagnosed. Similarly, antiviral agents such as acyclovir should be avoided
unless a viral infection is diagnosed.
Note:  Stomatitis/oral mucositis should be appropriately graded using the functional grading given 
on the NCI-CTCAE for adverse events, version 4.0.
5.3.5 Management of hyperlipidemia and hyperglycemia 
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary habits. 
Blood tests to monitor hyperlipidemia must be taken in the fasting state. Hyperlipidemia and 
hypertriglyceridemia should be treated according to local best clinical practice. Patients should be 
monitored clinically and through serum chemistry for the development of rhabdomyolysis and 
other adverse events as required in the product label/data sheets for HMG-CoA reductase 
inhibitors.
Hyperglycemia has been reported in clinical trials. Monitoring of fasting serum glucose is 
recommended prior to the start of everolimus therapy and periodically thereafter. Optimal 
glycemic control should be achieved before starting trial therapy.
5.3.6 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 (see Section 5.3.2 Adverse drug reactions). Some of these have been severe and on 
rare occasions, a fatal outcome was observed. 


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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. If symptoms are 
moderate (Grade 2), consideration should be given to interruption of therapy until symptoms 
improve. The use of corticosteroids may be indicated. Everolimus may be reintroduced at a 
reduced dose until recovery to Grade 1 or better. 
For cases where symptoms of non-infectious pneumonitis are severe (Grade 3), everolimus 
therapy should be discontinued and the use of corticosteroids may be indicated until clinical 
symptoms resolve. Therapy with everolimus may be re-initiated at a reduced dose depending on 
the individual clinical circumstances.
More detailed information regarding everolimus reported suspected toxicities and individual cases 
is provided in the RAD001/Everolimus Investigator’s Brochure. Novartis Pharma AG. Edition 11, 
release date 15-Nov-2012.


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Table 5.4
Management of non-infectious pneumonitis
Worst Grade 
Pneumonitis
Required 
Investigations
Management of 
Pneumonitis 
Everolimus Dose 
Adjustment
Grade 1
CT scans with lung 
windows and pulmonary 
function testing 
including: spirometry, 
DLCO, and room air O2 
saturation at rest. 
Repeat chest x-ray/CT 
scan every 2 Cycles until 
return to baseline.
No specific 
therapy is 
required
Administer 100% of 
everolimus dose.
Grade 2
CT scan with lung 
windows and pulmonary 
function testing 
including: spirometry, 
DLCO, and room air O2 
saturation at rest. 
Repeat each subsequent 
Cycle until return to 
baseline. Consider 
bronchoscopy * 
Symptomatic 
only. Prescribe 
corticosteroids if 
cough is 
troublesome.
Reduce everolimus dose 
until recovery to ≤ Grade 1. 
Everolimus may also be 
interrupted if symptoms are 
troublesome. Patients will be 
withdrawn from the study if 
they fail to recover to ≤ 
Grade 1 within 3 weeks.
Grade 3
CT scan with lung 
windows and pulmonary 
function testing 
including: spirometry, 
DLCO, and room air O2 
saturation at rest. 
Repeat each subsequent 
Cycle until return to 
baseline. Bronchoscopy 
is recommended *
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated.
Hold treatment until recovery 
to ≤ Grade 1. May restart 
protocol treatment within 2 
weeks at a reduced dose (by 
one level) if evidence of 
clinical benefit.
Patients will be withdrawn 
from the study if they fail to 
recover to ≤ Grade 1 within 2 
weeks. 
Grade 4
CT scan with lung 
windows and required 
pulmonary function 
testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. Repeat each 
subsequent Cycle until 
return to baseline. 
Bronchoscopy is 
recommended *.
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated.
Discontinue treatment.
*A bronchoscopy with biopsy and/or bronchoalveolar lavage is recommended.
5.3.7 Febrile neutropenia
Febrile neutropenia should be managed according to the local institutional guidelines.


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Measures include laboratory testing, blood and urine cultures, and institution of broad
spectrum antibiotics.
5.3.8 Diarrhea
Follow the loperamide dosing guidelines in Table 5.5 for patients experiencing diarrhea. 
Prophylactic administration is NOT recommended. Patients are advised to call with first signs of 
poorly formed stools or an increased frequency of bowel movements.
5.3.9 Neurosurgical Procedures
If a neurosurgical procedure is required for a reason other than tumor progression (i.e. the onset 
of hydrocephalus), these procedures should be documented, but will not constitute criteria for 
declaring the patient “off therapy”. Everolimus should be held until the patient is clinically stable 
and has recovered from the acute effects of surgery.
5.4
Treatment Plan
5.4.1 Everolimus Administration
The study drug everolimus will be self-administered (by the patients themselves). The investigator 
will instruct the patient to take the study drug exactly as specified in the protocol. Everolimus 
should be administered orally once daily, preferably in the morning, at the same time every day 
with or without food. 
The tablets should be swallowed whole with a glass of water and should not be chewed or 
crushed. For patients unable to swallow tablets, the tablet(s) should be dispersed completely in a 
glass of water (containing approximately 30 mL) by gently stirring, immediately prior to drinking. 
The glass should be rinsed with the same volume of water and the rinse completely swallowed to 
ensure the entire dose is administered.
Everolimus will be administered orally as once daily continuously from study day 1 until 
progression of disease or unacceptable toxicity. 
If vomiting occurs, no attempt should be made to replace the vomited dose. 
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded.
Table 5.5        Weight Specific Guidelines for Therapeutic Use of Loperamide
Weight (kg)
Initial (Loading) 
Loperamide dose 
(mg)
Subsequent daytime 
loperamide dose
Subsequent 
nighttime loperamide 
dose
8-10
1
0.5 mg q 3h
0.75 mg q4h
10-20
1
1 mg q 3h
1mg q 4h
20-30
2
1mg q 3h
2mg q 4h
30-43
2
1mg q 2h
2 mg q 4h
>42
4
2mg q 2h
4 mg q4h


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Medication labels will comply with US legal requirements and be printed in English. They will 
supply no information about the patient. The storage conditions for study drug will be described 
on the medication label.
5.4.2 Concomitant therapy
Patients will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without prior consultation with the investigator. At each 
visit, the investigator will ask the patient about any new medications he/she is or has taken after 
the start of the study drug.
All Concomitant medications/Significant non-drug therapies taken ≤ 30 days prior to start and 
after start of study drug, including physical therapy and blood transfusions, should be recorded.
The following restrictions apply during the entire duration of the study:

No other investigational therapy should be given to patients.

No anticancer agents other than the study medication should be given to patients. If such
agents are required for a patient then the patient must first be withdrawn from the study.

Oral contraceptives in preclinical and clinical data have shown everolimus to have CYP3A4
inhibitory activity rather than induction activity, induction of metabolism of contraceptive
hormones by everolimus is unlikely. Consequently, administration of everolimus should not
reduce the efficacy of oral contraceptives.
Inhibitors of CYP3A4 and/or PgP
Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) or 
P-glycoprotein (PgP) should be avoided.
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or PgP 
inhibitors should be used with caution.  If patient requires co-administration of moderate CYP3A4 
inhibitors or PgP inhibitors, reduce the dose of everolimus to 2.5 mg daily. Additional dose 
reductions to every other day may be required to manage toxicities. If the inhibitor is discontinued 
the everolimus dose should be returned to the dose used prior to initiation of the moderate 
CYP3A4/PgP inhibitor after a washout period of 2 to 3 days.
Seville orange, star fruit, grapefruit and their juices affect P450 and PgP activity. Concomitant use 
should be avoided.
Inducers of CYP3A4 and/or PgP
Avoid the use of strong CYP3A4 inducers. 
Table 5.6
Clinically relevant drug interactions: substrates, inducers, and inhibitors of 
isoenzyme CYP3A
SUBSTRATES
Antibiotics:
Clarithromycin, erythromycin, telithromycin
Calcium channel blockers:
Amlodipine, diltiazem, felodipine, 
lercanidipine, nifedipine, nisoldipine, 
nitrendipine, verapamil


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Anti-arrhythmics:
Quinidine
HMG CoA reductase inhibitors:
Cerivastatin, lovastatin, simvastatin
Benzodiazepines:
Alprazolam, diazepam, midazolam, triazolam
Steroid 6beta-OH:
estradiol, 
hydrocortisone, 
progesterone, 
testosterone
Immune modulators:
Cyclosporine, tacrolimus (FK506)
HIV Antivirals:
Indinavir, nelfinavir, ritonavir, saquinavir
Prokinetic:
Cisapride
Antihistamines:
Astemizole, chlorpheniramine, terfenadine
Miscellaneous:
Alfentanil, aprepitant, aripirazole, buspirone,  
cafergot, 
caffeine, 
cilostazol, 
cocaine, 
codeine-N-demethylation, 
dapsone, 
dexamethasone, 
dextromethorphan, 
docetaxel domperidone, eplerenone, fentanyl, 
finasteride, 
Gleevec/imatinib, 
haloperidol, 
irinotecan, LAAM, lidocaine, methadone, 
nateglinide, 
ondansetron, 
pimozide, 
propranolol, quetiapine, quinine, risperidone, 
salmeterol, sildenafil, sirolimus, sorafenib, 
sunitinib, tamoxifen, taxol, terfenadine, torisel, 
trazodone, vincristine, zaleplon, ziprasidone, 
zolpidem
INDUCERS
Barbiturates, carbamazepine, glucocorticoids, modafinil, oxcarbazepine, phenobarbital, 
phenytoin, pioglitazone, rifabutin, rifampin, St. John’s wort, troglitazone, efavirenz, nevirapine
INHIBITORS
Strong inhibitors: 
indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, 
saquinavir, telithromycin, 
Posaconazole (58)
Moderate inhibitors: 
aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil, 
Weak inhibitors:
Cimetidine, 
Seville orange (59)
Unclassified as per the Indiana University DDI listing:
Ciprofloxacin, delaviridine, troleandamycin, mibefradil, amiodarone, chloramphenicol, 
diethyldithiocarbamate, fluvoxamine, starfruit, gestodene, imatinib, mifepristone, norfloxacin, 
norfluoxetine, voriconazole*,


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Based on http://medicine.iupui.edu/clinpharm/ddis/table.asp as of December 01, 2009    
* Voriconazole (unclassified as per the Indiana University DDI table)
Strong inhibitor according to the following reference:
(http://www.nature.com/clpt/journal/v80/n5/pdf/clpt2006438a.pdf)
Table 5.7   
Clinically relevant drug interactions mediated by PgP
PgP Substrates
PgP Inhibitors in vivo
PgP Inducers
digoxin, fexofenadine, 
indinavir, vincristine, 
colchicine, topotecan, 
paclitaxel
amiodarone, azithromycin, 
captopril, carvedilol, 
clarithromycin, conivaptan, 
cyclosporine, diltiazem, 
elacridar, erythromycin, 
felodipine, (GF120918), 
itraconazole, ketocoanzole, 
lopinavir, (LY335979), 
mibefradil, nifedipine, 
nitrendipine, (PSC833), 
quinidine, ranolazine, 
ritonavir, talinolol, valspodar, 
verapamil
rifampin, St John’s wort
Reference:
Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Dec. 2, 2009, 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. " 
NOTES:http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM07
2101.pdf
**This list of clinically relevant drug interactions is updated as of December 02, 2009**

Seville orange, star fruit, grapefruit and their juices affect P450 and PgP activity. Concomitant
use should be avoided

No chronic treatment with systemic steroids or other immunosuppressive agents. Topical or
inhaled corticosteroids are allowed.

The use of live vaccines and close contact with those who have received live vaccines
should be avoided during treatment with everolimus. Examples of live vaccines include
intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and
TY21a typhoid vaccines.
Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no interaction with 
everolimus is expected. However, drug-drug interaction studies between macrolide antibiotics 
and warfarin have produced mixed outcomes and the disparity in these findings has led to the 
conclusion that multiple factors may alter the clearance of warfarin. The co-administration of 
everolimus and oral anticoagulants is possible but should be subject to verification of coagulation 
(INR) once steady state is reached (after one week’s treatment).
Examples are provided in Table 5.7 (CYP3A4 inhibitors/inducers) and Table 5.8 (Drug 
interactions mediated by P-glycoprotein). A comprehensive list of cytochrome P450 isoenzymes 
and 
CYP3A4 
inhibitors, 
inducers, 
and 
substrates 
can 
be 
found 
at 


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http://medicine.iupui.edu/flockhart.  This website is continually revised and should be checked 
frequently for updates.
5.5
Reasons to Withdraw a Subject
The Investigator will withdraw a patient whenever continued participation is no longer in the 
patient’s best interests.  Reasons for withdrawing a patient include, but are not limited to, 
disease progression, the occurrence of an adverse event or a concurrent illness, a patient’s 
request to end participation, or simply significant uncertainty on the part of the Investigator that 
continued participation is prudent.  There may also be administrative reasons to terminate 
participation, such as concern about a patient’s compliance with the prescribed treatment 
regimen.
5.6
Off Treatment Criteria
The “Off Treatment Date” and reason for discontinuation must be documented by the attending 
investigator in the medical record and recorded in two places within OnCore®, in the ‘Follow-Up’ 
section of OnCore® as well as in the ‘PNOC End of Treatment eCRF’
The “Off Arm Date” must be documented in the ‘Treatment’ section of OnCore®. The ‘Off Arm 
Date” should correspond with the “Off Treatment Date” and is the date the patient was 
discontinued from protocol treatment. 
The “Last Treatment Date” is recorded in two places within OnCore®, in the ‘Follow-Up section 
of OnCore®’ as well as in the ‘PNOC End of Treatment eCRF’. “Last Treatment Date” is defined 
as the last date that the patient received protocol based therapy.  
Patients will be considered Off Treatment for the following reasons:

Development of unacceptable toxicity

Progressive disease (PD).

Development of a medical or psychiatric illness, that in the investigator's judgment
renders the patient incapable of further therapy on this protocol

The patient, parent or legal guardian refuses further treatment on this protocol

Completion of all protocol defined treatment

Pregnancy
Patients who are off protocol therapy must be followed until an “Off Study Criterion” is met.  All 
patients will be followed until resolution (or return to baseline) of all adverse events occurring 
while on treatment and/or within 30 days of the last administration of study drug. Toxicities that 
are related to study therapy and are ongoing at the end of day 30 of last treatment date will be 
followed until resolution or return to baseline. Patients who are Off-treatment will be followed to 
collect any adverse events that are possibly, probably or definitely related to the study drug as 
well as the date of progression, date of last contact and date of death. The requested follow-up 
data is to be submitted quarterly from the date the patient went off treatment. 
5.7
Off Study Criteria
The date and reason for the patient coming off study must be documented in the ‘Follow-Up’ 
section of OnCore® as well as the ‘PNOC End of Treatment eCRF’. 
Patients will be considered Off Study for the following reasons:


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
Patient determined to be ineligible.

Parent, patient, or guardian withdraws consent for continued participation.

Patient death while on study.

Completion of protocol specific follow up period
No data will be collected documenting treatment or reporting events or disease status that occur 
subsequent to the official “off study” date.
6
Correlative Studies and Pathology Review
Pathology will be reviewed in the UCSF pathology department (Dr. Joanna Phillips and Dr. Arie 
Perry, Department of Neuropathology, UCSF).  
6.1
Obtaining tissue and blood samples
Please refer to Appendix 8 for more information.
6.2
Preparation of tissue samples
Please refer to Appendix 8 for more information.
6.3
Review of FFPE tissue samples
Pathology Materials Required for Review:

A copy of the Pathology Report

A  PNOC Specimen Submission Form

Tissue
A UCSF neuropathologist will review all H&E slides and will determine if the histology 
corresponds to the report and if it is appropriate for the study.  
If applicable, the neuropathologist will also choose the blocks from which to prepare unstained 
slides for additional analysis. 
In general, one to two representative H&E stained slides from a pre-registration biopsy and 
when available from the original surgery will be reviewed.
6.4
Immunohistochemical and molecular assays
All tumor tissue will be analyzed to assess the activation status of the PI3K/Akt/mTOR signaling 
pathway.  In addition, all tumors will be molecularly profiled based upon known alterations in 
pediatric astrocytomas.  First, tumors will be stratified into one of two categories, high 
PI3K/Akt/mTOR pathway activity and low PI3K/Akt/mTOR pathway activity, based upon the 
results of immunohistochemistry for phosphorylated-S6 ribosomal protein (Ser240/244) as 
described below.  Second, all tumor tissue samples will be further characterized by 
immunohistochemistry, tumor-DNA sequencing, and FISH, as described below.
For immunohistochemistry, all antigens to be assayed in this protocol are cytoplasmic, nuclear, 
or membranous and will be scored using a semi-quantitative scale as described herein.  The 
designated neuropathologists will identify areas of tumor on the glass slide that are 
appropriately stained with the antibody, and will review the positive and negative control 
samples.  The neuropathologist will then determine the ratio of tumor cells staining positive to 


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those staining negative for the particular antibody. This interpretation does not consider intensity 
of staining per cell, but defines as “positive” all cells staining with a similar pattern to positive 
control cells.   In general, immunohistochemical assays will be scored using a four-tiered system 
based on the extent of positive tumor cells staining positive:  0, no positive staining; 1, positive 
staining in less than or equal to 25% of the tumor cells; 2, positive staining in greater than 25% 
but less than or equal to 75% of the tumor cells; 3, positive staining in greater than 75% of the 
tumor cells. 
Visual estimation may be aided by dividing the interpretable areas of the tissue on the slide into 
four quadrants using a tissue marker. This scoring system has been previously used and 
representative images are illustrated (32). Based on our experience assessing activity of the 
PI3K/Akt/mTOR pathway in formalin fixed paraffin-embedded tumor sections, we will stratify 
patients into two categories based upon the results of immunohistochemistry for 
phosphorylated-S6 ribosomal protein (Ser240/244). PI3K/AKT/mTOR activated tumors will be 
those with a score of 2 or higher.
In addition to phosphorylated-S6 ribosomal protein (Ser240/244) we will also analyze the 
expression and phosphorylation of other proteins in the pathway by immunohistochemistry with 
the antibodies listed in Table 6.1 and score them as described above.  
Table 6.1
Summary of Assays to evaluate activation of the PI3K/AKT/mTOR pathway
Molecular feature
Assay (reagents)
PTEN expression
IHC: Cell Signaling  #9559  (Rabbit)
Phosphorylated S6 235/236 
IHC: Cell Signaling  #2211 (Rabbit)
Phosphorylated S6 240/244
IHC: Cell Signaling  #2215  (Rabbit)
Phosphorylated PRAS40 (pT246) 
IHC: Cell Signaling  #2997 (Rabbit)
Phosphorylated 4EBP1
IHC: Cell Signaling #2855 (Rabbit)
Phosphorylated Erk1/2
IHC:  Zymed #18-2389 (Rabbit)
PTEN promoter methylation
Methylation-specific primers as described
To further characterize the paired tumor tissue samples we will perform additional assays if not 
already available including: immunohistochemistry to determine p53 expression and MIB-1 
labeling index; sequencing of tumor DNA to detect the BRAFV600E mutation; and FISH on 
formalin fixed paraffin-embedded samples to determine PDGFRA amplification, CDKN2A loss, 
and KIAA1549-BRAF gene fusion.  
All immunohistochemistry assays will be performed on the Ventana Medical Systems 
Benchmark XT on a research basis but in a CLIA certified laboratory. Positive controls will 
include paraffin tissue sections from glioblastomas that have been previously confirmed to 
overexpress the phospho-epitopes by Western blotting, and confirmed on 
immunohistochemistry with serial dilutions of the antibody. In addition, a subependymal giant 
cell astrocytoma from a tuberous sclerosis patient in which p-S6 is present due to mutation in 
TSC1/TSC2, will also be used as a positive control. For PTEN, endothelial cells serve as an 
internal positive control and glioblastomas with PTEN expression confirmed by Western blot are 
used as external positive controls.  
To examine whether the PTEN promoter is methylated in glioma specimens, we will use 
methylation-specific primers that had previously been used to demonstrate methylation of the 
PTEN promoter in a subset of non-small-cell-lung cancer samples. These primers amplify a 181 


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base pair region of the PTEN promoter that starts 2477 nucleotides from the translation start 
site. The methylation-specific PCR (MSP) assay is sensitive to approximately 5% methylated 
product (31).
In addition to the targeted approaches described above that examine previously reported 
alterations additional genomic profiling studies will be performed including targeted sequencing, 
RNA sequencing, and/or exome (plus) next generation sequencing if sufficient tissue is 
available.  Such studies will include but are not limited to molecular analyses of DNA, RNA and 
protein in tumor biopsy specimens including fresh frozen tissue and blood as control. When 
possible and/or sufficient blood/tissue is provided sample will be used to establish tumor cell 
cultures, cell lines and/or transplantation models. 
DNA and RNA will be isolated and stored in the laboratory of Sabine Mueller, University of San 
Francisco 
 using the 
QIAamp DNA kit and the QIAamp RNA blood mini kit or similar available DNA and RNA 
isolation kits. DNA and RNA from tissue and blood will be stored at -80 degrees indefinitely for 
potential future genetic studies to further characterize pediatric low-grade gliomas.  These 
studies will be carried out in collaboration with Dr. Adam Resnick, Children’s Hospital of 
Philadelphia (CHOP). The samples (DNA and RNA) sent to CHOP will be de-identified. Patients 
may contact the study Co-Chair, Dr. Sabine Mueller 
at any time to 
request any remaining, identifiable samples be returned.
7
Reporting and Documentation of Results
7.1
Evaluation of Efficacy (or Activity)
The primary goal of this study is to evaluate efficacy as determined using 6-month progression 
free survival. Standard anatomic MRI in conjunction with clinical evaluation such as neurologic 
status and corticosteroid use remains the key determinant of response to therapy and the 
evaluation of tumor recurrence for low-grade glioma. Increase in contrast enhancement, 
worsening cerebral edema, and mass effect are traits of malignant transformation. Acquiring 
tissue samples to confirm tumor upgrade, although considered the “gold standard” for 
determining the presence of viable tumor, can result in both false positives and negatives that 
relate to sampling error.  Evaluating response in low-grade glioma by radiographic imaging is an 
accepted means of determining response and is the standard by which NIH grant-funded brain 
tumor consortiums operate.  Response will be determined by the bi-dimensional diameters.  
However, RECIST criteria will be collected and used for secondary evaluation.  Patients will 
have brain MRI scans with and without gadolinium performed prior to therapy, and before cycles 
3, 5, 7, 9, 11, 13, 16, 19, and 22. Spine MRIs should be performed prior to therapy and at the 
same time points as standard brain MRIs if clinically indicated.  
7.1.1
Definitions
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with the study drug.
Evaluable for objective response:  Only those patients who have measurable disease present at 
baseline, 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.)


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7.1.2 Disease Parameters
7.1.2.1
Methods for Evaluation of Measurable Disease
All measurements will be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations will be performed as closely as possible to the beginning of treatment and 
never more than 21 days before the beginning of the treatment.
The same method of assessment and the same technique will be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumor effect of a treatment.
Pathology Review
Pathology will be reviewed in the UCSF pathology department (Dr. Joanna Phillips and Dr. Arie 
Perry, Department of Neuropathology, UCSF).  This will not be part of the eligibility process but 
part of the final analysis upon study completion. 
Radiology Review
All objective responses must be reviewed by the neuro-oncology tumor board of UCSF. 
Exploratory analyses of perfusion and diffusion parameters will be assessed as predictive 
biomarkers of response.  Images will be viewed on PACS system and comparison will be made 
between the most recent MRI image and the previous MRI image.  Measurements and 
responses are judged based on criteria outlined below.  
For detailed imaging guidelines and transfer of images please see appendix 4. 
7.1.2.2 Response Criteria
Response Criteria for PNOC Trials
Measurable disease 
Measurable disease is defined as lesions that can be accurately measured in two dimensions 
(longest diameter to be recorded) with a minimum size of no less than double the slice 
thickness.
All tumor measurements will be recorded in millimeters or decimal fractions of centimeters.  
Previously irradiated lesions are considered non-measurable except in cases of documented 
progression of the lesion since the completion of radiation therapy.
Non-measurable disease
Non-measurable disease is all other lesions (or sites of disease), including small lesions. 
Leptomeningeal disease is non-measurable.
Target and Non-target lesion
Tumor dimensions are determined by measurement of the longest tumor dimension and its 
perpendicular for each target lesion. For most CNS tumors, only one lesion/mass is present and 
therefore is considered a “target” for measurement/follow up to assess for tumor 
progression/response. If multiple measurable lesions are present, up to 3 can be selected as 
“target” lesions. Target lesions should be selected on the basis of size and suitability for 
accurate repeated measurements. All other lesions will be followed as non-target lesions 


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(including CSF positive for tumor cells). The lower size limit of the target lesion(s) should be at 
least twice the thickness of the slices showing the tumor to decrease the partial volume effect.
Tumor Measurements
Regarding MRI imaging, the sequence that best highlights the tumor (T1 enhanced or T2 
weighted or FLAIR images) will be chosen to determine response criteria. The same sequence 
should be used for serial measurements. Response determination will be based on a 
comparison of an area [W (longest diameter of the target lesion) x T (transverse measurement, 
perpendicular to W)] between the baseline assessment and the study date designated in the 
follow-up Report Form. Reports for the follow-up exams should reiterate the measurements 
obtained at baseline for each target lesion. Nontarget lesions or newly occurring lesions should 
also be enumerated in these reports, and changes in non-target lesions should be described.
1. For MRI imaging (preferred), the longest diameter can be measured from the axial plane or
the plane in which the tumor is best seen or measured. The longest measurement of the tumor
is referred to as the width (W).
2. The perpendicular measurements should be determined - transverse (T) measurement,
perpendicular to the width in the selected plane.
3. The cystic or necrotic components of a tumor are not considered in tumor measurements.
Therefore only the solid component of cystic/necrotic tumors should be measured. If
cysts/necrosis composes the majority of the lesion, the lesion may not be “measurable”.
Options:

if the cyst/necrosis is eccentric, the W and T of the solid portion should be measured, the
cyst/necrosis will be excluded from measurement

if the cyst/necrosis is central but represents a small portion of the tumor (< 25%),
disregard and measure the whole lesion

if the cyst/necrosis is central but represents a large portion of the tumor, identify a solid
aspect of the mass that can be reproducibly measured

Leptomeningeal tumor spread is usually not a target lesion, and usually cannot be
measured accurately. Presence and location of leptomeningeal tumor spread should be
noted and change in extent/thickness assessed on follow up studies.
Overall Response Assessment:
The overall response assessment takes into account response in both the target and non-target 
lesion, and the appearance of new lesions, where applicable, according to the criteria described 
in the table below. The overall response assessment is shown in the last column, and depends 
on the assessments of target, non-target, and new lesions in the preceding columns. 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.
Target 
Lesion(s)
Non Target 
Lesion (s)
New 
Lesions
Overall 
Response
Best Response for this 
Category Also Requires
CR
CR
No
CR
> 8 weeks confirmation
CR
IR/SD
No
PR
> 8 weeks confirmation


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PR
CR/IR/SD
No
PR
SD
CR/IR/SD
No
SD
documented at least > 4 weeks 
from baseline
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR – Complete Response; PR – Partial Response; SD – Stable Disease; PD – Progressive Disease; IR – Incomplete 
Response
Response Criteria for Target/Non-Target Lesions:
Response criteria are assessed in 2 dimensions – the product of W x T.
To assess response/progression, the ratio is calculated: W x T (current scan) divided by W x 
T (reference scan). Development of new disease or progression in any established lesions is 
considered progressive disease, regardless of response in other lesions – e.g. when multiple 
lesions show opposite responses, the progressive disease takes precedence.
For purposes of this study, response criteria for target lesions are:
Complete Response (CR): Complete disappearance of all known disease for at least 8 weeks. 
Complete response is dated from the time all lesions have disappeared on a stable or 
decreasing dose of corticosteroids.
Partial response (PR): A reduction of at least 50% in the size of all measurable tumor as 
quantitated by the sum of the products of the largest diameters of measurable lesions and 
maintained for at least 8 weeks on a stable or decreasing dose of corticosteroids. Partial 
response is dated from the time of first observation. In addition, there can be no appearance of 
new lesions or progression of any lesion.
Stable Disease (SD): A decrease of <50% or an increase of <25% in the sum of the products of 
the largest diameters of measurable lesions and no evidence of new lesions for at least 4 weeks 
on a stable or decreasing dose of corticosteroids.
Progressive Disease (PD): ≥ 25% increase in the sum of the products of the largest diameters 
of the measurable lesions or the appearance of one or more new lesions. 
Progression free survival (PFS): PFS will be calculated at all times during follow-up, with 
particular interest in the 6-month time point. Progression free survival will be calculated from date 
of first treatment to the date of first observation of progressive disease, non-reversible 
neurological progression or increasing steroid requirements (applies to stable disease only), 
death due to any cause, or early discontinuation of treatment. 
Overall survival (OS): Overall survival will be calculated from date of original diagnoses to death 
and also from the date of study registration to death. The latter will be an endpoint for assessment 
of benefit of this therapy.


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7.2
Definitions of Adverse Events
7.2.1
Adverse Event
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related.  More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality.  An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. 
7.2.2
Adverse reaction
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event.
7.2.2.1 Suspected 
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the adverse event.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than an adverse reaction.
7.2.2.2 Unexpected 
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 
has been observed, or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure.  For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the investigator brochure.
Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation.  Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class 
effect, the first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes.


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7.2.2.3 Serious
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: 

Death,

Life-threatening adverse experience (See section 7.2.2.4 below),

Inpatient hospitalization or prolongation of existing hospitalization,

Persistent or significant disability/incapacity,

Congenital anomaly/birth defect, or cancer,

Any other experience that suggests a significant hazard, contraindication, side effect or
precaution that may require medical or surgical intervention to prevent one of the
outcomes listed above, or

Event that changes the risk/benefit ratio of the study.
Important medical events that may not result in death, are life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.
7.2.2.4 Life-threatening
An adverse event or suspected adverse reaction is considered life threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
7.3
Recording of an Adverse Event
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of study treatment and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is earlier. After 
this period, investigators should only report SAEs that are attributed to prior study treatment.
All Grade 3-5 adverse events will be entered into OnCore®, regardless of relationship.  Data 
about these events and their severity will be recorded using the NCI CTCAE v4.0.  
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below: 


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Relationship 
Attribution 
Description 
Unrelated
The AE is clearly NOT related to the 
intervention 
Unrelated to investigational 
drug/intervention
Unlikely
The AE is doubtfully related to the 
intervention 
Possible
The AE may be related to the intervention 
Probable
The AE is likely related to the intervention 
Related to investigational 
drug/intervention
Definite
The AE is clearly related to the intervention 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions:
Grade 0
No AE (or within normal limits)
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL)
Grade 
3:
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL
Grade 
4:
Life-threatening consequences; urgent intervention indicated
Grade 
5:
Death related to AE
7.4
Follow-up of Adverse Events
All adverse events will be followed with appropriate medical management until resolved or 
return to baseline.  Patients removed from study for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event.  For selected adverse events for 
which administration of the investigational drug was stopped, a re-challenge of the subject with 
the investigational drug may be conducted if considered both safe and ethical by the 
Investigator.
7.5
Adverse Events Monitoring 
The Investigator will assess all adverse events and follow reporting requirements to their 
institutional Data and Safety Monitoring Committee (DSMC) and Institutional Review Board 
(IRB).
All Adverse Events entered into OnCore® will be reviewed on a monthly basis by the PNOC 
Operations Office. The PNOC Operations Office will discuss the toxicity, grade, and relationship 
to study intervention for all AEs in question.
In addition, all adverse events and suspected adverse reactions considered “serious,” entered 
into OnCore® will be reviewed and monitored by the Data and Safety Monitoring Committee on 


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an ongoing basis, discussed at DSMC meetings which take place every six (6) weeks. For a 
detailed description of the Data and Safety Monitoring Plan please refer to Appendix 5.
Study Chair Reporting to Novartis
The study chair, co-chair or designee 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). 
All events must be reported, 
 to Novartis Pharmaceuticals DS&E 
Department within 24 hours of learning of its occurrence. 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 serious adverse event occurring after the patient has provided informed consent and until 4 
weeks after the patient has stopped study participation must be reported. This includes the 
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).
Serious adverse events occurring more than 4 weeks after study discontinuation need only be 
reported if a relationship to the Novartis study drug (or therapy) is suspected. 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator.
The date the SAE was sent to all required reporting agencies will be documented in the UCSF 
Clinical Trials Management System. 
7.6
Expedited Reporting
Participating Sites Reporting to Sponsor-Investigator (PNOC)
In addition to complying with all applicable regulatory reporting laws and regulations, each site 
must report the following:

All SAEs, regardless of relationship must be entered into the Subject Console in OnCore®
(https://oncore.ucsf.edu/) within one business day of first PI awareness, even if the SAE is
ongoing.  The SAE must be followed until resolution, and the OnCore® SAE record should
be updated immediately as new information becomes available.
Email notification to the PNOC Operations Office 
within one 
business day of first PI awareness:


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
Reports of pregnancy exposure (pregnancy encompasses the entire cycle of pregnancy and
delivery, perinatal and neonatal outcomes, even if there were no abnormal findings; both
maternal and paternal exposure is collected)

Reports of lactation exposure

Overdose (with or without an SAE)

Abuse (use for non-clinical reasons with or without an SAE)

Inadvertent or accidental exposure
Sponsor-Investigator (PNOC) Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the PNOC Operations Office will notify the DSMC Chair (or qualified 
alternate) within 1 business day of knowledge of the event.  The contact may be by phone or e-
mail. Each participating site will follow their institutional reporting guidelines to institutional 
DSMC. 
Sponsor-Investigator (PNOC)  Reporting to UCSF Institutional Review Board (IRB)
The PNOC Operations Office must report events meeting the UCSF IRB definition of 
“Unanticipated Problem” (UP) within 10 business days of awareness of the event. 
Each participating site will follow their institutional reporting guidelines to the IRB.
Sponsor-Investigator (PNOC) Reporting to Novartis
Investigators must report all SAEs to PNOC Operations Office within one business day of the 
Investigator’s first awareness of occurrence: PNOC will submit the completed safety report 
along with an Interventional Clinical Trial SAE Fax Cover Sheet to Novartis Pharmaceuticals 
within the timelines described below: 
All events, regardless of relationship, must be reported, by Email 
 OR Fax 
, to Novartis Pharmaceuticals 
DS&E Department within 24 hours of learning of their occurrence. 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 serious adverse event occurring after the patient has provided informed consent and until 4 
weeks after the patient has stopped study participation must be reported. This includes the 
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).
Serious adverse events occurring more than 4 weeks after study discontinuation need only be 
reported if a relationship to the Novartis study drug (or therapy) is suspected. 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator.
The date the SAE was sent to all required reporting agencies will be documented in the UCSF 
Clinical Trials Management System


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8
Statistical Considerations and Evaluation of Results
8.1
Study Endpoints
The primary objective of the proposed study is to estimate the efficacy of the proposed regimen 
based on the 6-month progression free survival rate (PFS6). More specifically, the primary aim 
is to determine whether the true, unknown, response observed prior to classical disease 
progression warrants additional study of everolimus in only those patients with activation of the 
PI3K/AKT/mTOR pathway measured by p-S6 positivity or the entire population of patients with 
symptomatic, progressive or recurrent pediatric low-grade glioma. 
In this setting of 2-staged phase II trials, the secondary objectives are considered exploratory.

PFS and OS distributions as well as objective response (CR+PR) rates associated with
everolimus treatment in recurrent pediatric LGGs.

Associations between activation of the PI3K pathway as measured by expression of
phospho-AKT, phospho-PRAS40, and phospho-4EBP1 and outcome as measured by
the 6-month disease stabilization rates as well as PFS for progressive or recurrent
pediatric low-grade glioma patients with measureable disease treated with everolimus.

Analyses of key molecular features including activation of the PI3K, mTOR and MAPK
pathways, aberrations in PTEN, p53, PDGFRA amplification, CDKN2A loss, and
activating mutations in BRAF (KIAA1549-BRAF fusion and BRAFV600E missense
BRAF mutation). In addition to the targeted approaches described above that examine
previously reported alterations additional genomic profiling studies will be performed
including targeted sequencing, RNA sequencing, and/or exome(plus) next generation
sequencing if sufficient tissue is available.  Such studies will include but are not limited
to molecular analyses of DNA, RNA and protein in tumor biopsy specimens and blood
samples.  When possible and/or sufficient blood/tissue is provided, sample will be used
to establish tumor cell cultures, cell lines and/or transplantation models. These studies
will be carried out in collaboration with Dr. Adam Resnick, Children’s Hospital of
Philadelphia.

MR quantitative measures of relative cerebral blood volume, permeability and apparent
diffusion coefficient within the region of hyper-intensity on T2-weighted images as
markers of disease response and/or progression in comparison to institutional
evaluation of disease response and/or progression and quantitative measures of tumor
response as determined by central review (based upon both area and volumetric
measures).
8.2
Determination of Sample Size and Accrual Rate
8.2.1
Sample Size and Power Estimate
To estimate the efficacy of everolimus we will employ an adaptive Simon two-stage design for 
Phase II studies of targeted therapies (60, 61) and depicted in Figure 1. In the first stage of the 
adaptive two-stage Phase II trial design, two parallel studies are initiated, one for non-activated 
PI3K/AKT/mTOR pathway (Pathnot-act) patients (enrolling 18 patients) and one for activated 
pathway (Pathact) patients (enrolling 7). Pathway activation is based on p-S6 positivity. Based on 
the results of the first stage, enrollment in the second stage will either be limited to Pathact 
patients or open to all subjects regardless of PI3K/AKT/mTOR activation status.


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If preliminary evidence in the first stage suggests efficacy of everolimus in Pathnot-act patients, 
enrollment in the second stage will be open to all patients regardless of activation status and a 
total of 65 patients will be enrolled. As detailed below, with α = 0.0512, the power for concluding 
efficacy when PFS6 is independent of PI3K/AKT/mTOR activation status is > 95%. If preliminary 
evidence in the first stage suggests efficacy of everolimus is limited to the Pathact patients, 
enrollment for the second stage will be restricted to only those patients and a total of 27 Pathact 
patients will be enrolled. As detailed below, with α = 0.0512, the power for concluding efficacy in 
the Pathact sub-population is 81%.
 Figure 1.  Adaptive Simon two-stage design for Phase II studies of targeted therapies
8.2.2
Accrual estimates
With the anticipated accrual numbers provided by the eight PNOC institutions, we anticipate that 
25-30 patients/year may be available. If we assume that 50% of these would be eligible for the
biology objective i.e. would have measureable disease and would have tissue available from
prior surgeries, we can expect that the interim analysis will take place within 2.5-3.5 years from
initiation of accrual, including the 6-month disease evaluation window. Hence at the time of the
interim analysis we expect to have accrued 25 patients.
If preliminary evidence in the first stage (at the interim analysis) suggests efficacy of everolimus 
is limited to the patients with pathway activation, an additional 20 pathway activated patients will 
be recruited. Assuming 50% of the eligible patients have pathway activation, we can expect 6-7 
patients per year for a full accrual in 5.5-6.5 years from initiation of accrual. If preliminary 
evidence in the first stage (interim analysis) suggests efficacy of everolimus is not limited to the 
patients with pathway activation, an additional 40 patients will be recruited regardless of their 
activation status. We can then expect 13-15 patients per year for a full accrual in 5.5-6.5 years 
from initiation of accrual. 


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8.3
Interim Analyses and Stopping Rules
The interim analysis will occur at or near the end of the first stage of the adaptive Simon 2-stage 
design for Phase II studies of targeted therapies. The first stage of this study design entails two 
parallel studies where accrual will stop, i.e. the trial will terminate early if evidence accumulates 
that the efficacy is lower than the acceptable levels. The probability of type I and type II errors 
will be set at 10%. The chosen values of these error probabilities reflect equal concerns for 
falsely continuing a regimen that is not effective and rejecting a regimen that has sufficient 
activity.
Accrual will continue until the first stage sample sizes are reached; however if the accrual is 
slow and current data with adequate follow-up indicates that the trial cannot result in expansion 
of the cohort beyond the first stage even if all future patients achieve PF status at 6 months, 
then the accrual will be stopped short of the planned sample size for the interim analysis. 
Similarly if this cohort is expanded beyond the interim analysis, i.e. beyond the first stage of the 
adaptive Simon 2-stage design and into the second stage, the accrual will continue until the final 
sample size is attained; however if the accrual is slow and current data with adequate follow-up 
indicates that the trial cannot result in a positive outcome even if all future patients achieve PF 
status at 6 months, then the accrual will be stopped short of the planned final sample size.
8.4
Analysis Plans
8.4.1
Analysis Population
Our primary analysis will be based on an intention to treat principle whereby all patients enrolled 
into the trial will be considered evaluable. All patients included in the study must be assessed 
for PFS6, even if there are major protocol treatment deviations or if they are ineligible.  Patients 
who die or are lost to follow-up prior to reaching the 6-month time point will be considered as 
failures for the PFS6 endpoint.
All conclusions should be based on all eligible patients.  Sub-analyses may then be performed 
on the basis of a subset of patients, excluding those for whom major protocol deviations have 
been identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these sub-analyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported. 
8.4.2
Primary Analysis (or Analysis of Primary Endpoints)
The primary objective of this study is to evaluate whether everolimus is active in only those 
patients with PI3K/AKT/mTOR pathway activation based on p-S6 positivity or in the population 
as a whole. To achieve this goal we will employ an adaptive Simon two-stage design for Phase 
II studies of targeted therapies (61). 
In the first stage of the adaptive two-stage Phase II trial design, two parallel studies are initiated, 
one for PI3K/AKT/mTOR non-activated (Pathnot-act) patients and one for PI3K/AKT/mTOR 
activated (Pathact) patients (see Figure 1). We expect that similar to the adult LGG population, 
approximately 50% of the patients will have PI3K/AKT/mTOR activation. Based on the results of 
the first stage, enrollment in the second stage will either be limited to Pathact patients or open to 
all subjects regardless of PI3K/AKT/mTOR activation status.  
First Stage: The two parallel first stage studies are identical to the first stage of Simon’s two-
stage optimal design. For both, everolimus will be deemed not worthy of further investigation, if 
the true PFS6 rate is less than 50%. To achieve an overall level α test of 0.05 the Type I error 


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rate for the two studies is set to α/2 = 0.025 while the Type II error probabilities are set at 0.2. 
For the Pathnot-act study everolimus will be of interest if the PFS6 is 70% or greater.  Thus 18 
Pathnot-act patients will be enrolled and everolimus will be considered preliminarily sufficiently 
active in this sub-population if 11 or more of the patients are PF at 6 months (the number of 
patients is denoted as PF1non-act in Figure 1). For the Pathact study everolimus will be of interest if 
the PFS6 is 80% or greater.  Thus 7 patients will be enrolled and everolimus will be considered 
preliminarily sufficiently active in this sub-population if 5 or more of the patients are PF at 6 
months (the number of patients is denoted as PF1act in Figure 1). In both studies, if the 'true' 
PFS6 rate is 50%, there is a 76% probability of ending the trial during the first stage. If less than 
11 Pathnot-act patients and less than 5 Pathact patients are PF at 6 months the trial will be closed 
to accrual and we will conclude that everolimus does not merit continued investigation in this 
disease due to lack of efficacy. Otherwise, recruitment will begin for the second stage. 
Second Stage: Recruitment in the second stage is entirely dependent on the results of the first 
stage. If preliminary evidence in the first stage suggests efficacy of everolimus in Pathnot-act 
patients, enrollment in the second stage will be open to all patients regardless of 
PI3K/AKT/mTOR status (i.e. unselected patients). Thus 40 additional patients will be enrolled, 
regardless of PI3K/AKT/mTOR status, for a total of 65 patients. 

If 25 or more of the total number of Pathnot-act patients are PF at 6 months (denoted as
PFTnon-act in Figure 1), everolimus will be considered sufficiently efficacious in the
unselected population to warrant recommendation for continued investigation.

If fewer than 25 of the total number Pathnot-act patients are PF at 6 months and 19 or
more of the total number of Pathact patients are PF at 6 months (denoted as PFTact in
Figure 1), everolimus will be considered sufficiently efficacious in the Pathact sub-
population.

If fewer than 25 Pathnot-act patients and fewer than 19 Pathact patients are PF at 6 months
(PFTnon-act  < 25  &  PFTact  < 19 ), everolimus will not be considered sufficiently efficacious.
With α = 0.0512, the power for concluding efficacy when PFS6 is independent of 
PI3K/AKT/mTOR status is > 95%. If the proportion of 40 patients with PI3K/AKT/mTOR 
activation is not approximately 50%, we will reassess the necessary calculations to avoid 
drawing incorrect conclusions.
On the other hand, if preliminary evidence in the first stage suggests efficacy of everolimus is 
limited to the Pathact patients, enrollment for the second stage will be restricted to only Pathact 
patients and no additional Pathnot-act patients will be accrued. An additional 20 Pathact patients 
will be recruited for a total of 27 Pathact patients. Everolimus will be considered sufficiently active 
in this sub-population to warrant recommendation for continued investigation if 19 or more of the 
27 Pathact patients are PF at 6 months. With α = 0.0512, the power for concluding efficacy in the 
Pathact sub-population is 81%.
8.4.3
Secondary Analysis (or Analysis of Secondary Endpoints)
In this setting of 2-staged phase II trials, the secondary objectives are considered exploratory 
and will be reported descriptively based on appropriate statistical methods.

Estimate PFS and OS distributions as well as objective response (CR+PR) rates
associated with everolimus treatment in recurrent pediatric LGGs.
The secondary endpoints for PFS and OS are survival times as defined in Section
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curve. Objective response rates and confidence intervals will be estimated based on the 
proportion of complete and partial responders. 

Explore associations between activation of the PI3K pathway as measured by
expression of phospho-AKT, phospho-PRAS40, and phospho-4EBP1 and outcome as
measured by the 6-month disease stabilization rates (a dichotomous variable; see
section 7.1.2.2) as well as PFS for progressive or recurrent pediatric low-grade glioma
patients with measureable disease treated with everolimus.
Association between activation of the PI3K pathway as measured by expression of
phospho-AKT, phospho-PRAS40, and phospho-4EBP1 and 6-month response rate will
be assessed via logistic regression. Estimates of the odds ratio and confidence intervals
will be reported. Association between activation of the PI3K pathway as measured by
expression of phospho-AKT, phospho-PRAS40, and phospho-4EBP1 and PFS will be
assessed via a Cox proportional hazards model. Estimates of the hazard ratio and
confidence intervals will be reported.
•
Collect tissue from all enrolled patients and prospectively analyze key molecular features
including activation of the PI3K, mTOR and MAPK pathways, aberrations in PTEN, p53,
PDGFRA amplification, CDKN2A loss, and activating mutations in BRAF (KIAA1549-
BRAF fusion and BRAFV600E missense BRAF mutation). In addition to the targeted
approaches described above that examine previously reported alterations additional
genomic profiling studies will be performed including targeted sequencing, RNA
sequencing, and/or exome(plus) next generation sequencing if sufficient tissue is
available.  Such studies will include but are not limited to molecular analyses of DNA,
RNA and protein in tumor biopsy specimens and blood samples.  When possible and/or
sufficient blood/tissue is provided, sample will be used to establish tumor cell cultures,
cell lines and/or transplantation models. These studies will be carried out in collaboration
with Dr. Adam Resnick, Children’s Hospital of Philadelphia.
Descriptive statistics will be reported for each molecular feature including means and
variances for continuous variables and proportions for categorical variables.

Explore MR quantitative measures of relative cerebral blood volume, permeability and
apparent diffusion coefficient within the region of hyper-intensity on T2-weighted images
as markers of disease response and/or progression in comparison to institutional
evaluation of disease response and/or progression and quantitative measures of tumor
response as determined by central review (based upon both area and volumetric
measures).
The relevant MR quantitative measures are defined in Section 7.1.  We hypothesize that
(a) high volumetric parameters, low nADC percentiles and high nCBV percentiles at the
baseline exam are predictive of poor outcome and (b) that early changes in these
parameters can predict tumor progression. To assess associations between the
parameters at baseline and subsequent poor outcome (both PFS and OS), we will
employ Cox proportional hazard models for each imaging parameter assessing whether
it should be included as a continuous (as recorded or after an appropriate
transformation) or a categorical (e.g. by dichotomizing or including as dummy variables)
covariate. A smoother (e.g. LOESS) can be used to assess the appropriateness of the
linearity assumption of the continuous covariate based on the martingale residuals.
Estimates of the hazard ratio and confidence intervals will be reported. For b) the binary
outcome denoting tumor progression (defined as categories 4—7 vs. categories 1—3 in


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Evaluation of Response in Section 7.1.1.3), we will explore logistic regression models. 
Early changes in the imaging parameters will be included on a continuous scale unless a 
nonlinear association indicates an alternative high/low behavior in the risks. If the latter 
is true, a different scale or categorization will be employed. Estimates of the odds ratio 
and confidence intervals will be reported.
8.5
Evaluation of Safety
Analyses will be performed for all patients having received at least one dose of study drug.  The 
study will use the NCI CTCAE v4.0.
8.6
Study Results
The primary hypothesis of this study is to determine the efficacy of everolimus in LGG patients. 
This final analysis will occur after 65 unselected or 27 pathway-activated patients have been 
followed for at least 6 months following the start of treatment. It will include tabulation of all 
cases entered and those excluded from the analyses with the reasons for such given; the 
distribution of the important prognostic baseline variables; and observed results with respect to 
the primary and secondary endpoints. 
9
Study Management
9.1
Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements.
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.  
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements.
9.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF Institutional Review Board (IRB).  Prior to obtaining IRB approval, the 
protocol must be approved by the Helen Diller Family Comprehensive Cancer Center Site 
Committee and by the Protocol Review Committee (PRC).  The initial protocol and all protocol 
amendments must be approved by the IRB prior to implementation.  
9.3
Informed Consent
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 


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must sign the IRB-approved informed consent and HIPAA form prior to participation in any study 
specific procedure.  The participant must receive a copy of the signed and dated consent/HIPAA 
document.  The original signed copy of the consent and HIPAA document must be retained in 
the medical record or research file. All subsite consent forms must be reviewed and approved 
by PNOC OPS prior to submitting to the local IRB.
9.4
Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the Study Chair 
and approved by PNOC, the PRC and the IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval.  In this circumstance, however,  PNOC 
must then notify the IRB in writing within five (5) working days after implementation.  PNOC 
OPS will be responsible for updating any participating sites. Once released by PNOC OPS, all 
major protocol amendments must be submitted to the local IRB within 30 business days by each 
participating institution. Minor amendments may be submitted at the time of continuing review. 
9.5
Handling and Documentation of Clinical Supplies
Each participating site will maintain complete records showing the receipt, dispensation, return, 
or other disposition of all investigational drugs.  The date, quantity and batch or code number of 
the drug, and the identification of patients to whom study drug has been dispensed by patient 
number and initials will be included.  The sponsor-investigator will maintain written records of 
any disposition of the study drug.
The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study patients.  Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol.
9.6
Case Report Forms (CRFs)
Each participating site will complete study specific Case Report Forms (CRFs) for safety 
monitoring and data analysis.  Each site will enter the study data into OnCore® via standardized 
CRFs in accordance with the CTMS study calendar, using a secure access account. The 
participating site’s Clinical Research Coordinator (CRC) will complete the CRFs; the Investigator 
will review and approve the completed CRFs – this process must be completed within the 
timelines specified in Appendix 7.. Study data from the participating site will be reported and 
reviewed in aggregate with data from patients enrolled at the coordinating center. All source 
documentation and CTMS data will be available for review/monitoring as needed.
The information collected on CRFs shall be identical to that appearing in original source 
documents. For participating sites, source documents will be maintained per institutional 
guidelines.  All source documentation should be kept in separate research folders for each 
patient.
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. 
The Principal Investigator at each participating institution will be responsible for ensuring the 
accurate capture of study data.  At study completion, when the CRFs have been declared to be 
complete and accurate, the database will be locked.  Any changes to the data entered into the 


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CRFs after that time can only be made by joint written agreement among the Study Chair, the 
Trial Statistician, and the PNOC Project Leader.
9.7
Oversight and Monitoring Plan
This is a multicenter trial.  The UCSF Helen Diller Family Comprehensive Cancer Center Data 
Safety Monitoring Committee (DSMC) will be the main monitoring entity for this study.  The 
UCSF DSMC will work together with participating member institution DSMCs to monitor the 
study in accordance with the available NCI approved Data Safety and Monitoring Plans 
(DSMPs).  For member institutions that do not follow an NCI approved DSMP, the UCSF DSMC 
will be considered the institutional DSMC.  The DSMC will routinely review all adverse events 
and suspected adverse reactions considered “serious”.  The UCSF DSMC will audit study-
related activities to ensure that the study is conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant 
results of the DSMC audit will be communicated to the IRB and the appropriate regulatory 
authorities at the time of continuing review, or in an expedited fashion, as applicable.  Please 
see Appendix 5 PNOC Data Safety and Monitoring Plan for more information.
9.8
Multicenter Communication
The PNOC operations office provides administration, data management, and organizational 
support for the participating sites in the conduct of the clinical trial.  The PNOC Operations 
Office will coordinate, at minimum, quarterly conference calls with the PNOC member 
institutions to discuss risk assessment. The following items will be discussed, as appropriate:

Enrollment information 

Adverse events (i.e. new adverse events and updates on unresolved adverse 
events and new safety information)

Protocol violations

Other issues affecting the conduct of the study
9.9
Record Keeping and Record Retention
The Principal Investigator for each PNOC institution is required to maintain adequate records of 
the disposition of the drug, including dates, quantity, and use by subjects, as well as written 
records of the disposition of the drug when the study ends per institutional guidelines.  
The site Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, 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.


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In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified.
9.10 Coordinating Center Documentation of Distribution 
It is the responsibility of the PNOC operations office to maintain adequate files documenting the 
distribution of study documents as well as their receipt (when possible). The HDFCCC 
recommends that the PNOC operations office maintain a correspondence file and log for each 
segment of distribution (e.g., FDA, drug manufacturer, participating sites, etc.).
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt.
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received.
At a minimum, the PNOC operations office must keep documentation of when and to whom the 
protocol, its updates and safety information are distributed.
9.11 Regulatory Documentation 
Prior to implementing the protocol at each PNOC institution, the protocol, informed consent 
form, HIPAA authorization and any other information pertaining to participants must be first 
approved by the UCSF Institutional Review Board (IRB) and by the PNOC operations office. 
Prior to implementing this protocol at the participating sites, approval for the UCSF IRB 
approved protocol must be obtained from the participating site’s IRB. 
Appendix 6 lists the documents which must be provided to PNOC Operations Office before the 
participating site can be initiated and begin enrolling participants.
Upon receipt of the required documents, PNOC operations office will formally contact the site 
and grant permission to proceed with enrollment.


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11
Appendices
Appendix 1
BSA Adjusted Daily Dose for RAD001
Target dose: 5 mg/m2 daily
Pill Sizes: 2.5 mg, 5 mg, 10 mg
The plot below illustrates what the BSA adjusted doses will look like if the objective is to get as close to 
the 5mg/m2 dose as possible.
Body Surface Area
BSA Adjusted Actual Daily Dose (mg/m2)
0.5
1.0
1.5
2.0
2.5
4
5
6
The table below contains the same information as the plot above where each row of the table 
corresponds to one of the arcs on the plot. The table provides instructions for the optimal dosing 
strategy for various BSA ranges and the associated mg/m2 doses. For example based on this dosing 
strategy patients within the 1.26-1.74 m2 BSA range should be given 7.5mg and the resulting BSA 
adjusted doses for this group will range from 4.31-5.95 mg/m2.
Dosing table for 5mg/m2 daily
BSA Range (m2)
Mg Dose
Mg/m2 Dose Range
0.5-0.74
2.5
3.38-5.00 mg/m2


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0.75-1.25
5
4.00-6.67 mg/m2
1.26-1.74
7.5
4.31-5.95 mg/m2
1.75-2.25
10
4.44-5.71 mg/m2
2.26-2.50
12.5
5.00-5.53mg/m2
The plot below shows the overlaps for 2.5mg/m2 daily vs. 5mg/m2 based on the minimum pill size of 
2.5mg. The orange dots are the BSA adjusted doses for 5mg/m2/day and the blue ones are for 
2.5mg/m2/day. The overlap on the far left is the region where dose reduction is not possible on the 
daily schedule. These are the patients who are already receiving 2.5mg/day total dose (BSA range 0.5-
0.74 in the table above) and hence cannot be dose reduced further unless they go to the every other 
day schedule. The dosing table for the 2.5mg/m2/day dose level is also below. 
0.5
1.0
1.5
2.0
2.5
Body Surface Area (m2)
2.5
5.0
BSA Adjusted Actual Daily Dose (mg/m2)
Dosing table for 2.5mg/m2 daily
Note that patients must have BSA≥0.75m2 in order to be dosed at the 2.5mg/m2/day.
BSA Range (m2)
Mg Dose
Mg/m2 Dose Range


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0.75-1.49
2.5
1.68-3.33 mg/m2
1.50-2.50
5.0
2.0-3.33 mg/m2
Dosing table for 2.5mg/m2 every other day
Please use the same dosing table as above for 2.5 mg/m2 daily but dose will be administered only 
every other day. No dosing will be possible using 2.5 mg/m2 every other day if less than 0.75 m2.


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Appendix 2
Performance Status Criteria
Karnofsky
Lansky
Score
Description
Score
Description
100
Normal, no complaints, no 
evidence of disease
100
Fully active, normal.
90
Able to carry on normal activity, 
minor signs or symptoms of 
disease.
90
Minor restrictions in physically 
strenuous activity.
80
Normal activity with effort; some 
signs or symptoms of disease.
80
Active, but tires more quickly
70
Cares for self, unable to carry on 
normal activity or do active work.
70
Both greater restriction of and less 
time spent in play activity.
60
Required occasional assistance, 
but is able to care for most of 
his/her needs.
60
Up and around, but minimal active 
play; keeps busy with quieter activities.
50
Requires considerable assistance 
and frequent medical care.
50
Gets dressed, but lies around much of 
the day; no active play, able to 
participate in all quiet play and 
activities.
40
Disabled, requires special care and 
assistance.
40
Mostly in bed; participates in quiet 
activities.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
30
In bed; needs assistance even for 
quiet play.
20
Very sick, hospitalization indicated.  
Death not imminent.
20
Often sleeping; play entirely limited to 
very passive activities.
10
Moribund, fatal processes 
progressing rapidly.
10
No play; does not get out of bed.


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Appendix 3 PNOC001 Archival Tissue Confirmation Form
This form may be submitted to confirm tissue eligibility at the time of registration. 
Patient Name 
institutional MRN:
Date of Surgery/Biopsy:
Date of Consent:
Institution Name:
Institution Address:
Contact Person:
Contact Phone #:
Please indicate what type of tissue will be submitted:
□Formalin fixed, paraffin embedded (FFPE) tumor material from any prior surgery
(pathologist should choose block(s) that is best representative of the tumor.)

Paraffin block should be in a container labeled with the PNOC patient ID and institutional
accession number
OR
□Unstained slides tumor material from any prior surgery

Please provide at least 15 unstained slides (5 um thick) labeled with the PNOC patient
ID and institutional accession number.
If available, sites should also collect and submit fresh frozen tissue (see appendix 8). 
I certify that the above-mentioned material is available for the stated participant and that tissue 
will be provided as requested. 
_______________________________    ____________
Neuropathologist
Date


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Appendix 4 Imaging Guidelines
Pre-Study Imaging Qualification 
The most critical aspect of the advanced imaging being performed in this study is to match 
quantitative exam protocols prior to the initial treatment and at follow-up studies, so that direct 
comparisons of parameter values can be made. Clearly each site must also be satisfied that the 
anatomic imaging sequences being used at these times satisfy clinical criteria for evaluating 
their patients. Hence, while there should be an attempt to make the protocols as similar as 
possible between institutions, it may not be feasible for them to be identical, and so any 
comparisons that are being made will focus on changes within the patient rather than 
differences between individuals. The images generated should be anonymized and sent to 
UCSF, either electronically or by CD so that they can be evaluated and confirmation provided 
that the protocol satisfies the requirements of the study. Sites should batch ship all images 
pertaining to each patient at the time the patient comes off treatment.  
Guidelines for Imaging Protocols
Serial exams should be performed on the same 3T MR system using the commercial 8-channel 
or other multi-channel head coil. The sequences may either be performed in a pure axial 
orientation or lined up with the AC-PC line, as is the default in many institutions. 
Outline of Protocol:
1.
3-plane localizer
2.
T1-weighted pre-Gadolinium images: used as a reference for comparing with the post-
Gadolinium images and to identify any sign of hemorrhage. 
3.
T2-weighted images:  used in conjunction with the FLAIR images to define the spatial 
extent of the T2 lesion. 
4.
FLAIR images: required for defining treatment response using the RANO criteria.
5.
Diffusion weighted images: the entire brain should be covered with at least 6 different 
gradient directions at b=1000 and with one acquisition having b=0. The slice thickness 
and spatial resolution should be chosen to allow calculation of maps of apparent 
diffusion coefficient and fractional anisotropy. 
6.
Echo planar gradient echo dynamic susceptibility contrast (DSC) images: A series of 
images should be acquired during the injection of a bolus of 0.1mmol/kg of Gadolinium 
contrast agent that is delivered at a rate of 3-5ml/s using a power injector and with a 15-
20ml flush of normal saline delivered at the same rate. Slice thickness (3-5mm) and 
location should be chosen to cover as much of the T2 lesion as possible. The injector 
delay should be set at 15-30s to allow a good definition of baseline intensities from the 
pre-bolus images.
7.
Post-Gadolinium T1-weighted volumetric images: this high-resolution image is used to 
define the spatial extent of the enhancing volume and for registration between 
examinations.
8.
Post-Gadolinium T1-weighted images: these should match the pre-Gadolinium images 
are used to define the extent of the enhancing lesion.


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Sequences 5, 6 and 7 represent the advanced imaging components that will be used for 
quantitative analysis of treatment effects. The other anatomic sequences are the ones 
commonly used for pre-surgery exams in a clinical setting. They will are used for clinical 
evaluation of the patient and to perform volumetric analysis of the anatomic lesions. The dose 
and timing of Gadolinium should be kept consistent to facilitate clinical interpretation. Please 
note that the radiologist at each site should interpret the anatomic images for clinical purposes 
and send them to UCSF for quantitative analysis. 
De-Identification and Labeling
De-Identification of Digital Images
It is the responsibility of the sites to de-identify images according to HIPAA, Institutional Review 
Board (IRB) guidelines, GCPs and local regulatory requirements.

Do not remove the date of the exam and the technical information (eg, slice location,
kVP, echo time, etc).

Do not modify time or date information before or during the de-identification process.
Labeling of Digital Images
Use the patient ID, the date (ddmmyy) and scan number (01 or 02 for the two advanced imaging 
exams) to label the data as follows:  PatientID_date_xx
Checklist for Media Submission

Completed Exam Data Sheet

De-identified DICOM images
Sending Digital Images via FedEx:

Sites should batch ship all images pertaining to each patient at the time the patient
comes off treatment.

All MRIs should be de-identified prior to shipment.

All shipping materials should be provided by the site

All shipments require signature for delivery

Include checklist items and address packages to:
Attn: PNOC001
PNOC Operations Office
UCSF - Mission Bay
DATA ANALYSIS PERFORMED AT UCSF


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The anatomic images are used to manually define the contrast enhancing lesion (CEL) and the 
T2 lesion (T2L). The T1 weighted pre-contrast image is used to define a brain mask so that 
intensity values can be normalized. The diffusion images are processed to generate maps of 
apparent diffusion coefficient (ADC) and fractional anisotropy (FA). The perfusion data are 
processed to calculate maps of relative cerebral blood volume (rCBV), peak height (PH) and 
percentage recovery (RECOV).  Both sets of images are registered to the anatomic images and 
histogram analysis of the map intensities within the CEL and T2L performed. Where relevant the 
estimated parameters are normalized by the median intensity in normal appearing white matter 
and used to define metrics for assessing treatment effects as follows:
i)
Volumes of the CEL and T2L
ii)
Volume within the T2l where nADC  < 1.5
iii) Volume within the T2L where nCBV >3
iv) 10th and 25th percentile of nADC in the T2L
v)
75th and 90th percentile of nCBV in the T2L.
We hypothesize that a) high volumetric parameters, low nADC percentiles and high nCBV 
percentiles at the baseline exam are predictive of poor outcome and b) that early changes in 
these parameters can predict tumor progression, based upon the RANO criteria. 


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Appendix 5
PNOC Data Safety and Monitoring 
PNOC Data Safety and Monitoring Plan for a Phase 2 Study
It is the responsibility of each PNOC member institution to follow the National Cancer Institute 
(NCI) approved Data Safety and Monitoring Plan (DSMP) for their site, and to be internally 
monitored by a Data Safety Monitoring Committee/Board (DSMC/DSMB). In addition to the 
guidelines laid out in this document, each PNOC member institution must comply with the 
policies and standards put forward by their own institutional DSMC/DSMB.   For member 
institutions that do not follow an NCI-approved DSMP, the UCSF DSMC will be considered the 
“institutional DSMC” mentioned in this document.  Such institutions will be electronically 
monitored and visited annually by the UCSF DSMC.  
The institutional DSMC/DSMB activities for this study will include: 

Review of subject data

Review of suspected adverse reactions considered “serious” (SAEs)  

Monitoring every six months (depending on patient accrual)

Minimum of a yearly regulatory audit
Monitoring and reporting guidelines
All institutional Phase 2 therapeutic studies are designated with a moderate risk assessment.  
The data is monitored every six months by the institutional DSMC/DSMB, with twenty percent of 
the subjects monitored (or at least three subjects if the calculated value is less than three).   
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) DSMC is responsible 
for monitoring data quality and patient safety for all HDFCCC institutional clinical studies. In the 
case of all PNOC protocols, the UCSF DSMC will work together with non-UCSF PNOC member 
institution DSMC/DSMBs in order to ensure DSMP compliance. Each non-UCSF DSMC/DSMB 
will be responsible for providing regular monitoring reports to PNOC and the UCSF DSMC. 
These reports will be used by the UCSF DSMC to assess data quality, patient safety, and 
protocol compliance as well as to make decisions about dose escalations, where applicable. 
PNOC and the UCSF DSMC reserve the right to conduct on-site monitoring at any non-UCSF 
member institution if DSMP requirements are not being met. If the need to perform a monitoring 
visit at a non-UCSF member institution arises, source documents will be provided by the 
member institution prior to the visit in order for the UCSF DSMC to monitor protocol compliance, 
patient safety, and to verify data entry. 
The PNOC Operations Office provides administration, data management, and organizational 
support for the PNOC member institutions in the conduct of any PNOC clinical trial.  The PNOC 
Operations Office will summarize and communicate adverse events, safety data, and other 
study matters to the PNOC member institutions on a quarterly basis.
The Study Chair is responsible for the overall conduct of any PNOC trial and for monitoring its 
safety and progress at all participating sites (as outlined in the PNOC Study Chair and Co-Chair 
Responsibilities SOP).  The Study Chair will conduct continuous review of data and subject 
safety and discuss each subject’s treatment with the PNOC Operations Office. The discussions 
are documented in the PNOC Operations Office meeting minutes.
Multicenter communication


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The PNOC Operations Office will coordinate, at minimum, quarterly conference calls with the 
PNOC member institutions to discuss risk assessment. The following items will be discussed, as 
appropriate:

Enrollment information

Adverse Events (e.g. new AEs, unresolved AEs, and new safety information)

Protocol violations

Other study conduct issues
Adverse event review and monitoring
PNOC uses the web-based OnCore® Clinical Trials Management System for all patient 
registrations and data entry.  The OnCore® System will also track patient level protocol 
compliance and safety information. 
For Phase II studies, all Grade 3-5 AEs will be entered into OnCore®, regardless of relationship. 
All Grade 3-5 Adverse Events entered into OnCore® will be reviewed on a monthly basis by the 
PNOC Operations Office. The PNOC Operations Office will discuss the toxicity, grade, and 
relationship to study intervention for all AEs in question. 
All Adverse Events must be entered into OnCore® within 10 business days of becoming aware 
of the event. Member institutions will submit this information to PNOC via the Adverse Event 
Form within OnCore®. 
In addition, all adverse reactions considered “serious” (also called Serious Adverse Events, or 
SAEs), regardless of relationship, must be entered in OnCore® and reported to the PNOC 
Operations Office within 1 business day.  SAEs will be reviewed and monitored by the UCSF 
DSMC on an ongoing basis, and will be discussed at the UCSF DSMC meeting, which take 
place every six (6) weeks. 
If a death occurs during the treatment phase of the study, or within 30 days after the last 
administration of the study drug(s), and is determined to be related either to the investigational 
drug or to any research related procedure, the Study Chair and the PNOC Operations Office 
must be notified by the member institution within 1 business day. The Study Chair or the 
PNOC Operations Office must then notify the UCSF DSMC Chair, or qualified alternate, within 1 
business day of this notification.  The contact may be by phone or e-mail.
Increase in adverse event rates
If an increase in the frequency of Grade 3, 4, or 5 Adverse Events (above the rate reported in 
the Investigator Brochure or package insert), the Study Chair or the PNOC Operations Office is 
responsible for notifying the UCSF DSMC at the time the increased rate is identified.  
If at any time the Study Chair or the PNOC Operations Office halts enrollment or ends the study 
due to safety issues, the UCSF DSMC Chair and Manager must be notified within 1 business 
day via e-mail.  The UCSF DSMC must receive a formal letter within 10 business days, and 
the UCSF IRB must be notified.
UCSF data and safety monitoring committee contacts:


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UCSF DSMC Chair
UCSF-
San Francisco, CA 94143
UCSF DSMC Manager
UCSF-
San Francisco, CA 94143
UCSF DSMC Monitors
UCSF
San Francisco, CA 94143


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Appendix 6 PNOC Institutions Required Regulatory Documents
Prior to opening a study at any member institution, the following regulatory 
documents must be submitted to the PNOC Operations Office: 

Participating Site IRB approval(s) for the protocol, appendices, informed consent form
and HIPAA authorization

Participating Site IRB approved consent form

Participating Site IRB membership list

Participating Site IRB’s Federal Wide Assurance number and OHRP Registration
number

Copy of the 1572 (Note: 1572 form is not required for FDA-exempt trials)

Curriculum vitae and medical license for each investigator and consenting professional

Documentation of Human Subject Research Certification training for investigators and
key staff members at the Participating Site

Participating site laboratory certifications and normals

Signed copy of the completed delegation of authority log (found in PNOC Documents >
Forms)

Signed copy of the protocol signature page

Signed copy of the final contract

Confirmation of a “Site Initiation Visit” (SIV) teleconference
Upon receipt of the required documents, the PNOC Operations Office will formally contact the 
site and grant permission to proceed with enrollment.  All documents can uploaded directly to 
SharePoint by navigating to your site's page and clicking "Add Documents".  
Each PNOC site is responsible for ensuring all regulatory documents in SharePoint are up to 
date. Sites will upload new or revised documents as applicable to reflect any changes, including 
changes in staff and approved/expired documents.


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Appendix 7 Required Data and Time Table for Submission
Form
Submission Timeline
Eligibility Checklist
Complete prior to registration
On Study Forms
Within 14 days of registration
Baseline Assessment Forms
Within 14 days of registration
Treatment Forms
Within 10 days of the last day of the cycle
Adverse Event Report Forms
Within 10 days of the last day of the cycle
Serious Adverse Event 
Reporting
Please refer to section 7.6 Expedited Reporting
Response Assessment Forms
Within 10 days of the completion of the cycle required for 
response evaluation
Off Treatment/Off Study Forms
Within 14 days of completing treatment or being taken off 
study for any reason
Follow up/Survival Forms
Within 14 days of the protocol defined follow up visit date


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Appendix 8 PNOC Specimen Collection and Shipping 
Research Tissue (required)
Depending on the stage of the protocol, PI3K activation status needs to be known prior to trial 
enrollment. A pre-screening process is now integrated into PNOC001 trial enrollment. To 
establish activation status for the PI3K a minimum of 2 unstained slides needs to be provided. 
Once the patient is deemed to be eligible additional tumor material needs to be submitted to 
UCSF. Tumor samples (at least 15 unstained slides or a tissue block) from a prior surgery will 
be used to test for molecular analyses. A completed Archival Tissue Confirmation Form 
(appendix 3) or an email confirmation may be submitted at the time of registration to confirm 
tissue availability. The tissue itself must be submitted within 90 days of registration. It is the 
responsibility of each participating institution to request and submit this tissue.
For details and shipping instruction refer to the PNOC Member’s SharePoint website under the 
documents section.
Fresh Frozen Tissue (if available)
If fresh frozen tissue is available we strongly encourage sending such frozen tissue with the 
paraffin embedded tissue. The study will provide adequate shipping boxes. For details and 
shipping instruction refer to the PNOC Member’s SharePoint website under the documents 
section.
Research Blood (required)
In addition to tumor tissue, blood samples from subjects will be obtained prospectively within 90 
days of registration for genomic profiling studies. At least one (1) blood sample (approximately 
8.5 ml) from the subject (research related, obtained for the purpose of this study). 
After the eligibility of a patient is confirmed and the patient is enrolled in study, the enrolling site 
will be provided with blood collection tubes for subsequent DNA isolation. For details and 
shipping instruction refer to the PNOC Member’s SharePoint website under the documents 
section.