Clinical Evaluation of Everolimus (a Rapamycin Analog) in Restoring Salivary Gland Function to Patients Treated With Radiotherapy for Head and Neck Cancer
Phase: EARLY_PHASE1
Conditions: Salivary Gland Dysfunction, Xerostomia, Head and Neck Cancer
Sponsor: University of Arizona

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Everolimus Investigator-initiated Protocol Template 
RAD001 (Everolimus)
Clinical evaluation of everolimus (a rapamycin analog) in restoring 
salivary gland function to patients treated with radiotherapy for head and 
neck cancer
CRAD001XUS274T
Authors:
Panayiotis Savvides, MD PhD MPH (Principal Investigator) 
Kirsten Limesand, PhD (co-Investigator)
Denise Roe, DrPH (co-Investigator) 
Sun Yi, MD (co-Investigator)
Julie Bauman, MD (co-Investigator)
Daruka Mahadevan, MD PhD (co-Investigator)
Version number: 1.2 
Release date 06/22/2018
Referenced Investigator Brochure 
Edition
15, release date 27-April-2016
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Table of contents
Table of contents..................................................................................................................2
List of figures.......................................................................................................................3
List of tables.........................................................................................................................3
List of abbreviations ............................................................................................................4
Glossary of terms.................................................................................................................6
Schema.................................................................................................................................8
1
Background..........................................................................................................................9
1.1
Overview of disease pathogenesis, epidemiology and current treatment ................9
1.2
Introduction to investigational treatment(s) and other study treatment(s)...............9
1.2.1
Overview of Everolimus........................................................................10
2
Rationale............................................................................................................................13
3
Objectives and endpoints...................................................................................................14
4
Study design.......................................................................................................................15
4.1
Description of study design....................................................................................15
5
Population..........................................................................................................................17
5.1
Inclusion and Exclusion criteria.............................................................................17
6
Treatment...........................................................................................................................20
6.1
Study treatment ......................................................................................................20
6.1.1
Dosing regimen .....................................................................................21
6.2
Dose modifications ................................................................................................22
6.2.1
Dose modification and dose delay.........................................................22
6.2.2
Management of specific toxicities.........................................................25
6.3
Concomitant medications.......................................................................................32
6.3.1
Permitted concomitant therapy..............................................................32
7
Visit schedule and assessments..........................................................................................36
7.1
Study flow and visit schedule ................................................................................36
7.2
Assessment types ...................................................................................................39
7.2.1
Pregnancy and assessments of fertility..................................................39
7.2.2
Correlatives............................................................................................40
8
Safety monitoring and reporting........................................................................................40
8.1
Adverse events.......................................................................................................40
8.1.1
Definitions and reporting.......................................................................40
8.1.2
Laboratory test abnormalities................................................................50
8.2
Serious Adverse Events .........................................................................................50
8.2.1
Definitions.............................................................................................50
8.2.2
Reporting...............................................................................................51
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8.3
Pregnancy.................................................................................................................52
9
Statistical methods .............................................................................................................52
9.1
Statistical methods .................................................................................................52
10 Protocol amendments, or changes in study conduct ..........................................................53
11 References:...........................................................................................................................55
12 Appendix A:  Visual Analog Scale (VAS) Xerostomia Questionnaire............................56
Appendix B:  The Xerostomia Inventory..........................................................................57
List of figures
Figure 1-1
Chemical structure of Everolimus .........................................................10
List of tables
Table 1-1
Everolimus - Drug substance.................................................................10
Table 6-1
Dosing guidelines for Everolimus-related non-hematologic
toxicities ..................................................................................................24
Table 6-2
Dosing guidelines for Everolimus-related hematologic toxicities ........24
Table 6-3
Management of non-infectious pneumonitis .........................................30
Table 6-4
Action to be taken based on screening hepatitis B results.....................31
Table 6-5
Guidelines for the management of hepatitis B reactivation ..................31
Table 6-6
Guidelines for the management of hepatitis C flare..............................32
Table 6-7
Clinically relevant drug interactions: inducers, and inhibitors of 
isoenzyme CYP3A ................................................................................34
Table 6-8
Clinically relevant drug interactions: substrates, inducers,
inhibitors of PgP and PgP/CYP3A dual inhibitors................................36
Table 7-1
Visit evaluation schedule.......................................................................37
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List of abbreviations
4E-BP1
4E-binding protein
AE
Adverse event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
AUC
Area under the curve
BAL
Bronchoalveolar lavage
BCG
Bacillus Calmette-Guérin
CDS
Core data sheet
CoA
Coenzyme A
CPK
Creatine phosphokinase
CRF
Case Report Form
CT
Computer tomography
CTCAE
Common terminology criteria for adverse events 
CYP3A4
Cytochrome P450 3A4
DDI
Drug-drug interaction
DLCO
Diffusing capacity of the Lung for Carbon Monoxide 
DNA
Deoxyribonucleic acid
DS&E
Drug Safety and Epidimology
EOT
End of treatment
EU
European Union
FDA
Food and drug administration
GERD
Gastroesophageal reflux disease
HbA1c
Hemoglobin A1c
HBcAb
Hepatitis B core antibody
HbsAb
Hepatitis B surface antibody
HbsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HMG
3-hydroxy-3-methyl-glutaryl
IB
Investigator brochure
INR
International Normalized Ratio
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine system
IV
Intravenous
log10
Decadic logarithm (common logarithm)
MRI
Magnetic resonance imaging
mTOR
Mammalian target of rapamycin
NCI
National Cancer Institute
PCR
Polymerase chain reaction
PgP
P-glycoprotein
PFT
Pulmonary function tests
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PI3K
Phosphoinositide 3-kinase
PNET
Pancreatic neuroendocrine tumor
RCC
Renal cell carcinoma
RMP
Risk management plan
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SEGA
Subependymal giant cell astrocytoma
TS
Tuberous sclerosis
ULN
Upper limit of normal
US
United States
VEGF
Vascular endothelial growth factor
WOCBP
Women of child-bearing potential
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Glossary of terms
Assessment
A procedure used to generate data required by the study
Baseline
For efficacy evaluations, the baseline assessment will be the last 
available assessment before or on the date of randomization.
For safety evaluations (i.e. laboratory assessments and vital signs), the 
baseline assessment will be the last available assessment before or on 
the start date of study treatment.
The value obtained at baseline assessments, referred to as “baseline 
value” will be used as reference for the patient.
Control drug
A study treatment used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Investigational 
drug
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug.”
Investigational 
treatment
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). 
This 
also 
includes 
approved 
drugs 
used 
outside 
of 
their 
indication/approved dosage, or that are tested in a fixed combination. 
Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required or 
allowed 
by 
the 
protocol 
when 
used 
in 
within 
approved 
indication/dosage
Medication 
number
A unique identifier on the label of each study treatment package which 
is linked to one of the treatment groups of a study
Other study 
treatment
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment
Patient
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller 
functional segments such as screening, baseline, titration, washout, etc.
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Premature
patient withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at 
this time all study treatment administration is discontinued and no 
further assessments are planned, unless the patient will be followed for 
progression and/or survival
Stop study 
participation
Point/time at which the patient came in for a final evaluation visit or 
when study treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non- 
investigational treatments in combination.
Study
treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for 
any reason; may or may not also be the point/time of premature patient 
withdrawal
Supportive 
treatment
Refers to any treatment required by the exposure to a study   treatment,
e.g. premedication of vitamin supplementation and corticosteroid for 
pemetrexed disodium.
Variable
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points
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R 
E 
G 
I 
S 
T 
E 
R
Schema
Step 11
Step 22
RT or chemoRT 
administration
Everolimus 
Administration3
↓↓↓↓↓
CORRELATIVE STUDIES4
1 Patients with locally advanced squamous cell carcinoma of the Head and Neck treated with 
curative intent either in the post-operative or definitive setting with high dose radiotherapy (RT
≥50 Gy) with or without chemotherapy (chemoRT) will be eligible
2 Verify eligibility for everolimus treatment. Patients with clinically severe gland dysfunction 
(i.e., those with loss of at least 50% of the pre-radiotherapy value) will be eligible for everolimus 
treatment.
3 Everolimus (5 or 10 mg) po qd, x 5days only, starting 2 weeks after definitive treatment 
completion
4 Saliva flow rates and xerostomia surveys will be obtained at baseline, after 3 and 6 weeks of 
RT/chemoRT, prior to everolimus administration, at completion of the 5 day everolimus course 
and at 1,3 and 6 months after RT/chemoRT completion
R 
E 
G 
I 
S 
T 
E 
R
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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current treatment 
The clinical symptom of xerostomia (dry mouth syndrome) has been reported as a principle side 
effect of chronic prescription drug use particularly in the elderly, chemotherapy, therapeutic 
radiation of the head and neck region, and systemic autoimmune diseases such as Sjögren’s 
syndrome. Approximately 500,000 new patients are diagnosed annually with head and neck 
cancer worldwide. It is estimated that the tolerance dose for 50% complications rate (TD50) for 
the parotid gland is 28.4 Gy and the submandibular glands is 39 Gy with the daily dose exposure 
of <2Gy/day. Regrettably, many surviving patients that received radiotherapy suffer from 
chronic consequences of oral complications including hyposalivation, increased dental caries, 
reduced taste and smell, increased risk for oral infections, hampered speech, and malnutrition. 
Regardless of causal etiology, xerostomia has a significant negative impact on quality of life 
and presents an elevated financial burden to these individuals.
1.2
Introduction to investigational treatment(s) and other study treatment(s)
Everolimus is a novel derivative of rapamycin. It has been in clinical development since 1996 
as an immunosuppressant in solid organ transplantation. Everolimus is approved in Europe and 
other global markets (trade name: Certican®) for cardiac and renal transplantation, and in the 
United States (trade name: Zortress®) for the prevention of organ rejection of kidney 
transplantation.
Afinitor® was approved for adults with advanced renal cell carcinoma (RCC) after failure of 
treatment with sunitinib or sorafinib in 2009. In 2010, Afinitor® received United States (US) 
approval for patients with subependymal giant cell astrocytoma (SEGA) associated with 
tuberous sclerosis complex (TSC). Everolimus is also available as Votubia® in the European 
Union (EU) for patients with SEGA associated with TSC who require therapeutic intervention 
but are not candidates for curative surgical resection. Afinitor® was approved for “progressive 
pancreatic neuroendocrine tumor (PNET) in patients with unresectable, locally advanced, or 
metastatic disease” in 2011 in various countries, including the US and Europe. In 2012 
Afinitor® received approval for the treatment of postmenopausal women with advanced 
hormone receptor-positive, HER2- negative breast cancer (advanced HR+ BC) in combination 
with exemestane, after failure of treatment with letrozole or anastrozole. Furthermore in 2012, 
Afinitor® received approval for the treatment of patients with TSC who have renal 
angiomyolipoma not requiring immediate surgery. In the US, Afinitor® was approved in 2016 
for advanced non-functional NET of gastrointestinal (GI) or lung origin.
Approximately 44,060 cancer patients (excluding those patients who received marketed 
Afinitor® , those on planned and roll over studies as well as excluding investigator-sponsored 
studies) have been treated with everolimus as of 31-Mar-2016:

25,356 patients in Novartis-sponsored clinical trials

2,043 patients in the individual patient supply program
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The following is a brief summary of the main characteristics of Everolimus. More complete 
information can be obtained from the Everolimus Investigator’s Brochure (IB).
1.2.1
Overview of Everolimus
Everolimus is a derivative of rapamycin which acts as a signal transduction inhibitor (Table 1- 
1, Figure 1-1). Everolimus selectively inhibits mTOR (mammalian target of rapamycin), 
specifically targeting the mTOR-raptor signal transduction complex. mTOR is a key serine- 
threonine kinase in the PI3K/AKT signaling cascade, which is known to be dysregulated in a 
wide spectrum of human cancers (Boulay and Lane 2007).
Everolimus is being investigated as an anticancer agent based on its potential to act

directly on the tumor cells by inhibiting tumor cell growth and proliferation;

indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent 
inhibition of tumor cell VEGF (vascular endothelial growth factor) production and 
VEGF-induced proliferation of endothelial cells).
Table 1-1
Everolimus - Drug substance
Chemical name
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-
{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}- 
19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza- 
tricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-tetraene-2,3,10,14,20-pentaone
International non- 
proprietary name
Everolimus
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of various components
Figure 1-1
Chemical structure of Everolimus
HO
H3C
H3C
CH3
CH3
1.2.1.1
mTOR pathway and cancer
At the cellular and molecular level, Everolimus acts as a signal transduction inhibitor. It 
selectively inhibits mTOR (mammalian target of rapamycin), a key protein kinase which 
regulates cell growth, proliferation and survival. The mTOR kinase is mainly activated via the 
phosphatidylinositol 3-kinase (PI3-Kinase) pathway through AKT/PKB and the tuberous 
sclerosis complex (TSC1/2). Mutations in these components or in PTEN, a negative  regulator
of PI3-kinase, may result in their dysregulation. Abnormal functioning 
of the signaling pathways contributes to the pathophysiology of numerous human cancers. 
Various preclinical models have confirmed the role of this pathway in tumor development 
(Cohen et al 2005).
The main known functions of mTOR include the following (Bjornsti and Houghton 2004):

mTOR functions as a sensor of mitogens, growth factors and energy and nutrient levels;

Facilitating cell-cycle progression from G1-S phase in appropriate growth conditions;

The PI3K/mTOR pathway itself is frequently dysregulated in many human cancers, and 
oncogenic transformation may sensitize tumor cells to mTOR inhibitors;

PI3-kinase mutations have been reported in the primary tumor in 10-20% of human 
colorectal cancers (Frattini 2005, Velho 2005);

The loss of PTEN protein, either through gene deletion or functional silencing (promoter 
hypermethylation), is reported in approximately 60% of primary human colorectal cancers 
(Goel et al 2004);

The mTOR pathway is involved in the production of pro-angiogenic factors (i.e., VEGF) 
and inhibition of endothelial cell growth and proliferation;

Through inactivating eukaryotic initiation factor 4E binding proteins and activating the 
40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates protein translation, including 
the HIF-1 proteins. Inhibition of mTOR is expected to lead to decreased expression of 
O
O
CH3
CH3
O
O
OH
N
H3C
O
O
H C
3
O
O
O
OH
CH3
O
O
H3C
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HIF-1.
1.2.1.2
Non-clinical experience
Everolimus inhibits the proliferation of a range of human tumor cell lines in vitro including 
lines originating from lung, breast, prostate, colon, melanoma and glioblastoma. IC50s range 
from sub/low nM to µM. Everolimus also inhibits the proliferation of human umbilical vein 
endothelial cells (HUVECS) in vitro, with particular potency against VEGF-induced 
proliferation suggesting that Everolimus may also act as an anti-angiogenic agent. The anti- 
angiogenic activity of Everolimus was confirmed in vivo. Everolimus selectively inhibited 
VEGF-dependent angiogenic response at well tolerated doses. Mice with primary and 
metastatic tumors treated with Everolimus showed a significant reduction in blood vessel 
density when compared to controls.
The potential of Everolimus as an anti-cancer agent was shown in rodent models. Everolimus 
is orally bioavailable, residing longer in tumor tissue than in plasma in a subcutaneous mouse 
xenograft model, and demonstrating high tumor penetration in a rat pancreatic tumor model. 
The pharmacokinetic profile of Everolimus indicates sufficient tumor penetration, above that 
needed to inhibit the proliferation of endothelial cells and tumor cell lines deemed sensitive to 
Everolimus in vitro.
Everolimus administered orally daily was a potent inhibitor of tumor growth, at well tolerated 
doses, in 11 different mouse xenograft models (including pancreatic, colon, epidermoid, lung 
and melanoma) and two syngeneic models (rat pancreatic, mouse orthotopic melanoma). These 
models included tumor lines considered sensitive and “relatively resistant” in vitro. In general, 
Everolimus was better tolerated in mouse xenograft models than standard cytotoxic agents (i.e., 
doxorubicin and 5-fluorouracil), while possessing similar anti-tumor activity. Additionally, 
activity in a VEGF-impregnated subcutaneous implant model of angiogenesis and reduced
vascularity (vessel density) of Everolimus-treated tumors (murine melanoma) provided 
evidence of in vivo effects of angiogenesis.
It is not clear which molecular determinants predict responsiveness of tumor cells to Everolimus. 
Molecular analysis has revealed that relative sensitivity to Everolimus in vitro correlates with 
the degree of phosphorylation (activation) of the AKT/PKB protein kinase and the S6 ribosomal 
protein; in some cases (i.e., glioblastoma) there is also a correlation with PTEN status.
In vivo studies investigating the anti-tumor activity of Everolimus in experimental animal tumor 
models showed that Everolimus monotherapy typically reduced tumor cell growth rates rather 
than produced regressions. These effects occurred within the dose range of 2.5 mg to 10 mg/kg, 
orally once a day.
In preclinical models, the administration of Everolimus is associated with reduction of protein 
phosphorylation in target proteins downstream of mTOR, notably phosphorylated S6 (p-S6) 
and p-4E-BP1, and occasionally with an increase in phosphorylated AKT, a protein upstream 
of mTOR signaling pathway.
All significant adverse events observed in toxicology studies with Everolimus in mice, rats, 
monkeys and mini-pigs were consistent with its anticipated pharmacological action as an anti- 
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proliferative and immunosuppressant and at least in part reversible after a 2 or 4-week recovery 
period with the exception of the changes in male reproductive organs, most notably testes.
In vitro genotoxicity studies covering relevant genotoxicity end-points showed no evidence of 
clastogenic or mutagenic activity.
In male fertility studies in rats, testicular morphology was affected at 0.5 mg/kg and above, and 
sperm motility, sperm head count and plasma testosterone levels were diminished at 5 mg/kg 
which corresponded to 0.7 times the estimated clinical exposure at 10 mg/day, and caused a 
decrease in male fertility. There was evidence of reversibility. Female fertility was not affected, 
but everolimus caused an increase of pre-implantation loss in female rats at doses > 0.1 mg/kg, 
suggesting it could also potentially impact fertility in females. Everolimus crossed the placenta 
and was toxic to the conceptus. In rats, everolimus caused embryo/fetotoxicity at systemic 
exposure below the planned therapeutic level comprising mortality and reduced fetal weight. 
The incidence of skeletal variations and malformations at 0.3 and 0.9 mg/kg (e.g. sternal cleft) 
was increased. In rabbits, embryo toxicity was evident by an increase in late resorptions. Effects 
of everolimus on the pre- and postnatal development of rats were limited to slightly affected 
body weight and survival in the F1-generation at ≥0.1 mg/kg, and did not indicate a specific 
toxic potential.
The potential reproductive risk for humans is unknown. However, due to the observed 
malformations in rats, everolimus should be considered potentially teratogenic. Everolimus 
should not be given to pregnant women unless the potential benefit outweighs the potential risk 
for the fetus. Women of childbearing potential should be advised to use highly effective 
contraception methods while they are receiving everolimus and up to 8 weeks after treatment 
has been stopped. It is not known whether everolimus is excreted in human milk. In animal 
studies, everolimus and/or its metabolites were readily transferred into the milk of lactating rats. 
Therefore women who are taking everolimus should not breastfeed.
Further details can be found in the Everolimus Investigator’s Brochure.
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2
Rationale
Limesand and colleagues developed a mouse model to study the effects of salivary gland 
radiation on glandular functions. Analysis of salivary gland cell proliferation and apoptosis in 
irradiated mice demonstrated that expression of Akt or treatment with IGF-1 protected 
irradiated salivary glands; the protective effect of IGF-1 was dependent on autophagy, as 
evidenced by the lack of protection in IGF-1 treated mice in which Atg5 was conditionally 
deleted in the salivary gland. Subsequently, Limesand and colleagues showed that mice 
irradiated with a single dose of radiation (5Gy) and treated with the mTOR inhibitor CCI-779 
for five days (experimental days 4-8) had salivary flow rates and amylase secretion similar to 
unirradiated controls and statistically increased when compared to irradiated mice (Morgan- 
Bathke 2014). A follow-up mouse pilot study was conducted with a radiation regimen of 2 
Gy/day for 5 consecutive days followed by three injections of CCI-779 at four (experimental 
days 9-11), fourteen (experimental days 22-24) or 30 days (experimental days 38-40) after the 
last radiation treatment. Preliminary analysis at 60 days post-radiation suggests that 
administration of CCI-779 four or fourteen days after radiation leads to improved 
salivary output while administration 30 days later did not produce an improvement.
Impact: Reduction in saliva production and oral dryness can have a devastating effect on oral 
health that potentially leads to malnutrition and poor quality of life. Common palliative 
therapies for xerostomia include oral lubricants, saliva substitutes, and saliva stimulants (gum, 
pilocarpine). Unfortunately, these therapies are short-lived and have not consistently 
demonstrated the ability to relieve xerostomia symptoms. Therefore these patients are left 
with very few options and this research could provide a long-term solution for these 
individuals.
This research project brings together a newly-formed, diverse, interdisciplinary team to solve 
this complex problem. This team takes advantage of the expertise at both Banner – University 
Medical Center and St. Joseph's Hospital and Medical Center and the ability to recruit patients 
in Phoenix and Tucson. It extends the mouse model work conducted by the Limesand lab to a 
phase 0 “proof of principal” clinical trial.
Rapamycin derivatives exhibit considerable similarities in mechanism of action constituting a 
drug class effect. Therefore, this trial is proposing the use of everolimus due to the ease of 
administration (orally), which we postulate will have similar biological effects as CCI-779. If 
successful, the opportunity to expand to a randomized, placebo-controlled, double-blind 
clinical trial is envisioned.
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3
Objectives and endpoints
Initial Objective
Document the safe everolimus dose (5 mg versus 10 mg) to be used in the post radiation or 
chemoradiation setting for salivary function restoration, using a 3 + 3 design.
Once the safe dose has been defined:
Primary Objective
To describe the recovery of salivary gland function after administration of a 5-day course of 
everolimus, administered two weeks after completion of radiation or chemoradiation therapy
Primary endpoint
The primary end point of the analysis will be the percent recovery of salivary gland function, 
with pre-everolimus treatment saliva flow rate as the denominator and the saliva flow rate at 3 
months after completion of radiation or chemoradiation therapy as the numerator.
Secondary Objectives
-To describe the decrease of saliva flow rates during radiation or chemoradiation therapy
-To describe the changes in saliva protein composition during radiation or chemoradiation 
therapy and following administration of a 5-day course of everolimus
Secondary endpoints
Secondary endpoints will be:
- the decrease of saliva flow rates (compared to baseline prior to definitive treatment) during 
radiotherapy treatment at 3, 6 weeks and prior to everolimus administration and the 
subsequent recovery of saliva flow rates at completion of the 5 day everolimus course
and 1, 3 and 6 months after RT/chemoRT completion to determine the kinetics and stability of 
saliva flow rate recovery.
- protein composition within the saliva will be measured and will be expressed as percent 
decrease and recovery of amylase at all available time points.
- Xerostomia Visual Analog Scale survey and Xerostomia Inventory survey will be obtained 
from each participant at all available time points (See Appendix A and B).
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4
Study design
4.1
Description of study design
Patients treated with curative intent either in the post-operative or definitive setting with high 
dose radiotherapy (>50 Gy) with or without chemotherapy will be eligible. There will be one 
treatment group with each patient serving as their own control. Patients would have their 
salivary output measured before radiotherapy, 3 weeks after the start of radiotherapy, and at 
the end of radiotherapy (6 weeks). Patients who demonstrate more than a 50% decrease in
saliva flow rates will enter the treatment phase of the trial. Based on expert experience, we 
estimate that half the treated patients will exhibit a decrease of 50% or more in flow rate. 
These affected patients will then receive the planned dose of everolimus once a day for 5 
days, starting two weeks after the completion of radiotherapy. Salivary output 
measurements will be obtained prior to everolimus administration and at completion of the 5 
day everolimus course and at 1 month, 3 months and 6 months after the completion of 
radiation or chemoradiation therapy.
It is our expectation that because of the short exposure to everolimus (a total of 5 days only), 
the well described everolimus related toxicities will not develop.
However, following discussions with the company (Novartis), two dose levels will be 
evaluated: a starting dose of 5 mg po daily, will initially be evaluated in a cohort of 3 patients.
For the purpose of this trial, dose-limiting toxicity (DLT)is defined as an everolimus-related 
grade 3 or higher AE.
Toxicity will be graded based on the Common Terminology Criteria for Adverse Events 
(CTCAE) Version4.03. 
(http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf)
As mentioned, we will start treating enrolled patients on the lower dose level.
-If no DLT occurs, will proceed with dose escalation to the full FDA-approved dose (10 mg 
po daily) [in this case, total number of patients in the trial: 13; 3 in the 5 mg cohort, 10 in the 
10 mg cohort] .
-If 1 DLT occurs, cohort will be expanded to additional 3 patients;
and if another DLT occurs in this expanded cohort, no escalation to full dose (10 mg po 
daily) will be attempted, and cohort will be expanded to 10 patients [in this case, total 
number of patients in the trial: 10; all in the 5 mg cohort];
and if no additional DLT occurs in the expanded cohort, dose escalation to full dose (10 mg 
po daily) will follow [in this case, total number of patients in the trial: 16; 6 in the 5 mg 
cohort, 10 in the 10 mg cohort] .
-If 2 DLT occur, no escalation to full dose (10 mg po daily) will be attempted, and cohort will 
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be expanded to 10 patients. ) [in this case, total number of patients in the trial: 10; all in the 5 
mg cohort].
As a result of these possibilities, total number of patients included in this phase 0, proof of 
principle trial can range from a minimum of 10 to a maximum of 16 total patients.
Maximum number of 16 patients will occur if a DLT occurs in one of the first 3 patients in the 
5 mg cohort, and no DLT occurs in the additional 3 expanded cohort patients (for a total of 6 
patients in the 5 mg cohort). Subsequently, 10 additional patients will be enrolled in the 10 mg 
cohort, for a maximum total of 16 patients.
Procedures:
Stimulated Salivary flow measurements:
Patients will undergo both unstimulated whole saliva collection and stimulated whole 
saliva collection at each visit. Stimulated whole saliva collection measures the ability of 
the gland to respond to an external stimulus, which is necessary when eating. It is also 
likely that this measurement will correlate with swallowing difficulties. The average 
stimulated saliva output for a normal person is 1.5–2.0 mL/min and some studies have 
used a ≤0.5–0.7 mL/min cutoff for hyposalivation determination.
-
Patients must fast overnight, however, they may eat 2 hours prior to their scheduled 
appointment. They are encouraged to perform oral hygiene immediately after eating 
their meal to remove any remaining food particles, but no later than the two hour time 
period before their scheduled appointment. They also need to refrain from smoking 
two hours prior to their scheduled appointment.
-
Saliva production is stimulated by the patient chewing unflavored gum base or 
paraffin wax (1-2g) for 1 minute. The saliva is then collected by the patient spitting 
into pre-weighed specimen cups during this time frame
Unstimulated Whole Saliva Flow Rate and Collection
1) On the day of saliva collection, patient is to not have eaten for 2 hours prior to their 
scheduled collection appointment
a) No enteral feedings for 2 hours prior to collection appointment
b) Patient may eat no later than 2 hours prior to collection appointment; they are 
encouraged to perform oral hygiene immediately after eating their meal, however, 
refrain from any additional oral hygiene products 2 hours prior to collection 
appointment
c) Patient must refrain from smoking 2 hours prior to collection appointment 
2) During the collection period, the patient shall be seated straight up with eyes open and 
head tilted slightly forward
3) The patient will be instructed to minimize oro-facial movements to minimize influence 
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on salivary flow (the patient should not swallow and should not speak during the 
collection process).
4) Immediately before the collection begins, the patient is instructed to swallow.
5) The patient allows the saliva to accumulate on the floor of the mouth for 60 seconds 
without swallowing.
6) The patient empties the entire accumulated saliva into the pre-weighed specimen cup. 
The procedure is then repeated 2 additional times for a total of 3 minutes. Patients are 
instructed not to swallow during the entire 5-minute collection period.
Stimulated Whole Saliva Flow Rate and Collection
1) On the day of saliva collection, patient is not to have eaten for 2 hours prior to their 
scheduled collection appointment
a) No enteral feedings for 2 hours prior to collection appointment
b) Patient may eat no later than 2 hours prior to collection appointment; they are 
encourage to perform oral hygiene immediately after eating their meal, however, 
refrain from any additional oral hygiene products 2 hours prior to collection 
appointment
c) Patient must refrain from smoking 2 hour prior to collection appointment
2) Patient will chew unflavored sugarless gum for 1 minute (60 seconds).
3) Instruct patient to sit motionless. 
4) Instruct patient to lean their head forward over the specimen cup.
5) Instruct patient to swallow to void the mouth of saliva (starting time).
6) Every one minute, ask patient to spit saliva into the cup without swallowing. Tell 
patient “spit out, keep chewing” after first minute, “spit out, keep chewing” after 
second minute, etc. Discard the first 2-minute collection. A plastic or paper cup may 
be used for this collection. Proceed with another 3-minute collection. Save this 
sample for further analysis.
7) Ask the patient to spit everything (both saliva and gum base) into the specimen cup.
8) Remove the gum base from the specimen cup before weighing the cup with saliva.
9) If the patient is too dry, (dry mouth), it is possible to add the weight of the gum base 
to the pre-weight measure with the gum base in the cup of saliva.
Analysis of saliva: The collection tubes are weighed before and after saliva collection. The 
difference equates to the total mL collected which is divided by the number of minutes of 
collection. Saliva is stored at -80oC for further analysis on salivary protein composition at 
a later date (described in correlatives below).
The comorbidity of mucositis is an important consideration in this study due to the 
development of this condition following radiotherapy and as a side effect from chronic use of 
everolimus. Treatment with everolimus has been designed to begin two weeks after 
radiotherapy to allow radiation-induced mucositis to start improving. In a pre-clinical model, 
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concurrent rapamycin treatment with radiotherapy (6Gy/day X 5 days) prevents mucositis due 
in part to increased expression of mitochondrial superoxide dismutase (MnSOD) (Iglesias- 
Bartolome 2012). Given the short duration of treatment in this trial (5 days), a delay in the 
start of everolimus until two weeks after radiotherapy and evidence from this pre-clinical 
study, we postulate that mucositis will not be a major concern. Patients will be closely 
monitored for worsening mucositis response once treated with everolimus and if mucositis 
worsens in 2 out of the first 6 patients, then everolimus 50% dose reduction will be 
implemented.
5
Population
Patients with locally advanced squamous cell carcinoma of the head and neck, treated with 
curative intent either in the post-operative or definitive setting with high dose radiotherapy 
(>50 Gy) with or without chemotherapy will be eligible. Patients will be stratified for 
exploratory analyses in the analysis phase on the basis of ipsilateral vs bilateral neck 
irradiation. There will be one treatment group with each patient serving as their own control.
This study will evaluate the response in 10 – 16 patients enrolled at both facilities: St. 
Joseph's Hospital and Medical Center in Phoenix and Banner – University Medical 
Center in Tucson (details and justification of sample size in statistical methods) to 
determine if the proposed everolimus dosing schedule of 5 days is sufficient to show 
recovery of salivary gland function to pre-treatment levels.
These data will also provide guidance on an option for a longer delivery of everolimus in 
patients with a partial improvement of salivary flow or an option for de-escalation of dose if a 
large number of patients demonstrate improvements in salivary flow at early time points.
5.1
Inclusion and Exclusion criteria
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria. Results of all baseline evaluations, which assure that 
all inclusion and exclusion criteria have been satisfied, must be reviewed by the Principal 
Investigator or his/her designee prior to enrollment of that patient. 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.
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Inclusion criteria:
1. Age 18-75 years
2. Performance status ECOG ≤ 2
3. Adequate bone marrow function as shown by: ANC ≥1.5 x 109/L, Platelets ≥100 x 109/L, 
Hgb >9 g/dL;
4. Adequate liver function as shown by:
a. Total serum bilirubin ≤2.0 mg/dL,
b. ALT and AST ≤2.5x ULN (≤5x ULN in patients with liver metastases),
c. INR ≤2;
5. Adequate renal function: serum creatinine ≤1.5x ULN;
6. Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤2.5x 
ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be 
included after initiation of appropriate lipid lowering medication;
7. Signed informed consent obtained prior to any screening procedures.
8. Patients with locally advanced squamous cell carcinoma of the head and neck, treated with 
curative intent either in the post-operative or definitive setting with high dose radiotherapy 
(>50 Gy) with or without chemotherapy.
Exclusion criteria:
1. Patients currently receiving anticancer therapies or who have received anticancer therapies 
within 2 weeks of the start of Everolimus (including chemotherapy, radiation therapy, 
antibody based therapy, etc.);
2. Known intolerance or hypersensitivity to Everolimus or other rapamycin analogs (e.g. 
sirolimus, temsirolimus);
3. Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of oral Everolimus;
4. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. 
Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may 
be included, however blood glucose and antidiabetic treatment must be monitored closely 
throughout the trial and adjusted as necessary;
5. Patients who have any severe and/or uncontrolled medical conditions such as:
a. unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction
≤6 months prior to start of Everolimus, serious uncontrolled cardiac arrhythmia, or 
any other clinically significant cardiac disease
b. Symptomatic congestive heart failure of New York heart Association Class III or IV
c. active (acute or chronic) or uncontrolled severe infection, liver disease such as 
cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e. 
quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA),
d. known severely impaired lung function (spirometry and DLCO 50% or less of normal 
and O2 saturation 88% or less at rest on room air),
e. active, bleeding diathesis;
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6. Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or 
inhaled corticosteroids are allowed;
7. Known history of HIV seropositivity;
8. Patients who have received live attenuated vaccines within 1 week of start of Everolimus 
and during the study. Patient should also avoid close contact with others who have 
received live attenuated vaccines. Examples of live attenuated vaccines include intranasal 
influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a 
typhoid vaccines;
9. Patients who have a history of another primary malignancy, with the exceptions of: non- 
melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from which the 
patient has been disease free for ≥3 years;
10. Patients with a history of non-compliance to medical regimens or who are considered 
potentially unreliable or will not be able to complete the entire study;
11. Patients who are currently part of or have participated in any clinical investigation with an 
investigational drug within 1 month prior to dosing;
12. Pregnant or nursing (lactating) women;
13. Women of child-bearing potential (WOCBP) (including female pediatric patients who are 
menarcheal or who become menarcheal during the treatment), defined as all women 
physiologically capable of becoming pregnant, must use highly effective methods of 
contraception during the study and 8 weeks after. Women are considered post-menopausal 
and not of child-bearing potential if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor 
symptoms). Highly effective contraception  methods include combination of any two of 
the following:
Use of oral, injected or implanted hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example, hormone 
vaginal ring or transdermal hormone contraception. In case of use of oral  contraception 
women should have been stable on the oral agent for a minimum of 3 months before taking 
everolimus
a. Total abstinence or;
b. Male partner sterilization. (The vasectomized male partner should be the sole partner 
for that subject)
c. Female sterilization have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks prior to 
randomization. In the case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child-bearing potential.
14. Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate 
contraception, during the study and for 8 weeks after the end of treatment
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Screening for hepatitis B
Prior to randomization/start of Everolimus, the following three categories of patients should be 
tested for hepatitis B viral load and serologic markers, that is, HBV-DNA, HBsAg, HBs Ab, 
and HBc Ab:

All patients who currently live in (or have lived in) Asia, Africa, Central and South 
America, Eastern Europe, Spain, Portugal and Greece. 
[http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to- 
travel/hepatitis-b.htm]

Patients with any of the following risk factors:

known or suspected past hepatitis B infection,

blood transfusion(s) prior to 1990,

current or prior IV drug users,

current or prior dialysis,

household contact with hepatitis B infected patient(s),

current or prior high-risk sexual activity,

body piercing or tattoos,

mother known to have hepatitis B

history suggestive of hepatitis B infection, e.g., dark urine, jaundice, right upper 
quadrant pain.

Additional patients at the discretion of the investigator
The management guidelines, in Section 6.2.3.10, are provided according to the results of the 
baseline assessment of viral load and serological markers for hepatitis B.
Screening for hepatitis C
Patients with any of the following risk factors for hepatitis C should be tested using 
quantitative RNA-PCR:

known or suspected past hepatitis C infection (including patients with past interferon 
‘curative’ treatment),

blood transfusions prior to 1990,

current or prior IV drug users,

current or prior dialysis,

household contact of hepatitis C infected patient(s),

current or prior high-risk sexual activity,

body piercing or tattoos.
At the discretion of the investigator, additional patients may also be tested for hepatitis C.
The management guidelines, in Section 6.2.3.10, are provided according to the results of the 
baseline assessment of hepatitis C viral load.
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6
Treatment
6.1
Study treatment
It is our expectation that because of the short exposure to everolimus (a total of 5 days only), 
the well described everolimus related toxicities will not develop.
However, following discussions with the company (Novartis), two dose levels will be 
evaluated: a starting dose of 5 mg po daily, will initially be evaluated in a cohort of 3 patients.
For the purpose of this trial, dose-limiting toxicity (DLT) is defined as an everolimus-related 
grade 3 or higher AE.
Toxicity will be graded based on the Common Terminology Criteria for Adverse Events 
(CTCAE) Version4.03. 
(http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf)
As mentioned, we will start treating enrolled patients on the lower dose level.
-If no DLT occurs, will proceed with dose escalation to the full FDA-approved dose (10 mg 
po daily).
-If 1 DLT occurs, cohort will be expanded to additional 3 patients; and if another DLT occurs 
in this expanded cohort no escalation to full dose(10 mg po daily) will be attempted, and 
cohort will be expanded to 10 patients. If no additional DLT occurs in the expanded cohort, 
dose escalation to full dose (10 mg po daily) will follow.
-If 2 DLT occur, no escalation to full dose (10 mg po daily) will be attempted, and cohort will 
be expanded to 10 patients.
As a result of these possibilities, total number of patients included in this phase 0, proof of 
principle trial can range from a minimum of 10 to a maximum of 16 total patients.
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded.
Medication labels will comply with US legal requirements and be printed in English. They will 
supply no information about the patient. The storage conditions for Everolimus will be 
described on the medication label.
Everolimus is supplied by Novartis. Everolimus is formulated as tablets for oral administration 
of 2.5mg, 5mg, and 10mg strength. Tablets are blister-packed under aluminum foil, which 
should be opened only at the time of administration as drug is both hygroscopic and light- 
sensitive. Refer to label for expiration date and storage conditions.
The extent of absorption of everolimus through topical exposure is not known. Therefore, 
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caregivers are advised to avoid contact with suspensions of Afinitor Tablets. Wash hands 
thoroughly before and after preparation of either suspension.
6.1.1
Dosing regimen
The investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient should be instructed to contact the investigator if he/she is 
unable for any reason to take the study drug as prescribed.
Everolimus should be administered orally once daily at the same time every day, either 
consistently with or consistently without food.
Tablets
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 until the tablet(s) is fully 
disintegrated (approximately 7 minutes), 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.
If vomiting occurs, no attempt should be made to replace the vomited dose. Patients should be 
instructed that if they miss a dose on one day, they must not take any extra dose the next day, 
but instead to immediately contact the study center as soon as possible to ask for advice.
6.2
Dose modifications
6.2.1
Dose modification and dose delay
6.2.1.1
Hepatic impairment dose modifications
Hormone receptor-positive advanced breast cancer, advanced neuroendocrine tumors of 
gastrointestinal, lung, or pancreatic origin, and advanced renal cell carcinoma:
Severe hepatic impairment (Child-Pugh C) – not recommended. TSC with SEGA
Patients ≥ 18 years of age:

Severe hepatic impairment (Child-Pugh C) – not recommended.
Everolimus whole blood trough concentrations should be assessed approximately 2 weeks after 
commencing treatment or after any change in hepatic (Child-Pugh) status.
Patients < 18 years of age:
Afinitor is not recommended for patients <18 years of age with TSC who have SEGA and 
hepatic impairment.
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Afinitor is not recommended for patients with hepatic impairment who require doses below 2 
mg every other day or 2.5 every other day. Everolimus exposure was increased in patients 
with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic 
impairment (see Section 5.2.3). Everolimus is not recommended for use in postmenopausal 
women with hormone receptor positive advanced breast cancer, or in patients with advanced 
neuroendocrine tumors of gastrointestinal, lung, or pancreatic origin or advanced renal cell 
carcinoma with severe hepatic impairment (Child-Pugh C) unless the potential benefit 
outweighs the risk.
Special Populations
Geriatrics (≥ 65 years) :
No dosage adjustment is required. 
Renal impairment :
No dosage adjustment is required.
Ethnicity :
Pharmacokinetic characteristics are similar for Caucasian and Japanese subjects. 
Pharmacokinetic studies in Black transplant patients have shown an average 20% higher 
clearance.
6.2.1.2
Dosing modifications
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
not permitted.
Table 6-1 and Table 6-2 list the dosing guidelines for Everolimus-related non-hematologic and 
hematologic toxicities.
Management of severe or intolerable adverse drug reactions (ADRs) may require temporary 
dose interruption  of Afinitor therapy.
The proceeding sections summarize recommendations for dose interruption, or discontinuation 
of Afinitor in the management of ADRs. General management recommendations are also 
provided as applicable. Clinical judgment of the treating physician should guide the 
management plan of each patient based on individual benefit/risk assessment.
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Table 6-1
Dosing guidelines for Everolimus-related non-hematologic toxicities
Toxicity
Action
Non-Infectious Pneumonitis
Discontinue Everolimus. 
Reactivation of HBV or HCV flare
Discontinue Everolimus.
AST or ALT elevation
Grade 1 (> ULN - 3.0 x ULN) 
Grade 2 (> 3.0 - 5.0 x ULN)
AST or ALT elevation 
Grade 3 (> 5.0 - 20.0 ULN)*
AST or ALT elevation 
Grade 4 (> 20 x ULN)*
Maintain current dose level
Discontinue Everolimus 
Discontinue Everolimus
Intolerable grade 2 mucositis, or grade 
3 AE, except hyperglycemia or 
hypertriglyceridemia or 
hypercholesterolemia (see Section 
6.2.3.8)
Discontinue Everolimus
Any other grade 4
Discontinue Everolimus
Grade 3 or 4 clinical liver failure 
(asterixis or encephalopathy/coma)
* Should HCV flare be confirmed, the 
guidelines for flare must take 
precedence (Table 6-6)
Discontinue Everolimus
Table 6-2
Dosing guidelines for Everolimus-related hematologic toxicities
Toxicity
Action
Grade 2 thrombocytopenia (platelets <75,
≥ 50x109/L)
Grade 3 thrombocytopenia (platelets <50,
≥ 25 x109/L)
Grade 4 thrombocytopenia (platelets < 25 
x109/L)
Grade 3 neutropenia or anemia 
(neutrophil <1, ≥0.5 x109/L)
No action
Discontinue Everolimus 
Discontinue Everolimus 
Discontinue Everolimus
Grade 4 neutropenia or anemia
Discontinue Everolimus
Febrile neutropenia
Discontinue Everolimus
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6.2.2      Management of specific toxicities
Overall, safety data available from completed, controlled and uncontrolled studies indicate that 
everolimus is generally well tolerated at weekly or daily dose schedules. The safety profile is 
characterized by manageable adverse events (AEs). These AEs are generally reversible and 
non-cumulative.
Adverse events most frequently observed with everolimus are stomatitis, rash, fatigue, diarrhea, 
infections, nausea, decreased appetite, anemia, dysgeusia, pneumonitis, edema peripheral, 
hyperglycemia, asthenia, pruritus, weight decreased, hypercholesterolemia, epistaxis, cough, 
and headache. Overall, the most frequently observed laboratory abnormalities include 
decreased hematology parameters including hemoglobin, lymphocytes, platelets, and 
neutrophils (or collectively as pancytopenia).; increased clinical chemistry parameters 
including cholesterol, triglycerides, glucose, aspartate transaminases, creatinine, alanine 
transaminases, and bilirubin; and decreased clinical chemistry parameters including phosphate 
and potassium.. The majority of these AEs have been of mild to moderate severity (NCI CTC 
grade 1-2).
6.2.2.1   Management of infections
Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, 
viral or protozoal infections, including infections with opportunistic pathogens. Localized and 
systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, 
such as aspergillosis or candidiasis and viral infections including reactivation of hepatitis B 
virus, have been described in patients taking Everolimus. Some of these infections have been 
severe (e.g. leading to sepsis, respiratory or hepatic failure) and occasionally have had a fatal 
outcome.
Physicians and patients should be aware of the increased risk of infection with Everolimus. 
Treat pre-existing infections prior to starting treatment with Everolimus. While taking 
Everolimus, be vigilant for symptoms and signs of infection; if a diagnosis of infection is made, 
institute appropriate treatment promptly and consider interruption or discontinuation of 
Everolimus.
If a diagnosis of invasive systemic fungal infection is made, discontinue Everolimus and treat 
with appropriate antifungal therapy.
Cases of pneumocystis jirovecii pneumonia (PJP), some with a fatal outcome, have been 
reported in patients who received everolimus. PJP may be associated with concomitant use of 
corticosteroids or other immunosuppressive agents. Prophylaxis for PJP should be considered 
when concomitant use of corticosteroids or other immunosuppressive agents are required.
6.2.2.2   Management of skin toxicity
For patients with grade 1 toxicity, no specific supportive care is usually needed or indicated. 
Rash must be reported as an AE. Patients with grade 2 or higher toxicity may be treated with 
the  following  suggested  supportive  measures  at  the  discretion  of  the  investigator:     oral
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minocycline, topical tetracycline, topical clindamycin, topical silver sulfadiazine, 
diphenhydramine, oral prednisolone (short course), topical corticosteroids, or pimecrolimus.
6.2.2.3 Management of Hypersensitivity reactions
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.
6.2.2.4 Angioedema with concomitant use of angiotensin-converting enzyme (ACE) 
inhibitors
Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema 
(e.g. swelling of the airways or tongue, with or without respiratory impairment).
6.2.2.5 Renal Failure Events
Cases of renal failure (including acute renal failure), some with fatal outcome, occurred in 
patients treated with everolimus. Renal function of patients should be monitored particularly 
where patients have additional risk factors that may further impair renal function.
Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients 
taking everolimus. Monitoring of renal function, including measurement of blood urea nitrogen 
(BUN), urinary protein, or serum creatinine, is recommended prior to the start of everolimus 
therapy and periodically thereafter.
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6.2.2.6 Management of stomatitis / oral mucositis / mouth ulcers
Adverse Drug Reaction
Severity
Afinitor Dose Adjustment and Management
Recommendations
Stomatitis
Grade 1
(Minimal 
symtpoms, 
normal diet)
Grade 2 
(Symptomatic 
but can eat and 
swallow 
modified diet)
Grade 3 
(Symptomatic 
and unable to 
adequately eat 
or hydrate 
orally)
Grade 4 
(Symptoms 
associated with 
life-threatening 
consequences)
No dose adjustment required.
Manage with non-alcoholic or salt water (0.9%) mouth 
wash several times a day.
Temporary dose interruption until recovery to grade ≤1.
Re-initiate Afinitor at the same dose.
If stomatitis recurs at grade 2, discontinue Afinitor. 
Manage with topical analgesic mouth treatments (e.g. 
benzocaine, butyl aminobenzoate, tetracaine hydrochloride,
menthol or phenol) with or without topical corticosteroids
(i.e. triamcinolone oral paste)*. 
Discontinue Everolimus
Discontinue Afinitor and treat with appropriate medical 
therapy.
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* using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis 
as they may worsen mouth ulcers.
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with 
gastrointestinal morbidity associated with mouth/dental infections, irritation of esophageal 
mucosa e.g. gastroesophageal reflux disease (GERD) and pre-existing stomatitis/mucositis 
must be monitored even more closely. Patients should be instructed to report the first onset of 
buccal mucosa irritation/reddening to their study physician immediately.
Stomatitis/oral mucositis/mouth ulcers due to Everolimus should be treated using local 
supportive care. Please note that investigators in earlier trials have described the oral toxicities 
associated with Everolimus as mouth ulcers, rather than mucositis or stomatitis. If your 
examination reveals mouth ulcers rather than a more general inflammation of the mouth, please 
classify the adverse event as such. The suggested paradigm for treatment of stomatitis/oral 
mucositis/mouth ulcers is as follows:
1. For mild toxicity (grade 1), no dose adjustment required. Manage with non-alcoholic 
mouth wash or salt water (0.9%) mouth wash several times a day until resolution.
2. For more severe toxicity (grade 2 in which case patients have pain but are able to maintain 
adequate oral alimentation, or grade 3 in which case patients cannot maintain adequate 
oral alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., 
local anesthetics such as, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral 
paste 0.1% (Kenalog in Orabase®).
3. Agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers.  These agents should be avoided.
4. Antifungal agents should be avoided unless a fungal infection is diagnosed. In particular, 
systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) 
should be avoided in all patients due to their strong inhibition of Everolimus metabolism, 
therefore leading to higher Everolimus exposures. Therefore, topical antifungal agents are 
preferred if an infection is diagnosed.
6.2.2.7 Management of diarrhea
Appearance of grade 1-2 diarrhea attributed to study drug toxicity may be treated with 
supportive care such as loperamide, initiated at the earliest onset (for example 4 mg orally 
followed by 2 mg orally every 2 hours until resolution of diarrhea).
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6.2.2.8 Management of hyperlipidemia and hyperglycemia
Adverse Drug Reaction
Severity
Afinitor Dose Adjustment and Management 
Recommendations
Metabolic events 
(e.g. 
hyperglycemia, 
dyslipidemia)
Grade 1
No dose adjustment required.
Initiate appropriate medical therapy and monitor.
Grade 2
No dose adjustment required.
Manage with appropriate medical therapy and monitor.
Grade 3
Discontinue Everolimus
Grade 4
Discontinue Everolimus
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary habits 
of the patient. Grade 2 or higher hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) or grade 
2 hypertriglyceridemia or higher (>2.5x upper normal limit) should be treated with a 3-hydroxy- 
3-methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g. atorvastatin, pravastatin, fluvastatin) or 
appropriate triglyceride-lowering medication, in addition to diet.
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated 
with an increased risk of a rare but serious skeletal muscle toxicity manifested by 
rhabdomyolysis, markedly elevated creatine phosphokinase (CPK) levels and myoglobinuria, 
acute renal failure and sometimes death. The risk versus benefit of using this therapy should be 
determined for individual patients based on their risk of cardiovascular complications of 
hyperlipidemia.
Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been reported in 
patients taking everolimus. Monitoring of blood cholesterol and triglycerides prior to the start 
of everolimus therapy and periodically thereafter as well as management with appropriate 
medical therapy is recommended.
Hyperglycemia has been reported in patients taking everolimus. Monitoring of fasting serum 
glucose is recommended prior to the start of Everolimus and periodically thereafter. More 
frequent monitoring is recommended when everolimus is co-administered with other drugs that
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may induce hyperglycemia. Optimal glycemic control should be achieved before starting a 
patient on Everolimus.
6.2.2.9 Management of non-infectious pneumonitis
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious 
pneumonitis (including interstitial lung disease) have also been described in patients taking 
Everolimus. Some of these have been severe and on rare occasions, a fatal outcome was 
observed.

A diagnosis of non-infectious pneumonitis should be considered in patients presenting 
with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough 
or dyspnea, and in whom infectious, neoplastic and other non-medicinal causes have been 
excluded by means of appropriate investigations. Opportunistic infections such as PJP 
should be ruled out in the differential diagnosis of non-infectious pneumonitis. 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 Afinitor 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. Afinitor may be 
reintroduced at a daily dose approximately 50% lower than the dose previously administered.
For cases of grade 3 non-infectious pneumonitis, discontinue Afinitor. For cases of grade 4 non-
infectious pneumonitis, Afinitor therapy should be discontinued. Corticosteroids may be 
indicated until clinical symptoms resolve.
For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, 
prophylaxis for pneumocystis jirovecii pneumonia (PJP) may be considered. The two 
compounds studied most extensively for prophylaxis against PJP have been trimethoprim- 
sulfamethoxazole, given orally, and pentamidine, given as an aerosol.
If non-infectious pneumonitis develops, the guidelines in Table 6-3 should be followed. 
Consultation with a pulmonologist is recommended for any case of pneumonitis that develops 
during the study.
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Table 6-3
Management of non-infectious pneumonitis
Worst grade 
pneumonitis
Grade 1 
(Asymptomatic, 
radiographic 
findings only)
Suggested investigations
Management of 
pneumonitis
CT scans with lung windows.
No specific therapy 
is required
Everolimus dose adjustment
No dose adjustment required. 
Initiate appropriate monitoring.
Grade 2 
(Symptomatic, 
not interfering 
with Activities 
of Daily Living)
Grade 3 
(Symptomatic, 
Interfering with 
Activities of 
Daily Living.
O2 indicated
CT scan with lung windows. Consider 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Consider a 
bronchoscopy with biopsy and/or BAL. 
Monitoring at each visit until return to ≤ 
grade 1. Return to initial monitoring 
frequency if no recurrence.
CT scan with lung windows and 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Monitoring at each 
visit until return to ≤ grade 1. Return to 
initial monitoring frequency if no 
recurrence.  Bronchoscopy  with biopsy
Symptomatic only. 
Consider 
corticosteroids 
and/or other 
supportive therapy if 
symptoms are 
troublesome.
Consider 
corticosteroids
if 
infective origin is 
ruled out. Taper as 
medically indicated.
Rule out infection and consider 
interruption of Everolimus until 
symptoms improve to Grade ≤ 1.
Rule out infection and discontinue 
Everolimus until symptoms improve 
to Grade ≤ 1.
 
and/or BAL is recommended.
Grade 4 (Life- 
threatening, 
ventilator 
support 
indicated)
CT scan with lung windows and required 
pulmonary function testing, if possible, 
includes: spirometry, DLCO, and room 
air O2 saturation at rest. Monitoring at 
each visit until return to ≤ grade 1. 
Return to initial monitoring frequency if 
no 
recurrence. 
Bronchoscopy 
with 
biopsy and/or BAL is recommended    if
Consider 
corticosteroids
if 
infective origin is 
ruled out. Taper as 
medically indicated.
Rule out infection and discontinue 
Everolimus.
 
possible.
6.2.2.10
Management of hepatitis reactivation / flare
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving 
chemotherapy (Yeo 2004). 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 
(Loomba 2008). 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.
Monitoring and prophylactic treatment for hepatitis B reactivation
Table 6-4 provides detail of monitoring and prophylactic therapy according to the screening 
results of viral load and serologic markers testing.
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Table 6-4
Action to be taken based on screening hepatitis B results
Test
Result
Result
Result
Result
Result
HBV-DNA
+
+ or -
-
-
-
HBsAg
+ or -
+
-
-
-
HBsAb
+ or -
+ or -
+
and no prior HBV 
vaccination
+ or -
-
or + with prior 
HBV vaccination
HBcAb
+ or -
+ or -
+ or -
+
-
Recommendation
Prophylaxis treatment should 
be started 1-2 weeks prior to 
first dose of Everolimus
Monitor HBV-DNA 
approximately every 4-8 
weeks
No prophylaxis
Monitor HBV-DNA 
approximately every 3-4 weeks
No specific action
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of Everolimus. 
For HBV reactivation definition and management guidelines, seeTable 6-5.
Table 6-5
Guidelines for the management of hepatitis B reactivation
HBV reactivation (with or without clinical signs and symptoms)*
For patients with baseline 
results:
Positive HBV-DNA
OR
positive HBsAg
--------------------------------------
reactivation is defined as: 
[Increase of 1 log in HBV-DNA 
relative to baseline HBV-DNA 
value OR new appearance of 
measurable HBV-DNA]
Treat: Start a second antiviral medication 
AND
Discontinue  Everolimus administration.
For patients with baseline 
results:
Negative HBV-DNA and HBsAg
AND
[Positive HBsAb (with no prior 
history of vaccination against 
HBV), OR positive HBcAb]
-------------------------------------
Reactivation is defined as: 
New appearance of measurable 
HBV-DNA
Treat : Start first antiviral medication 
AND
Discontinue Everolimus
* All reactivations of HBV are to be recorded as grade 3 (e.g. CTCAE Version 3.0 - Investigations/Other: Viral 
Reactivation), unless considered life threatening by the investigator, in which case they should be recorded as grade 4. Date 
of viral reactivation is the date on which the rise or reappearance of HBV-DNA was recorded.
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Monitoring for hepatitis C flare
The following two categories of patients should be monitored every 4–8 weeks for HCV flare:

Patients with detectable HCV RNA-PCR test at screening.

Patients known to have a history of HCV infection, despite a negative viral load test at 
screening (including those that were treated and are considered ‘cured’)
For definitions of HCV flare and actions to be taken in the event of a flare, please refer to Table 
6-6.
Table 6-6
Guidelines for the management of hepatitis C flare
Baseline results
HCV flare definition*
HCV flare management
Detectable HCV-RNA
> 2 log10 IU/mL increase in HCV-RNA
AND
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher.
Discontinue Everolimus
Knowledge of past hepatitis C 
infection with no detectable 
HCV-RNA
New appearance of detectable HCV-RNA
AND
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher.
Discontinue Everolimus
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* All flares of HCV are to be recorded as grade 3 (e.g. CTCAE Version 3.0 - Investigations - Other: Viral Flare), 
unless considered life threatening by the investigator; in which case they should be recorded as grade 4. Date of 
viral flare is the date on which both the clinical criteria described above were met. (e.g., for a patient whose 
HCV-RNA increased by 2 logs on 01 JAN 2011 and whose ALT reached > 5 x ULN on 22 JAN 2011, the date 
of viral flare is 22 JAN 2011).
6.3
Concomitant medications
Patients must be instructed not to take any medications (over-the-counter or other products) 
during the protocol treatment period without prior consultation with the investigator. The 
investigator should instruct the patient to notify the study site about any new medications he/she 
takes after the start of study drug. All medications (other than study drug) and significant non- 
drug therapies (including physical therapy and blood transfusions) taken within 28 days of 
starting study treatment through the 30-day safety follow up visit should be reported on the CRF.
6.3.1         Permitted concomitant therapy
Cytochrome P450 and P-glycoprotein inhibitors/inducers/substrates
Co-administration with strong inhibitors of CYP3A4 or PgP should be avoided; and may
cause increased everolimus concentrations. For a current table of Substrates, Inhibitors and 
Inducers please access the following website:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera 
ctionsLabeling/ucm093664.htm
Everolimus is metabolized by CYP3A4 in the liver and to some extent in the intestinal wall. Therefore, 
the following are recommended:

Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
ritonavir) or P-glycoprotein (PgP) inhibitor should be avoided.

Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or 
PgP inhibitors should be used with caution. If a patient requires co-administration of 
moderate CYP3A4 inhibitors or PgP inhibitors, reduce the dose of everolimus by 
approximately 50%. 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.

TSC with SEGA: Everolimus trough concentrations should be assessed 
approximately 2 weeks after the addition of a moderate CYP3A4/PgP inhibitor. If the 
inhibitor is discontinued the Afinitor dose should be returned to the dose used prior to 
initiation of the inhibitor and the everolimus trough concentration should be re- 
assessed approximately 2 weeks later.

Grapefruit, Seville oranges, and starfruit affect P450 and PgP activity. Concomitant use 
should be avoided.

If patients require co-administration of a strong CYP3A4 inducer, consider doubling the 
daily dose of Afinitor (based on pharmacokinetic data), using increments of 5 mg or less. 
This dose of Afinitor is predicted to adjust the AUC to the range observed without 
inducers. However, there are no clinical data with this dose adjustment in patients 
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receiving strong CYP3A4 inducers. If the strong inducer is discontinued, consider a 
washout period of at least 3 to 5 days (reasonable time for significant enzyme de- 
induction), before the Afinitor dose is returned to the dose used prior to initiation of the 
strong CYP3A4 inducer.

TSC with SEGA Patients receiving concomitant strong CYP3A4 inducers (e.g., the 
enzyme inducing antiepileptic drugs carbamazepine, phenobarbital, and phenytoin) 
may require an increased Afinitor dose to attain trough concentrations of 3 to 15 
ng/mL. Double the daily dose of Afinitor and assess tolerability. Assess the 
everolimus trough level two weeks after doubling the dose. Further adjust the dose if 
necessary to maintain the trough within the 3 to 15 ng/mL range. If the strong inducer 
is discontinued, the Afinitor dose should be returned to the dose used prior to initiation 
of the strong CYP3A4 inducer and the everolimus trough concentrations should be 
assessed approximately 2 weeks later.

This dose adjustment of Everolimus is intended to achieve similar AUC to the range 
observed without inducers. However, there are no clinical data with this dose adjustment 
in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the 
Everolimus dose should be returned to the dose used prior to initiation of the strong 
CYP3A4/PgP inducer.
Please refer to Table 6-8 listing relevant inducers and inhibitors of CYP3A and Table 6-9 for a 
list of relevant substrates, inducers, and inhibitors of PgP.
Everolimus and drugs influencing CYP3A4 enzyme
Everolimus is a substrate of CYP3A4, and a substrate and moderate inhibitor of the multidrug 
efflux pump, PgP (PgP, MDR1, and ABCB1). Therefore, extent of absorption and subsequent 
elimination  of  systemically  absorbed  everolimus  may  be  influenced  by  products  that are 
substrates, inhibitors, or inducers of CYP3A4 and/or PgP. Concurrent treatment with strong 
CYP3A4-inhibitors should be avoided. Refer to Table 6-2 in section 6 for a comprehensive list 
of inducers and inhibitors of CYP3A4 and Table 6-3 ]for a list of relevant substrates, inducers 
and inhibitors of PgP. Inhibitors of PgP may decrease the efflux of everolimus from brain or 
tumor and therefore increase everolimus concentrations in these tissues. In vitro studies showed 
that everolimus is a competitive inhibitor of CYP3A4 and of CYP2D6, potentially increasing 
the concentrations of products eliminated by these enzymes. Thus, caution should be exercised 
when co-administering everolimus with CYP3A4 and CYP2D6 substrates with a narrow 
therapeutic index. Clinical studies have been conducted in healthy subjects to assess 
pharmacokinetic drug interactions between everolimus and potential CYP3A modifiers 
(ketoconazole, verapamil, erythromycin, rifampin, midazolam, and HMGCoA reductase 
inhibitors (statins).
Table 6-7
Clinically relevant drug interactions: inducers, and inhibitors of isoenzyme 
CYP3A
Strong inducers:
Inducers
avasimibe, carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St.
John's wort
(hypericum perforatum)
Moderate inducers:
bosentan, efavirenz, etravirine, genistein,lersivirine, lopinavir, modafinil, nafcillin, ritonavir, semagacestat, 
[talviraline], thioridazine, tipranavir
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Weak inducers:
amprenavir, aprepitant, armodafinil (R-modafinil), bexarotene, boceprevir, brivacetam, clobazam, danshen, 
dexamethasone, Echinacea,eslicarbazepine,
garlic (allium sativum), ginseng, gingko (ginkgo biloba), glycyrrhizin, methylprednisolone, nevirapine, 
oxcarbazepine,
pioglitazone, prednisone, [pleconaril], primidone,quercetin, raltegravir, ritonavir, rufinamide, sorafenib, stribild 
(combo of elvitegravir, cobicistat, emtricitabine, and tenofovir), sulfinpyrazone, telaprevir, terbinafine, ticagleror, 
ticlopidine,
topiramate, [troglitazone] , vemurafenib, vicriviroc/ritonavir vinblastine
Inhibitors
Strong inhibitors:
boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir / ritonavir, eltegravir/ritonavir, grapefruit juice, 
indinavir,indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir,
mibefradil, nefazodone, nelfinavir, posaconazole , ritonavir, saquinavir, saquinavir/ritonavir, telaprevir, 
telithromycin, tipranavir/ritonavir, troleandamycin, voriconazole
Moderate inhibitors:
Amprenavir, aprepitant, atazanavir, atazanavir/ritonavir casopitant, cimetidine, ciprofloxacin, crizotinib, 
cyclosporine, darunavir, darunavir/ritonavir, diltiazem,
dronedarone, erythromycin, fluconazole, fosamprenavir, grapefruit juice (citrus parasidi fruit juice), 
imatinib,lomitapide, netupitant, nilotinib
schisandra sphenanthera, tofisopam, verapamil
Weak inhibitors:
almorexant, alprazolam, alprazolam, amiodarone, amlodipine, amlodipine, atorvastatin, azithromycin, berberine, 
bicalutamide, bicalutamide, blueberry juice, cilostazol, cilostazol, cimetidine, clotrimazole, clozoxazone, cranberry 
juice, cyclosporine, delavirdine, everolimus, fluoxetine, fluvoxamine, fosaprepritant, ginkgo, goldenseal, isoniazid, 
isoniazid, ivacaftor, lacipidine, linagliptin, nilotinib, oral contraceptives, pazopanib, peppermint oil, propiverine, 
ranitidine, ranitidine, ranolaxine, ranolazine, resveratrol, roxithromycin, Seville orange, simeprevir, sitaxentan, 
tabimorelin, tacrolimus, teriflunomide, ticagrelor, tipranavir/ritonavir, tolvaptan, zileuton
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Table 6-8
Clinically relevant drug interactions: substrates, inducers, inhibitors of  PgP and 
PgP/CYP3A dual inhibitors
Substrates
afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, apremilast, aprepitant, atorvastatin acid, 
atorvastatin, azithromycin, boceprevir, bosentan, carvedilol, caspofungin, ceritinib, cerivastatin, citalopram, 
colchicine, CP-481,715, cyclosporine, dabigatran, digoxin, docetaxel, domperidone, doxepin, doxorubicin, eribulin, 
everolimus, fentanyl, fexofenadine, fidaxomicin, fluvastatin, fosamprenavir, gatifloxacin, idelalisib, iloperidone, 
indacaterol, indinavir, irbesartan, lacosamide, lapatinib, levetiracetam, levofloxacin, linagliptin, linezolid, 
loperamide, losartan, maraviroc, mirabegron, moxifloxacin, naloxegol, nateglinide, nevirapine, nintedanib, 
lodaterol, paclitaxel, pantoprazole, paroxetine, pazopanib, phenytoin, posaconazole, pravastatin, proguanil, 
quinidine, quinine, ranolazine, riociguat, risperidone, ritonavir, rivaroxaban, saquinavir, silodosin, simeprevir, 
simvastatin, sirolimus, sitagliptin, sofosbuvir, sorafenib, tacrolimus,talinolol, telaprevir, tenofovir, ticagrelor, 
tipranavir, tolvaptan, topotecan, umeclidinium, valsartan, vardenafil, vincristine, voclosporin,
voriconazoleeverolimus
Inducers
avasimibe, carbamazepine, efavirenz, genistein, phenytoin, quercetin, rifampin, St John’s wort
PgP Inhibitors and PgP/CYP3A Dual Inhibitors
PgP Inhibitors
alogliptin, canaglifozin, cremophor RH40, curcumin, ketoconazole, lapatinib, lopinavir/ritonavir, mirabegron, 
propafenone, simepravir, valspodar, vandetanib, voclosporin
PgP/CYP3A Dual Inhibitors
amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, elacridar, 
erythromycin, felodipine, fluvoxamine, ginkgo (ginkgo biloba), indinavir, indinavir/ritonavir, itraconazole, 
mibefradil, milk thistle (silybum marianum), nelfinavir, nifedipine, nitrendipine, paroxetine, quercetin, quinidine, 
ranolazine, rifampin, ritonavir, saquinavir/ritonavir, Schisandra chinensis, St John’s wort (hypericum perforatum), 
talinolol,
Telaprevir, telmisartan, ticagrelor, tipranavir/ritonavir, tolvaptan, verapamil
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Oct. 2, 2011,29-Oct-2012 
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.
Vaccinations
Immunosuppressants may affect the response to vaccination and vaccination during treatment 
with Everolimus may therefore be less effective. The use of live vaccines should be avoided 
during treatment with Everolimus. For pediatric patients with SEGA that do not require 
immediate treatment, complete the recommended childhood series of live virus vaccinations 
prior to the start of therapy according to local treatment guidelines. Examples of live vaccines 
are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and 
TY21a typhoid vaccines.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
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Table 7-1
Visit evaluation schedule
Screening / 
Baseline
RT
Day 
22
RT
Day 
43
Post 
RT
day 
15
Post 
RT
day 
22
Post 
RT
week 
6
Post 
RT
week 
14
Post 
RT
week 
26
Visit no.
1
2
3
4
5
6
7
8
Treatment days*
-21 to -1
Demography/informed consent (D)
X
Inclusion/exclusion criteria (D)
X
Relevant medical history/current medical 
conditions (D)
X
Diagnosis and extent of cancer (D)
X
Prior/post antineoplastic therapy (D)
X
HIV history (S)
X
Vital signs (D)
X
 X
 X
 X
 X
 X
 X
 X
Height (D)
X
Weight (D)
X
 X
 X
 X
 X
 X
 X
 X
Physical examination (S)
X
 X
 X
 X
 X
 X
 X
 X
ECOG performance status (D)
X
 X
 X
 X
 X
 X
EKG1 (D)
 X
Correlative studies
X
 X
 X
 X
 X
 X
 X
 X
Hematology2 (D)
X
 X
 X
 X
Coagulation (D)
X
 X
 X
 X
Biochemistry3 (D)
X
 X
 X
 X
Serum Lipid Profile4 (D)
X
 X
 X
 X
Prior/concomitant medications (D)
X
 X
 X
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Screening / 
Baseline
RT
Day 
22
RT
Day 
43
Post 
RT
day 
15
Post 
RT
day 
22
Post 
RT
week 
6
Post 
RT
week 
14
Post 
RT
week 
26
Visit no.
1
2
3
4
5
6
7
8
Treatment days*
-21 to -1
Everolimus5
 x
HBV-DNA, HBsAg, HBs Ab, HBc Ab, HCV- 
RNA-PCR6 (D)
X
HBV DNA, HCV RNA-PCR7 (D)
X
* (+/- 1 day for visits 2,3,4,5; +/- 1 week for visits 6,7,8)
1. Baseline ECG is a standard 12 lead and must be performed within 21 days of first dose for patients enrolled and may be repeated at the 
investigator’s discretion if clinically indicated
2. Hematology tests include a complete blood count (CBC). A total white blood cell (WBC) with absolute differentials (including neutrophil count plus 
bands, lymphocyte, monocyte, eosinophil, basophil counts), red blood cells (RBC), hemoglobin (Hgb), and a platelet count.
3. Serum Chemistry must include: BUN or uric acid, creatinine, LDH, total protein, electrolytes (sodium, potassium and calcium), total bilirubin, GGT, 
albumin, alkaline phosphatase, AST/sGOT fasting glucose.
4. Serum fasting lipid profile must include: total cholesterol and triglycerides. Patients should be in fasting state.
5. Everolimus is taken once daily for a total of five days, with drug dispensed at Visit 4. 
6. All patients should be screened for hepatitis risk factors and any past illnesses of hepatitis B and hepatitis C. It is highly recommended that patients 
positive HBV-DNA or HBsAg are treated prophylactically with an antiviral for 1-2 weeks prior to receiving study drug (see Section 6.7.3). The antiviral 
treatment should continue throughout the entire study period and for at least 4 weeks after the last dose of study drug. Patients with viral hepatitis C risk 
factors should be screened for HCV RNA-PCR.
7. Patients on antiviral prophylaxis treatment or positive HBV antibodies should be tested for HBV-DNA according to study visit schedule. Patients with 
positive HCV-RNA PCR or a history of past infection, even if treated and considered ‘cured’ – should be followed by HCV-RNA PCR according to visit 
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7.2
Assessment types
7.2.1
Pregnancy and assessments of fertility
There are no adequate data from the use of everolimus in pregnant women. Studies in animals have 
shown reproductive toxicity effects including embryo-toxicity and feto-toxicity. The potential risk for 
humans is unknown. Everolimus should not be given to pregnant women unless the potential benefit 
outweighs the potential risk to the fetus. If a pregnancy occurs while on study treatment, the newborn 
will be followed for at least 12 months.
It is not known whether everolimus is excreted in breast milk. However, in animal studies everolimus 
and/or its metabolites readily passed into the milk of lactating rats. Women taking everolimus should 
therefore not breast-feed.
Women of childbearing potential
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, 
(including female pediatric patients who are menarcheal or who become menarcheal during the 
treatment) must use highly effective contraception during the study and for 8 weeks after stopping 
treatment. Highly effective contraception is defined as either:

Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
[Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception]

Female Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy), 
total hysterectomy or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment

Male partner sterilization: The vasectomized male partner should be the sole partner for that 
subject with the appropriate post-vasectomy documentation of the absence of sperm in the 
ejaculate.

Use of oral, injected or implanted hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception 
that have comparable efficacy (failure rate <1%), for example, hormone vaginal ring or 
transdermal hormone contraception. In case of use of oral contraception women should have been 
stable on the oral agent for a minimum of 3 months before taking everolimus.
Male Contraception
Sexually active males must use a condom during intercourse while taking the drug and for 8 weeks 
after stopping treatment and should not father a child in this period.
A condom is required to be used also by vasectomised men in order to prevent delivery of the drug via 
seminal fluid.
Female partners of male patients must also be advised to use one of the following contraception 
methods: Use of (1) oral, injected, implanted or other hormonal methods of contraception, or (2) 
intrauterine device (IUD) or intrauterine system (IUS), or (3) prior male/female sterilization.
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Fertility
The potential for everolimus to cause infertility in male and female patients is unknown. 
However, menstrual irregularities, secondary amenorrhea and associated luteinizing hormone 
(LH)/follicle stimulating hormone (FSH) imbalance has been observed.
Based on non-clinical findings, male and female fertility may be compromised by treatment with 
everolimus.
7.2.2
CORRELATIVES:
The decrease of saliva flow rates (compared to baseline prior to definitive treatment) during 
radiotherapy treatment at 3, 6 weeks and prior to everolimus administration and the subsequent 
recovery of saliva flow rates at completion of the 5 day everolimus course and 1, 3 and 6 months after 
RT/chemoRT completion to determine the kinetics and stability of saliva flow rate recovery.
The production of the saliva protein amylase also decreases with salivary gland dysfunction following 
irradiation. Hence, we will measure protein composition within the saliva on an Experion 
microfluidic chip as previously described by the Limesand lab (Grundmann 2010, Morgan-Bathke 
2014, Hill 2014). ). Briefly, a small amount of saliva (1-2 μl) will be loaded on the Experion 
microfluidic chips according to manufacturer’s instructions. Sample analysis will focus on the profile 
and concentration of all proteins present in saliva. Percent decrease and recovery of amylase will be 
measured at all available time points and confirmed using immunoblotting techniques.
.
Surveys that will administered include:
a.
Xerostomia Inventory survey (Thomson 1999, appendix A )
b. Xerostomia Visual Analog Scale survey (Pai 2001, appendix B)
8
Safety monitoring and reporting
Information about all adverse events, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be collected 
and recorded and followed as appropriate.
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), 
symptom(s), or medical condition(s) that occur after patient’s signed informed consent has been 
obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse events 
only if they induce clinical signs or symptoms, are considered clinically significant, require therapy
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(e.g., hematologic abnormality that requires transfusion or hematological stem cell support), or require 
changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse Events 
CRF. Conditions that were already present at the time of informed consent should be recorded in the 
Medical History page of the patient’s CRF. Adverse event monitoring should be continued for at least 
30 days (or 5 half-lives, whichever is longer) following the last dose of study treatment. Adverse events 
(including lab abnormalities that constitute AEs) should be described using a diagnosis whenever 
possible, rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate Adverse Event. Adverse events will 
be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, and life- 
threatening, corresponding to Grades 1 - 4, will be used.
The occurrence of adverse events should be sought by non-directive questioning of the patient (subject) 
during the screening process after signing informed consent and at each visit during the study. Adverse 
events also may be detected when they are volunteered by the patient (subject) during the screening 
process or between visits, or through physical examination, laboratory test, or other assessments. As 
far as possible, each adverse event should be evaluated to determine:
1.   The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates) (add or Ongoing at End of Study for)
3. Its relationship to the  study  treatment  (Reasonable  possibility  that  AE  is  related:  No,  Yes) 
or
Its  relationship  to  the  study  treatment  (Reasonable  possibility  that  AE  is  related:  No,    Yes, 
investigational treatment, Yes, the study treatment (non-investigational), Yes, both and/or 
indistinguishable)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, temporarily 
interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 and which 
seriousness criteria have been met
Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, recovered/resolved 
with sequalae, fatal, unknown) If the event worsens the event should be reported a second time in the 
CRF noting the start date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if 
improvement to a lower grade is determined a new entry for this event should be reported in the CRF 
noting the start date when the event improved from having been Grade 3 or Grade 4.
Any AE that constitutes a DLT will be reported like a grade 3 and 4 adverse event.
All adverse events should be treated appropriately. If a concomitant medication or non-drug therapy 
is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of any
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changes in severity, the suspected relationship to the study treatment, the interventions required to treat 
it, and the outcome.
Any and all adverse events will be recorded on the UACC adverse events record form and reviewed by 
the Principal Investigator.
NOTE : This only applies to non-interventional trials. All non-serious AEs suspected to be causally related to the Novartis drug 
of focus i.e. ADRs must be periodically transferred to Novartis.
Adverse Drug Reactions
Oncology
The most common ADRs, suspected to be related to treatment by the investigator (incidence ≥1/10) 
from the pooled safety data were (in decreasing order): stomatitis, rash, fatigue, diarrhea, infections, 
nausea, decreased appetite, anemia, dysgeusia, pneumonitis, edema peripheral, hyperglycemia, asthenia, 
pruritus, weight decreased, pruritus, asthenia, peripheral edema, hypercholesterolemia, epistaxis, cough 
and headache.
The most common grade 3/4 ADRs, suspected to be related to treatment by the investigator (incidence
≥1/100 to <1/10) were stomatitis, anemia, hyperglycemia, fatigue, infections, 
pneumonitis, diarrhea, asthenia, thrombocytopenia, neutropenia, dyspnea, lymphopenia,
proteinuria, hemorrhage, hypophosphatemia, rash, hypertension, aspartate aminotransferase 
(AST) increased, alanine aminotransferase (ALT) increased, and pneumonia and diabetes 
mellitus.
The below table presents the frequency category of ADRs reported in the pooled safety analysis.
ADRs are listed according to MedDRA system organ class. Within each system organ class, 
the adverse reactions are ranked by frequency, with the most frequent reactions first. In 
addition, the corresponding frequency category using the following convention (CIOMS III) 
is also provided for each adverse reaction: very common (≥1/10); common (≥1/100 to <1/10); 
uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000)
Infections and infestations
Very common - Infectionsa
Blood and lymphatic system disorders
Very common  - Anemia,
Common
- Thrombocytopenia, neutropenia, leukopenia, lymphopenia 
Uncommon
- Pancytopenia
Rare
- Pure red cell aplasia
Immune system disorders
Uncommon
- Hypersensitivity
Metabolism and nutrition disorders
Very common - Decreased appetite, hyperglycemia, hypercholesterolemia 
Common
- Hypertriglyceridemia, hypophosphatemia, diabetes mellitus, 
hyperlipidemia, hypokalemia, dehydration
Psychiatric disorders
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Common
- Insomnia
Nervous system disorders
Very common - Dysgeusia, headache 
Uncommon
- Ageusia
Cardiac disorders
Uncommon
- Congestive cardiac failure
Vascular disorders
Common
- Hemorrhageb, hypertension, 
Uncommon
- Deep vein thrombosis
Respiratory, thoracic and mediastinal disorders 
Very common
- Pneumonitisc, epistaxis, cough, 
Common
- dyspnea
Uncommon
- Hemoptysis, pulmonary embolism 
Rare
- , acute respiratory distress syndrome
Gastrointestinal disorders
Very common    - Stomatitisd, diarrhea, nausea
Common
-   Vomiting,  dry mouth, abdominal pain, oral pain, dyspepsia, dysphagia
Skin and subcutaneous tissue disorders
Very common  -  Rash, pruritus
Common
- Dry skin, nail disorder, acne, erythema, hand-foot syndrome 
Rare
- Angioedema
Musculoskeletal and connective tissue disorders
Common
- Arthralgia
Renal and urinary disorders
Common
- Proteinuria, Renal failure
Uncommon
- Increased daytime urination, acute renal failure
Reproductive system and breast disorders 
Common
- Menstruation irregular f 
Uncommon
-, amenorrhea
General disorders and administration site conditions 
Very common
- Fatigue, asthenia,  edema peripheral, , 
Common
- Pyrexia, mucosal inflammation
Uncommon
- Non-cardiac chest pain, impaired wound healing
Investigations
Very common
- Weight decreased
Common
-  aspartate aminotransferase increased, Alanine aminotransferase increased, blood 
creatinine increased
a Includes all reactions within the ‘infections and infestations’ system organ class including common: pneumonia, urinary 
tract infection and uncommon: bronchitis, herpes zoster, sepsis, abscess and isolated cases of opportunistic infections 
(e.g. aspergillosis,
and rare : viral myocarditis 
candidiasis and hepatitis B)
b Includes different bleeding events from different sites not listed individually
c Includes common: pneumonitis: interstitial lung disease, lung infiltration, and rare - alveolitis, pulmonary 
alveolar hemorrhage, and pulmonary toxicity
d Includes very common: stomatitis; common: aphthous stomatitis, mouth and tongue ulceration; uncommon: 
glossitis, glossodynia
e reported as palmar-plantar erythrodysaesthesia syndrome
f frequency is based upon number of women age 10 to 55 years of age in the safety pool
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Clinically relevant laboratory abnormalities
In the pooled double-blind phase III safety database, the following new or worsening 
clinically relevant laboratory abnormalities were reported with an incidence of ≥1/10 (very 
common, listed in decreasing frequency).

Hematology: hemoglobin decreased, lymphocytes decreased, white blood cells decreased, 
platelets decreased, and neutrophils decreased (or collectively as pancytopenia);

Clinical chemistry: glucose (fasting) increased, cholesterol increased, triglycerides increased, 
AST increased, phosphate decreased, ALT increased, creatinine increased, potassium 
decreased, and albumin decreased.
Most of the observed abnormalities (> 1/100) were mild (grade 1) or moderate (grade 2). Grade 3/4 
hematology and chemistry abnormalities include:

Hematology: lymphocytes decreased, hemoglobin decreased, (very common); neutrophils 
decreased, platelet count decreased, white blood cells decreased (all common).

Clinical chemistry: glucose (fasting) increased, phosphate decreased, potassium decreased, 
AST increased, ALT increased, creatinine increased cholesterol (total) increased, triglycerides 
increased, albumin decreased (all common).
Tuberous sclerosis complex (TSC)
The most frequent ADRs (incidence ≥1/10 and suspected to be related to treatment by the
investigator) from the pooled safety database are (in decreasing order): stomatitis, upper respiratory 
tract infections, amenorrhea, hypercholesterolemia, nasopharyngitis, acne, menstruation irregular, 
sinusitis, and pneumonia
The most frequent grade 3/4 adverse reactions (incidence ≥1/100 to <1/10 and suspected to be
related to treatment by the investigator) were stomatitis, amenorrhea, pneumonia, neutropenia, pyrexia, 
and gastroenteritis viral.
The below table shows the incidence of ADRs based on pooled data in patients receiving everolimus 
in the TSC studies (including both the double-blind and open-label study and extension periods). ADRs 
are listed according to MedDRA system organ class. Frequency categories are defined using the 
following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to
<1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the 
available data). Within each frequency grouping, ADRs are presented in order of decreasing frequency.
Infections and infestations
Very common - Upper respiratory tract infection, nasopharngitis, sinusitis, pneumonia 
Common
- Otitis media, urinary tract infection, pharyngitis, cellulitis,
pharyngitis streptococcal, gastroenteritis viral, , gingivitis
Uncommon
- Herpes zoster, bronchitis viral
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Blood and lymphatic system disorders
Common
- Neutropenia, anemia, leukopenia, lymphopenia,  thrombocytopenia
Immune system disorders
Uncommon         - Hypersensitivity
Metabolism and nutrition disorders
Very common     - Hypercholesterolemia
Common
- Hyperlipidemia, decreased appetite, hypophosphatemia, hypertriglyceridemia
Psychiatric disorders
Common
- Insomnia,
Uncommon          - aggression
Nervous system disorders
Common
- Headache, dysgeusia
Vascular disorders
Common
- Hypertension, lymphedema
Respiratory, thoracic and mediastinal disorders
Common
- Cough, epistaxis, Pneumonitis
Gastrointestinal disorders
Very common         - Stomatitisa
Common
- Diarrhea, nausea, vomiting, abdominal pain, oral pain, flatulence, constipation, gastritis
Skin and subcutaneous tissue disorders
Very Common        - Acne
Common
- rashb, dermatitis acneiform, dry skin 
Uncommon
- Angioedema
Renal and urinary disorders
Common
- Proteinuria
Reproductive system and breast disorders
Very Common
- Amenorrhea C, menstruation irregular C, 
Common
- menorrhagia, vaginal hemorrhage, menorrhagia,
ovarian cyst, menstruation delayed C
General disorders and administration site conditions
Common
-  Fatigue, pyrexia, irritability
Investigations
Common
- Blood lactate dehydrogenase increased, blood luteinizing hormone increased 
Uncommon
- Blood follicle stimulating hormone increased
a Includes very common: stomatitis, mouth ulceration aphthous stomatitis; uncommon: gingival 
pain, glossitis, lip ulceration, tongue ulceration
b Includes common: rash, rash erythematous; uncommon: erythema, rash macular, rash maculo-papular, rash generalized.
C frequency is based upon number of women age 10 to 55 years of age while on treatment in the safety pool
Clinically relevant laboratory abnormalities
In the pooled TSC safety database the following new or worsening clinically relevant 
laboratory abnormalities reported with an incidence of ≥ 1/10 (very common, listed in 
decreasing frequency):
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
Hematology: partial thromboplastin time increased, hemoglobin decreased, white blood cells 
decreased, neutrophils decreased, lymphocytes decreased, and platelet count decreased.

Clinical chemistry: cholesterol increased, triglycerides increased, AST increased, ALT 
increased, phosphate decreased, alkaline phosphatase increased, potassium decreased, and 
glucose (fasting) increased.
Most of the laboratory abnormalities were mild (grade 1) or moderate (grade 2). Grade 3/4 
hematology and chemistry abnormalities included:

Hematology: neutrophils decreased, partial thromboplastin time increased (common) and 
lymphocytes decreased, hemoglobin decreased (uncommon).

Clinical chemistry: phosphate decreased, alkaline phosphatase increased, AST increased 
(common); cholesterol increased, triglycerides increased, ALT increased, potassium 
decreased, and glucose (fasting) increased (uncommon).
Description of selected adverse drug reactions
In clinical trials and post-marketing spontaneous reports, everolimus has been associated with 
serious cases of the following :

hepatitis B reactivation, including fatal outcome. Reactivation of infections is 
an expected event during periods of immunosuppression.

renal failure events (including fatal ones) and proteinuria. Monitoring of renal function is 
recommended.

amenorrhea (including secondary amenorrhea).

Pneumocystis jirovecii pneumonia (PJP) some with a fatal outcome.

Angioedema has been reported with and without concomitant use of everolimus and ACE 
inhibitors
The table below lists all fatal adverse events reported by investigators across all RAD001 studies as 
having a suspected causal relationship to everolimus and occurring on or before the cut off date of 31- 
Mar-2014.
MedDRA system organ class
Event
Blood and lymphatic system disorders
Thrombocytopenia
Cardiac disorders
Acute cardiopulmonary event, cardiogenic shock, 
cardio-respiratory arrest, myocardial infarction
Gastrointestinal disorders
Diarrhea, duodenal ulcer, GI hemorrhage, intestinal 
perforation, esophageal perforation, internal hernia
General disorders/administration site conditions
Cold sweat, concomitant disease progression, general 
physical health deterioration, multi-organ failure, 
sudden death
Infections and infestations
Candidal sepsis, EBV pneumonia, neutropenic sepsis, 
pneumocystis jiroveci pneumonia, reactivation of
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Hepatitis B, septic shock, septicemia with massive 
Epstein-Barr viremia
Injury, poisoning and procedural complications
Bone fissure
Metabolism and nutrition disorders
Dehydration, ketoacidosis, hyperglycemia
Neoplasms benign, malignant and unspecified 
(including cysts and polyps)
Squamous cell carcinoma of skin
Nervous system disorders
Cerebral hemorrhage, embolic stroke, restlessness
Renal and urinary disorders
Renal tubular necrosis
Respiratory thoracic and mediastinal disorders
Acute cardiopulmonary event, acute respiratory 
distress syndrome, cardio-respiratory arrest, dyspnea, 
chronic obstructive pulmonary disease, interstitial 
pneumonia, pulmonary embolism, pulmonary edema, 
pneumonitis
Vascular Disorders
Cerebral hemorrhage, disseminated intravascular 
coagulation, embolic stroke, hemorrhage, hypovolemic 
shock, myocardial infarction, pulmonary hypertension
The table below lists all serious, unexpected, life-threatening adverse events considered related to study 
drug, and reported on
at least one occasion up to the cut-off date of 31-Mar-2014. It should be stressed that many of 
these SAE reports have been reported only on a single occasion making an accurate
assessment of causality difficult, if not impossible. Due to the imprecision of causality, the causality 
assessments should not be assumed that all of these events are indeed the result of therapy with 
everolimus. Moreover, the assessment of causality is particularly difficult in critically ill patients where 
confounding factors are present relating mainly to complications of the underlying disease and to the 
use of prior therapy and/or concomitant medications. In addition to the SAE reports presented below, 
disease progression has on occasions been reported somewhat paradoxically as an SAE with a suspected 
causal relationship to everolimus and reported on at least one occasion.
Individual events are presented for each MedDRA system organ class.
MedDRA system organ 
class
Event
Blood
and
lymphatic 
system disorders
Acute leukemia, anemia, bone marrow failure, disseminated intravascular 
coagulation, febrile neutropenia, hemorrhagic diathesis, leukemoid reaction, 
leukocytosis, leukopenia, lymphadenopathy, lymphedema, lymphopenia, 
neutropenia, pancytopenia, platelet disorder, retroperitoneal lymphadenopathy, 
thrombocytopenia, white blood cell disorder, hemolytic uremic syndrome
Cardiac disorders
atrial fibrillation, atrioventricular block, ardiorespiratory arrest, cardiopulmonary 
arrest, congestive cardiomyopathy, cyanosis, diastolic dysfunction, dilatation left 
atrial and left ventricular, hypertrophy, left ventricular hypertrophy, left ventricular 
dysfunction, myocardial infarction, myocardial ischemia, hypertensive heart 
disease, palpitations, pericardial effusion, right ventricular failure, sinus tachycardia, 
stress cardiopathy, supraventricular tachycardia, tachycardia, ventricular 
dysfunction
Valve incompetence: mitral/pulmonary/tricuspid
Ear and labyrinth disorders
Vertigo, sudden hearing loss, deafness unilateral
Endocrine disorders
Hyperthyroidism , hyperglycemic non-ketotic syndrome, hypercalcemia, 
hypothyroidism
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Eye disorders
Conjunctivitis, eyelid edema, scleral discoloration, ocular discomfort, ocular surface 
disease, phthalmoplegia_cranial nerve paralysis, papilloedema, photophobia, retinal 
artery thrombosis, retinal detachment, retinal hemorrhage, steroid Induced
cataract, senile cataract, visual acuity reduced.
Gastrointestinal disorders
Abdominal abscess, abdominal adhesions, abdominal: 
discomfort/distension/pain/tenderness, anorectal discomfort, anal fissure, anal 
fistula, anastomotic leak, ascites, colitis, constipation, diarrhea, diverticulum, 
duodenal ulcer, dyspepsia, dysphagia, esophageal perforation, feces discolored, 
gastric perforation, gastric ulcer hemorrhage, gastric ulceration, gastrointestinal 
angiodysplasia, gastrointestinal ischemia, gastrointestinal oedema, 
gastroenteritis,
hemorrhoids,hematemesis, hematochezia, hiccups, ileus, intestinal perforation, 
melena, mesenteric vein thrombosis, mouth ulceration, nausea, pancreatitis, 
proctalgia, proctitis, recall phenomenon radiation enteritis, rectal 
discharge/hemorrhage, small intestinal obstruction, stomatitis, swollen tongue, 
vomiting, oral pain, enterovesical fistula, radiation esophagitis, necrotizing 
esophagitis, salivary gland calculus, small bowel thickness, thickened bowel Wall 
Gastritis: erosive/ hemorrhagic Lip: edema/swelling/ulceration
Gastrointestinal: disorder/hemorrhage/sounds 
Mucosal: hemorrhage/inflammation
General disorders and 
administration site 
conditions
Application site erythema, asthenia, bloody discharge, calcinosis, chest 
discomfort/pain, chills, concomitant disease progression, condition aggravated, 
crepitations, death, discomfort, disease progression, drug ineffective, and drug 
withdrawal syndrome (asthenia and flushing) edema peripheral, face edema, facial 
pain, fatigue, feeling of body temperature change, general physical health 
deterioration, generalized edema, goiter, granuloma, hypertrophy, hypothermia, 
impaired healing, inflammation, influenza like illness, irritability, local swelling, 
malaise, mass, multi-organ failure, necrosis, non-cardiac chest pain, pain, 
performance status decreased, pitting edema, pyrexia, sudden death, swelling, 
tenderness, thirst
Hepatobiliary disorders
Cholecystitis, cholelithiasis, cholestasis, cytolytic hepatitis, hepatic cirrhosis, hepatic 
failure, hepatic function abnormal, hepatic necrosis, hepatorenal failure, hepatitis 
B and C reactivation, hepatomegaly, hyperbilirubinemia, jaundice, portal vein 
thrombosis
Immune system disorders
Acute disseminated encephalomyelitis, autoimmune disorder, cytokine release 
syndrome, Guillian Barre syndrome, hypersensitivity, immunosuppression, Stevens- 
Johnson syndrome
Infections and infestations
Bronchitis, bronchopneumonia, bronchopulmonary aspergillosis. candida sepsis, 
cellulitis, citrobacter sepsis, clostridium bacteremia, endocarditis, escherichia 
bacteremia, folliculitis, gastroenteritis, hepatitis fulminant. infected lymphocele, 
klebsiella sepsis, liver abscess, meningitis, herpes, nasopharyngitis, neutropenic 
sepsis, perirectal/anal abscess, pharyngitis, pneumococcal sepsis, pseudomonal 
bacteremia, purulent discharge, pyelonephritis, respiratory moniliasis, sepsis 
syndrome, septic shock, sinusitis, staphylococcal bacteremia, staphylococcal 
sepsis,
streptococcal bacteremia, tonsillitis, tuberculosis, urosepsis 
lnfection(s): alpha hemolytic streptococcal/atypical
mycobacteriallbacteriallclostridiallenterobacter/enterococcal/epstein-barr virus/ 
escherichia/escherichia urinary tracVgastrointestinal/haemophilus/herpesvirus/ 
general/ localized/ morganella/ proteus/ skin/streptococcal/staphylococcal/urinary 
tract/ wound staphylococcal
Injury, poisoning and 
Procedural complications
Abdominal adhesion, anastomotic leak, bone fissure, collapse of lung, contusion, 
eschar, fall, head injury, lung injury, medical device complication, medication error, 
post procedural swelling, recall phenomenon radiation enteritis, surgical procedure 
repeated, vena cava injury, wound dehiscence/secretion
Investigations
Aspiration pleural cavity, antinuclear antibody positive, bleeding time prolonged, 
breath sounds abnormal, cardiac function test abnormal, chest X-ray abnormal, 
clostridium difficile toxin test positive, computerised tomogram abnormal, ejection 
fraction decreased, endoscopy upper gastrointestinal tract, general physical 
condition abnormal, granulocyte count decreased, hematocrit/hemoglobin 
decreased, hypophosphatemia, liver function test abnormal, neutrophil count
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abnormal/decreased, occult blood positive, oxygen saturation abnormal/decreased, 
peak expiratory flow rate decreased, protein urine present, QRS axis abnormal, 
urine output decreased, X-ray abnormal; Increased: alanine aminotransferase, 
ammonia, aspartate aminotransferase, aspartate aminotransferase, body 
temperature, C-reactive protein, eosinophil count, gamma-glutamyltransferase, 
international normalised ratio, lipase, red blood cell count, sedimentation rate, 
transaminases, troponin T, troponin Platelet count: abnormal/decreased/increased 
White blood cell(s): count abnormal/decreased/in urine Lymphocyte count: 
decreased/increased Blood: amylase increased/albumin decreased/alkaline 
phosphatase increased/bilirubin increased/creatine phosphokinase 
increased/creatinine increased/magnesium decreased/glucose increased/lactate 
dehydrogenase increased/potassium decreased/pressure diastolic 
decreased/pressure orthostatic abnormal/pressure systolic decreased/triglycerides 
increased/urea increased/urine present Electrocardiogram: T wave abnormal/T 
wave amplitude decreased/poor R-wave progression Weight: decreased/ increased
Metabolism and 
nutrition disorders
Acidosis, anorexia, appetite disorder, cachexia, cushing’s syndrome, decreased 
appetite, dehydration, diabetes mellitus, diabetic ketoacidosis, electrolyte 
imbalance, failure to thrive, fluid overload/retention, food intolerance, glucose 
tolerance impaired, gout, hypothyroidism, malnutrition, metabolic acidosis, oral 
intake reduced, polydipsia, type 2 diabetes mellitus Hyper: 
cholesterolemia/glycemia/kalemia/lipidemia/calcaemia uricemia/
triglyceridemia, glycemic non-ketotic syndrome
Hypo: calcemia/glycemia/kalemia/magnesemia/natremia/ proteinemia/ 
hypophosphatemia
Musculoskeletal and 
connective tissue 
disorders
Arthritis, bone fissure, fistula, gout mobility decreased, joint effusion, 
rhabdomyolysis Pain: back/flank/musculoskeletal/musculoskeletal 
chest/extremity/neck Muscle: spasms/weakness; myalgia, arthralgia 
Osteoarthritis; Osteonecrosis, Osteoreadionecrosis
Neoplasms benign, 
malignant and 
unspecified (incl cysts 
and polyps)
Acute leukemia, adenocarcinoma of pancreas, Burkitt’s lymphoma, carcinoid 
syndrome, colon neoplasm, lung neoplasm, lymphoproliferative disorder, malignant 
neoplasm progression, malignant melanoma, malignant pleural effusion, 
pancreatic carcinoma, squamous cell carcinoma of skin, uterine leiomyoma 
Metastases: central nervous system/lung/lymph nodes/neoplasm; Tumor: 
hemorrhage/necrosis
Nervous system 
disorders
Acute disseminated encephalomyelitis, asterixis, ataxia, cerebrovascular accident, 
cognitive disorder, complex partial seizures, complex regional pain syndrome, 
convulsion, depressed level of consciousness, dizziness, dyslalia, encephalitis, 
encephalopathy, facial palsy, headache, hemiparesis, hemiplegia, hyperglycemic 
non-ketotic syndrome, hypersomnia, hypoglycemic coma, lethargy, loss of 
consciousness, ophthalmoplegia_cranial nerve paralysis, neuralgia, neuropathy 
peripheral, presyncope, sinus headache, somnolence, speech disorder, tremor, 
vertigo Cerebral: hemorrhage/ infarction/ischemia; transient ischemic attack
Psychiatric disorders
Agitated depression, anxiety, confusional state, delirium, delusional disorder, 
disorientation, drug withdrawal syndrome, libido decreased insomnia, mental 
disorder/status changes, mood altered, persecutory type, personality disorder, 
neurosis, staring
Renal and urinary 
disorders
Acute renal failure, anuria, bladder tamponade, dysuria, hematuria, hemolytic 
uremic syndrome, hydronephrosis, leukocyturia, nephrolithiasis, oliguria, pollakiuria, 
polyuria, postrenal failure, renal failure/acute/impairment, urinary bladder 
hemorrhage, urinary incontinence, renal atrophy, renal colic, renal tubular necrosis
Reproductive/breast 
disorders
Azospermia, endometrial hyperplasia, libido decreased, menorrhagia, pelvic 
pain, ovarian cyst, scrotal edema
Respiratory, thoracic and 
mediastinal disorders
Alveolitis, alveolitis allergic, asthma, atelectasis, bronchomalacia, bronchospasm, 
cough, cryptogenic organizing pneumonia, diffuse alveolar damage, dysphonia, 
dyspnea/dyspnea exertional, emphysema, epistaxis, hemoptysis, hydrothorax, 
hypercapnia, hypoxia, laryngeal edema, interstitial lung disease, laryngeal 
inflammation, pneumothorax, rales, sinus congestion, stridor, tachypnea, wheezing 
Acute: respiratory distress syndrome/respiratory failure
Lung: consolidation/disorder/infiltration, obstructive airways disorder, orthopnoea, 
pharyngolaryngeal pain, pleural disorder/effusion/pleurisy/pain; pneumonia 
aspiration, pneumonitis, pneumothorax, productive cough, rhinorrhoea
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Pulmonary: congestion/alveolar/hemorrhage/artery 
dilatation/cavitation/embolism/fibrosis/haemorrhage/hypertension/edema/toxicity 
Respiratory: arrest/disorder/distress/failure/gas exchange disorder
Skin and subcutaneous 
tissue disorders
Acute febrile neutrophilic dermatosis, Angioedema, blister, dermatitis, dermatitis 
acneiform, erythema, hyperhidrosis, leukocytoclastic vasculitis, night sweats, 
petechiae, photosensitivity reaction, pruritus, Stevens-Johnson syndrome  
Rash: erythematous/generalized/ maculo-papular/pruritic/skin
disorder/exfoliation/lesion/reaction/ulcer/palmar plantar erythrodysesthesia/hand 
foot syndrome
Surgical and medical 
procedures
Abscess drainage, biliary drainage, bladder irrigation, catheter removal, chest tube 
insertion, cholecystectomy, debridement, endotracheal intubation, fistula repair, 
gastric ulcer surgery, gastrointestinal tube insertion, ileojejunal bypass, incisional 
drainage, laparotomy, mechanical ventilation, pleurodesis, sinus operation, surgery, 
thoracic cavity drainage, tracheostomy Pericardial: drainage/excision/operation 
Wound: closure/drainage/treatment
Vascular disorders
Capillary leak syndrome, circulatory collapse, embolism, flushing, gastrointestinal 
angiodysplasia, gastrointestinal ischaemia, haemorrhoids, hematoma, 
hemodynamic instability, hemorrhage, hypertension, hypertensive angiopathy, 
hypertensive crisis, hypotension, lymphangiopathy, lymphedema, pallor, shock; 
transient ischemic attack, retinal hemorrhage,
Thrombosis: deep vein/jugular vein
*New events added to IB Editions 12 and 13 are noted in bold
8.1.2
Laboratory test abnormalities
Laboratory abnormalities that constitute an Adverse event in their own right (are considered clinically 
significant, induce clinical signs or symptoms, require concomitant therapy or require changes in study 
treatment), should be recorded on the Adverse Events CRF. Whenever possible, a diagnosis, rather than 
a symptom should be provided (e.g. anemia instead of low hemoglobin). Laboratory abnormalities that 
meet the criteria for Adverse Events should be followed until they have returned to normal or an 
adequate explanation of the abnormality is found. When an abnormal laboratory or test result 
corresponds to a sign/symptom of an already reported adverse event, it is not necessary to separately 
record the lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be reported as 
adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a SAE 
unless it meets the definition of serious as defined below and/or as per investigator’s discretion. A dose 
hold or medication for the lab abnormality may be required by the protocol and is still, by definition, 
an adverse event.
8.2
Serious Adverse Events
8.2.1
Definitions
A serious adverse event is an undesirable sign, symptom or medical condition which:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization 
is for:
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
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of 
a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the patient’s general 
condition

is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above
8.2.2
Reporting
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB, and 
Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E) (For patients taking 
Novartis drugs).
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A 
(MedWatch Form).
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient has 
provided informed consent and until at least 30 days after the patient has stopped study 
treatment/participation must be reported to Novartis within 24 hours of learning of its occurrence. 
Information about all SAEs is collected and recorded on a Serious Adverse Event Report Form. The 
investigator must assess and record the relationship of each SAE to each specific study treatment (if 
there is more than one study treatment), complete the SAE Report Form in English, and send the 
completed, signed form along with the Novartis provided fax cover sheet to the Novartis Oncology 
Drug Safety and Epidemiology (DS&E) department by fax (fax: 877-778-9739) within 24 hours.
Any additional information for the SAE including complications, progression of the initial SAE, and 
recurrent episodes must be reported as follow-up to the original episode within 24 hours of the 
investigator receiving the follow-up information. An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one should be reported separately 
as a new event.
Any SAEs experienced after this 30 days period should only be reported to Novartis if the investigator 
suspects a causal relationship to the study drug. Follow-up information is submitted in the same way as 
the original SAE Report. Each re-occurrence, complication, or progression of the original event should 
be reported as a follow-up to that event regardless of when it occurs. The follow-up information should 
describe whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Everolimus Investigator Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study drug, a DS&E associate may 
urgently require further information from the investigator for Health Authority reporting. Novartis may 
need to issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics  committees
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in accordance with Directive 2001/20/EC or as per national regulatory requirements in participating 
countries.
All serious adverse events and any deaths will be reported to the DSMB and to the University 
of Arizona Human Subjects Protection Program per the guidelines set forth in University of 
Arizona Cancer Center Data and Safety Monitoring Board Charter, Table 5: Adverse Event 
Reporting.
All submitted serious adverse events will be processed by the DSMB Coordinator monthly for 
initial trend analysis and then reviewed by the DSMB Chair. The assigned QA/QC Monitor 
will review the SAE reporting process to confirm reporting requirements are met.
8.3
Pregnancy
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed 
up to determine outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications.
Pregnancy should be reported by the investigator to the oncology Novartis Drug Safety and 
Epidemiology Department (DS&E) by fax (fax : 877-778-9739). Pregnancy follow-up should include 
an assessment of the possible relationship to the investigational/study treatment and any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes must be collected for the female partners of any males who took study treatment 
in this study. Consent to report information regarding these pregnancy outcomes should be obtained 
from the mother.
9
Statistical methods
9.1
Statistical methods
All patients will have their salivary output measured before radiotherapy, 3 weeks after the start of 
radiotherapy, and at the end of radiotherapy (6 weeks). Patients with clinically severe gland 
dysfunction (i.e., those with loss of at least 50% of the pre-radiotherapy value) will be eligible for 
everolimus treatment. Follow-up measurements will be obtained prior to everolimus administration, 
at completion of the 5 day everolimus course at 1 month, 3 months and 6 months after RT/chemoRT 
completion.
The primary end point of the analysis will be the percent recovery of salivary gland function, with 
pre-everolimus treatment saliva flow rate as the denominator and the saliva flow rate at 3 months 
after completion of radiation or chemoradiation therapy as the numerator.
It is our expectation that because of the short exposure to everolimus (a total of 5 days only), the well 
described everolimus related toxicities will not develop.
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However, following discussions with the company (Novartis), two dose levels will be evaluated: a 
starting dose of 5 mg po daily, will initially be evaluated in a cohort of 3 patients.
For the purpose of this trial, dose-limiting toxicity (DLT)is defined as an everolimus-related grade 3 
or higher AE.
Toxicity will be graded based on the Common Terminology Criteria for Adverse Events (CTCAE) 
Version4.03.
(http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf)
As mentioned, we will start treating enrolled patients on the lower dose level.
-If no DLT occurs, will proceed with dose escalation to the full FDA-approved dose (10 mg po daily) 
[in this case, total number of patients in the trial: 13; 3 in the 5 mg cohort, 10 in the 10 mg cohort] .
-If  1 DLT occurs, cohort will be expanded to additional 3 patients;
and if another DLT occurs in this expanded cohort, no escalation to full dose (10 mg po daily) will be 
attempted, and cohort will be expanded to 10 patients [in this case, total number of patients in the 
trial: 10; all in the 5 mg cohort];
and if no additional DLT occurs in the expanded cohort, dose escalation to full dose (10 mg po daily) 
will follow [in this case, total number of patients in the trial: 16; 6 in the 5 mg cohort, in the 10 mg 
cohort] .
-If 2 DLT occur, no escalation to full dose (10 mg po daily) will be attempted, and cohort will be 
expanded to 10 patients. ) [in this case, total number of patients in the trial: 10; all in the 5 mg 
cohort].
As a result of these possibilities, total number of patients included in this phase 0, proof of principle 
trial can range from a minimum of 10 to a maximum of 16 total patients.
Maximum number of 16 patients will occur if a DLT occurs in one of the first 3 patients in the 5 mg 
cohort, and no DLT occurs in the additional 3 expanded cohort patients (for a total of 6 patients in the 
5 mg cohort). Subsequently, 10 additional patients will be enrolled in the 10 mg cohort, for a 
maximum total of 16 patients.
Planned analyses will be performed by strata (patients enrolled at the 5 mg dose level versus the 10 
mg dose level).
Statistical analysis will compute the mean percent recovery of all treated patients (with a 95% 
confidence interval). Ten patients at the selected dose will allow estimating the mean percent recovery 
with standard error that is 0.32 of the observed standard deviation. Exploratory analysis will determine 
if any clinical factors are predictive of treatment response, specifically ipsilateral vs bilateral neck 
irradiation. Changes in the secondary endpoints across time, including the saliva flow rates, saliva 
protein composition, total score obtained on the Xerostomia Inventory survey, and total score on the 
Xerostomia Visual Analog Scale survey, will be explored using graphical methods.
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10
Protocol amendments, or changes in study conduct
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed by Novartis and the investigator before implementation.
Amendments significantly affecting the safety of subjects, the scope of the investigation or the 
scientific quality of the study require additional approval by the IRB at each study center. A copy of 
the written approval of the IRB must be provided to Novartis. Examples of amendments requiring 
such approval are:
1. increases in drug dose or duration of exposure of subjects,
2. significant changes in the study design (e.g. addition or deletion of a control group),
3. increases in the number of invasive procedures,
4. addition or deletions of a test procedure required for monitoring of safety.
These requirements for approval should in no way prevent any immediate action from being taken by 
the investigator or by Novartis in the interests of preserving the safety of all patients included in the 
trial. If an immediate change to the protocol is felt to be necessary by the investigator and is 
implemented for safety reasons Novartis must be notified and the IRB at the center must be informed 
immediately. Amendments affecting only administrative aspects of the study do not require formal 
protocol amendments or IRB approval but the IRB must be kept informed of such administrative 
changes. Examples of administrative changes not requiring formal protocol amendments and IRB 
approval include:
1.
changes in the staff used to monitor trials
2.
minor changes in the packaging or labeling of study drug.
11. Data and Safety Monitoring Plan
11.1 Identification of the DSMB obligated for oversight responsibilities:
The University of Arizona Cancer Center Data and Safety Monitoring Board (DSMB) will 
provide ongoing oversight for this trial. This study has been assigned a High Risk level by the 
DSMB.
11.2 Identification of the entity obligated for routine monitoring duties:
Routine monitoring will be provided by The University of Arizona Cancer Center Quality 
Assurance/Quality Control (QA/QC) Program to ensure that the investigation is conducted 
according to protocol design and regulatory requirements.
Data from each subject visit will be entered into the OnCore system within 1 week of the 
subject visit.
This trial will also undergo real-time monitoring by the PI and study team, including 
documentation of real-time monitoring of any new or ongoing safety issues. Weekly 
conference calls will be conducted with PI and study staff to address the following:

adverse events (including serious adverse events);
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
screening and enrollment including cohort management.

protocol deviations and corrective action plans for any identified deviations

accuracy and timeliness of data collection/entry
11.3 Monitoring progress and data review process:
Routine monitoring of subject data will be conducted at least every month. 
The first routine monitoring visit will include at a minimum:

Informed consent – 100% of cases enrolled;

Subject eligibility – 100% of cases, up to three subjects;

Data review – 100% of cases, up to three subjects.
All subsequent monitoring visits will consist of randomly selected subject cases based on 
current enrollment and include continuing review of previously selected cases, as applicable.
A monitoring visit report and follow-up letter will be completed approximately two weeks 
after the routine monitoring visit; a copy will be maintained in the study file. The monitor will 
request additional source documentation, clarification, information, or corrections to the CRF 
and/or regulatory records from the Clinical Research Coordinator (CRC) or other applicable 
staff responsible for the study and resolution of queries/findings. Documentation of such a 
request will be maintained with a copy of the monitor’s visit report for follow-up at the next 
monitoring visit. Electronic records will be available in the institutional database or provided 
by the QA/QC Program staff.
The Principal Investigator will ensure the accuracy, completeness, legibility and timeliness of 
the data reported in the Case Report Form (CRF), or other acceptable data formats. Source 
documentation supporting the study data should indicate the subject’s participation in the trial 
and should document the dates and details of study procedures, adverse events, and patient 
status.
All Case Report Forms (CRF) will be entered into the institutional database and completed 
electronically.
Note: Routine monitoring of regulatory documents will be conducted at least every six 
months, and routine monitoring of test article will be conducted at least every three months.
11.4 Process to implement study closure when significant risks or benefits are identified:
Please see section 9.1 for escalation and de-escalation procedure which may include study closure as 
determined by occurrence of dose limiting toxicities.
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11.5 Plan for assuring data accuracy and protocol compliance:
Routine study activity and safety information will be reported to the DSMB on a monthly 
basis, or more frequently if requested. These reports will include:

Study activity, cumulative and for the period under review;

Safety (narrative description on non-serious and serious adverse events, protocol pre- 
determined early stopping rules for safety or treatment-emergent adverse events);

Predetermined protocol early stopping rules for efficacy/futility;

Status of study in relationship to stopping rules;

Current dose level of study agent;

Routine monitoring and protocol compliance (describe the monitoring process and identify 
the status of the monitoring);

Comments;

Attachments (AE data reviewed by the PI to compile the report, SAE letters and reports, 
results of any review(s), applicable correspondence with the IRB or other regulatory 
agencies.
Data, safety and study progress will be reported to:

Human Subjects Protection Program (IRB) at least annually;
11.6  Identification of the sponsor or funding agency, as applicable:
The PI will immediately notify, in writing, Novartis, if applicable, any action resulting in a 
temporary or permanent suspension of the study. A copy of this correspondence will also be 
forwarded to the DSMB and the SRC.
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11
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Boulay A, Lane HA (2007) The mammalian target of rapamycin kinase and tumor growth inhibition. 
Recent Results Cancer Res. 2007;172:99-124.
Cohen HT, McGovern FJ (2005) Renal Cell Carcinoma. N Engl J Med; 353(23):2477-90.
Frattini M, Signoroni S, Pilotti S (2005) Phosphatase protein homologue to tensin expression and 
phosphatidylinositol-3 phosphate kinase mutations in colorectal cancer. Cancer Res; 65(23):11227.
Goel A, Arnold CN, Niedzwiecki D, et al (2004) Frequent inactivation of PTEN by promoter 
hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res; 
64(9):3014-21.
Grundmann O., J.L. Fillinger, K.R. Victory, R. Burd and K.H. Limesand (2010). Restoration of 
radiation therapy-induced salivary gland dysfunction in mice by post therapy IGF1 administration. 
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IRB NUMBER: PHXB-17-0072-70-15
IRB APPROVAL DATE: 07/03/2018
IRB NUMBER: PHXB-17-0072-70-15
IRB APPROVAL DATE: 07/03/2018

Confidential 
Protocol No.
Page 57
Appendix A:  The Xerostomia Inventory (Thomson 1999 )
1.
I sip liquids to aid in swallowing food
1
2
3
Never
Hardly ever
Occasionally
4
Fairly often
5
Very often
2.
My mouth feels dry when eating a meal
1
2
3
4
5
Never
Hardly ever
Occasionally
Fairly often
Very often
3.    I get up at night to drink
1
2
3
4
5
Never
Hardly ever
Occasionally
Fairly often
Very often
4.    My mouth feels dry
1
2
3
4
5
Never
Hardly ever
Occasionally
Fairly often
Very often
5.    I have difficulty in eating dry foods
1
2
3
4
5
Never
Hardly ever
Occasionally
Fairly often
Very often
6.  I suck sweets or cough lollies to relieve dry mouth 
1
2
3
4
5
Never
Hardly ever
Occasionally
Fairly often
Very often
7.   I have difficulties swallowing certain foods
1
2
3
4
5
Never
Hardly ever
Occasionally
Fairly often
Very often
8.    The skin on my face feels dry
1
2
3
4
5
Never
Hardly ever
Occasionally
Fairly often
Very often
9.    The skin on my face feels dry
1
2
3
4
5
Never
Hardly ever
Occasionally
Fairly often
Very often
10.  My lips feel dry
1
2
3
4
5
Never
Hardly ever
Occasionally
Fairly often
Very often
11.  The inside of my nose feels dry
1
2
3
4
5
Never
Hardly ever
Occasionally
Fairly often
Very often
IRB NUMBER: PHXB-17-0072-70-15
IRB APPROVAL DATE: 07/03/2018
IRB NUMBER: PHXB-17-0072-70-15
IRB APPROVAL DATE: 07/03/2018

Confidential 
Protocol No.
Page 58
Appendix B:  Visual Analog Scale (VAS) Xerostomia Questionnaire (Pai 2001)
1. Rate the difficulty you experience in speaking due to dryness
Not difficult at all
Very difficult
2.
Rate the difficulty you experience swallowing due to dryness
Not difficult at all
Very difficult
3. Rate how much saliva is in your mouth
A lot
None
4. Rate the dryness of your mouth
Not dry at all
Very dry
5. Rate the dryness of your throat
Not dry at all
Very dry
6.
Rate the dryness of your lips
Not dry at all
Very dry
7. Rate the dryness of your tongue
Not dry at all
Very dry
8.
Rate the level of your thirst
Not thirsty at all
Very thirsty
IRB NUMBER: PHXB-17-0072-70-15
IRB APPROVAL DATE: 07/03/2018
IRB NUMBER: PHXB-17-0072-70-15
IRB APPROVAL DATE: 07/03/2018