Clinical trial NCT01111058
Conditions: Head and Neck Cancer
Keywords: Squamous Cell Cancer
Sponsor: University of Chicago
Start date: 2010-04-01; Completion date: 2018-10-01
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary: Two-year progression-free (tumor does not grow or spread) survival in subjects treated with everolimus versus placebo after definitive local therapy.

Detailed description:

Arms: arm 1: Subjects will receive Everolimus 10 mg daily arm 2: Subjects will receive double-blind placebo
Interventions: intervention 1: Everolimus (RAD 001) intervention 2: Placebo
Intervention descriptions: intervention 1: 10mg of Everolimus or Placebo taken by mouth once daily for 1 year or until progression (whichever comes first). intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
University of Chicago IRB #: 09-266-B 
VERSION DATE: 02/14/2012
 
THE UNIVERSITY OF CHICAGO 
DIVISION OF MEDICINE 
 
Randomized Double-Blind Phase II Trial of Everolimus versus Placebo as 
Adjuvant Therapy in Patients with Locally Advanced Squamous Cell Cancer of 
the Head and Neck (SCCHN) 
 
Coordinating Site: 
 
The University of Chicago 
 
Study Chairman: 
 
Ezra Cohen, MD 
University of Chicago  
 
Study Co-Chairman: 
Cherie-Ann Nathan, M.D.  
Louisiana State University Health Science Center  
 
Co-Investigators:  
 
Tanguy Seiwert, MD 
Victoria Villaflor, MD 
Everett Vokes, MD 
Jonas DeSouza, MD 
Katherine Cunningham, PA 
 
Statistician:  
 
Masha Kocherginsky, PhD 
 
Research Nurses: 
 
Patricia Heinlen, RN, BSN, OCN 
 
 
 
 
 
Study Coordinator:  
Brandon Hatch, MPH 
 
Phase II Manager:  
Brittany Gauthier 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Participating Sites: 
 
Louisiana State University Health Sciences 
Center- Shreveport 
The University of Texas  
Medical Branch at Galveston 
Site PI: Glenn M. Mills, MD 
Site PI: Vicente A. Resto, MD 
 
University of Mississippi Medical Center
Ingalls Cancer Research Center 
Site PI: Karen T. Pitman, MD 
 
Site PI: Mark K. Kozloff , MD 
Tufts Medical Center 
Medical University of South Carolina 
Site PI: Miriam O'Leary, M.D 
Site PI: Terrance A. Day, MD 
 
The University of North Carolina 
University of Minnesota 
Site PI: Juneko Grilley-Olson, MD 
Site PI: Bevan Yueh, MD, MPH 
 
Vanderbilt University 
Northwestern University 
Site PI: Jill Gilbert, MD 
 
Site PI: Mark Agulnik, MD 
University of Illinois Chicago 
University of Kansas Medical Center 
Site PI: Lawrence E. Feldman, MD 
Site PI: Prakash Neupane, MD 
 
University of Miami 
University of Michigan 
Site PI: Zoukaa Sargi, MD 
 
Site PI: Francis Worden, MD 
 
Washington University in St. Louis 
The Ohio State University  
Site PI: Douglas R. Adkins, MD 
Site PI: Maura L. Gillison, MD, PhD 
 


 
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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 8 
1.1 
Everolimus (RAD001) ............................................................................................. 8 
1.1.1 
mTOR pathway and mechanism of action .............................................. 8 
1.1.2 
Preclinical studies.................................................................................. 10 
1.1.3 
Clinical experience ................................................................................ 11 
1.1.4 
Study Rationale ..................................................................................... 14 
2 
Study objectives ................................................................................................................. 17 
3 
Investigational plan ........................................................................................................... 17 
3.1 
Overall study design .............................................................................................. 17 
3.2 
Study population .................................................................................................... 17 
3.2.1 
Patient population .................................................................................. 17 
3.2.2 
Inclusion and exclusion criteria ............................................................ 18 
3.2.3 
Interruption or discontinuation of treatment ......................................... 20 
3.2.4 Monitoring of Everolimus suspected toxicities ............................................ 23 
3.2.5 Known Undesirable Side Effects of Everolimus .......................................... 23 
3.3 
Treatments ............................................................................................................. 27 
3.3.1 
Everolimus Administration ................................................................... 27 
3.3.2 
Treatment assignment ........................................................................... 27 
3.3.3 
Concomitant therapy ............................................................................. 28 
Inhibitors of CYP3A4 and/or PgP ..................................................................................... 29 
Inducers of CYP3A4 and/or PgP ....................................................................................... 29 
3.3.4 
Treatment compliance ........................................................................... 31 
3.3.5 
Definition of Curative Intent Therapy for Locally Advanced 
Squamous Cell Carcinoma of the Head and Neck ................................ 31 
3.4 
Visit schedule and assessments ............................................................................. 32 
3.4.1 
Pre-study Procedures ............................................................................. 32 
3.4.2 
Visit schedule ........................................................................................ 33 
3.4.3 
Efficacy assessments ............................................................................. 34 
3.4.4 
Safety assessments ................................................................................ 34 
3.4.5 
Laboratory Evaluations ......................................................................... 37 
3.4.6 
Vital signs.............................................................................................. 37 
3.4.7 
Research tests ........................................................................................ 38 
4 
Regulatory Procedures ....................................................................................................... 40 


 
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4.1 
New Protocol Distribution and IRB Submission ................................................... 40 
4.2 
Amendment Distribution and IRB Submission ..................................................... 41 
4.3 
Annual IRB Renewals, Continuing Review and Final Reports ............................. 42 
4.4 
Departure from the Protocol .................................................................................. 42 
4.5 
Registration ............................................................................................................ 43 
4.6 
Reporting of Adverse Events ................................................................................. 43 
4.6.1 
Novartis instructions for rapid notification of serious adverse 
events..................................................................................................... 45 
4.7 
Data and Safety Monitoring................................................................................... 46 
5 
Data management .............................................................................................................. 47 
5.1 
Data collection ....................................................................................................... 47 
6 
Statistical methods ............................................................................................................. 47 
6.1 
Statistical methods ................................................................................................. 47 
7 
References ......................................................................................................................... 48 
8 
Procedures and instructions ............................................................................................... 51 
8.1.1 
Publication of results ............................................................................. 51 
8.1.2 
Disclosure and confidentiality ............................................................... 51 
8.1.3 
Discontinuation of study ....................................................................... 51 
8.2 
Ethics and Good Clinical Practice ......................................................................... 51 
8.2.1 
Institutional Review Board/Independent Ethics Committee ................. 52 
8.2.2 
Informed consent ................................................................................... 52 
8.2.3 
Declaration of Helsinki ......................................................................... 52 
9 
Appendices ........................................................................................................................ 53 
9.1 
Appendix A - Procedure for Administration of Everolimus in Water via 
Gastrostomy Tube .................................................................................................. 53 
9.2 
Appendix B - Patient’s Medication Diary ............................................................. 54 
9.3 
Appendix C - Tissue and Blood Sample Collection Forms ................................... 57 
9.4 
Appendix D - PBMC isolation protocol ................................................................ 57 
 
 
 
 
 
 
 
 


 
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List of abbreviations  
4E-BP1 
4E-binding protein 
Ab 
Antibodies 
ADR 
Adverse Drug Reaction 
AE 
adverse event 
ALT/SGPT 
alanine aminotransferase/glutamic pyruvic transaminase/Serum 
glutamic-pyruvic transaminase 
AST/SGOT 
aspartate aminotransferase/glutamic oxaloacetic 
transaminase/Serum glutamic-oxaloacetic transaminase 
ATC 
Anatomical Therapeutic Chemical classification system 
AUC 
Area under the plasma-concentration time curve 
BAC 
Bronchoalveolar carcinoma 
Cmax 
Maximum plasma concentration 
CR 
Clinical research 
CRF 
Case report/Record form 
CRO 
Contract Research Organization 
CT 
Computer tomography 
CTC 
Common toxicity criteria 
CV 
Coefficient of Variation 
CYP3A4 
CytochromeP450 3A4 isoenzyme 
DNA 
Deoxyribonucleic Acid 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiogram 
EGF 
Epidermal growth factor 
EGFR 
Epidermal growth factor receptor 
eIF-4E 
Eukaryotic Initiation Factor 4E 
EPR 
Early progression rate 
FDG-PET 
Fluorine-18-2-fluoro-Deoxy-D-Glucose Positron Emission 
Tomography 
FKBP-12 
FK506-binding protein 12 
GF 
Growth factor 
HBV 
hepatitis B virus 
HBcAb 
hepatitis B core antibodies 
HBs Ab 
hepatitis B surface antibodies 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HDL 
High-density lipoproteins 
HER 
Human Epidermal Receptor 


 
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HUVECS 
human umbilical endothelial cells 
IC50 
Inhibitory concentration at 50% 
IEC 
Independent Ethics Committee 
IGF1-R 
Insulin-like Growth Factor 1 Receptor 
IHC 
immunohistochemistry 
INN 
International Non-proprietary Name 
INR 
International Normal Ratio 
IRB 
Institutional Review Board 
LC-MS 
liquid chromatography method with mass spectrometry 
LDL 
Low-density lipoproteins 
LFTs 
liver function tests 
LLOQ 
Lower limit of quantification 
MAPK 
Mitogen Activated Protein Kinase 
mRNA 
messenger Ribonucleic acid 
mTOR 
mammalian Target of Rapamycin 
NIH/NCI 
National Institutes of Health/National Cancer Institute 
nM 
nano-molar 
NSCLC 
Non-small cell lung cancer 
OS 
overall survival 
P-AKT 
phospho-AKT 
PCR 
Polymerase Chain Reaction  
PD 
Pharmacodynamics 
PET 
Positron emission tomography 
PFS 
progression free survival 
P-gp 
P-glycoprotein 
PI3K 
Phosphoinositide 3-kinase 
PK 
Pharmacokinetics 
PK/PD model 
Pharmacokinetic/pharmacodynamic model 
PT/PTT 
prothrombin time 
PTEN 
Phosphatase and Tensin homolog deleted on chromosome 10 
RBC 
red blood cell count 
REB 
Research Ethics Board 
RNA 
Ribonucleic acid 
RR 
response rate 
S6K1 
S6 kinase 1 
SAE 
serious adverse event 
SCLC 
Small cell lung cancer 
STAT3 
Signal Transducer and Activator of Transcription 3 


 
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TK 
Tyrosine kinase 
TSC2 
Tuberous Sclerosis Complex 2 
TUNNEL 
Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-
biotin Nick End Labeling 
ULN 
upper limit of normal 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
total white blood cell count 
WHO 
World Health Organization 


 
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1 
Introduction 
1.1 
Everolimus (RAD001)  
Everolimus is a novel oral derivative of rapamycin. Everolimus has been in clinical 
development since 1996 as an immunosuppressant in solid organ transplantation and has 
obtained marketing authorization (Certican®) for prophylaxis of rejection in renal and cardiac 
transplantation in a number of countries, including the majority of the European Union. 
Everolimus has been in development for patients with various malignancies since 2002. 
Everolimus 5mg and 10mg tablets were recently approved under the trade name Afinitor® for 
patients with advanced renal cell carcinoma (RCC) after failure of treatment with Sutent® 
(sunitinib) or Nexavar® (sorafenib) in the US, EU and several other countries and is 
undergoing registration in other regions worldwide. 
 
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 HIF-1 activity, VEGF production and VEGF-induced proliferation 
of endothelial cells). The role of angiogenesis in the maintenance of solid tumor growth is 
well established, and the mTOR pathway has been implicated in the regulation of tumor 
production of proangiogenic factors as well as modulation of VEGFR signaling in 
endothelial cells. 
At weekly and daily schedules and at various doses explored, RAD0001 is generally well 
tolerated. The most frequent adverse events (rash, mucositis, fatigue and headache) associated 
with Everolimus therapy are manageable. Non-infectious pneumonitis has been reported with 
mTOR inhibitors but is commonly low-grade and reversible. 
1.1.1 
mTOR pathway and mechanism of action 
At cellular and molecular level Everolimus acts as a signal transduction inhibitor. Everolimus 
selectively inhibits mTOR (mammalian target of rapamycin), a key and a highly conservative 
serine-threonine kinase, which is present in all cells and is a central regulator of protein 
synthesis and ultimately cell growth, cell proliferation, angiogenesis and cell survival. mTOR 
is the only currently known target of Everolimus [Reviewed in 1]. 
mTOR is downstream of PI3K/AKT pathway, a pathway known to be dysregulated in a wide 
spectrum of human cancers (e.g. through loss/mutation of the PTEN negative regulator; 
through PI3K mutation/amplification; through AKT/PKB overexpression/overactivation; 
through modulation of TSC1/TSC2 tumor suppressors). In addition, activation of the 
PI3K/AKT/mTOR pathway is frequently a characteristic of worsening prognosis through 
increased aggressiveness, resistance to treatment and progression.  
The main known functions of mTOR include the following 1, 2: 
 mTOR functions as a sensor of mitogens, growth factors and energy and nutrient levels, 
facilitating cell-cycle progression from G1 to S phase in appropriate growth conditions. 


 
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 The PI3K-mTOR pathway itself is frequently activated in many human cancers, and 
oncogenic transformation may sensitize tumor cells to mTOR inhibitors.  
 Through inactivating eukaryotic initiation factor 4E binding proteins (4E-BP1) and 
activating the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates translation of 
important messages, including those encoding the HIF-1 proteins, c-myc, ornithine 
decarboxylase, and cyclin D1, as well as ribosomal proteins themselves.  
 The activation of mTOR pathway leads to the increased production of pro-angiogenic 
factors (i.e., VEGF) in tumors and to tumor, endothelial and smooth muscle cell growth 
and proliferation. 
 The regulation of mTOR signaling is complex and involves positive regulators, such as 
AKT that phosphorylate and inactivate negative regulators such as the Tuberous Sclerosis 
Complex (TSC1/TSC2). 
mTOR is represented by two structurally and functionally distinct multiprotein signaling 
complexes, mTORC1 (mTOR complex 1, rapamycin sensitive) and mTORC2 (mTOR 
complex 2, rapamycin insensitive)3.  
mTORC1 is mainly activated via the PI3 kinase pathway through AKT (also known as PKB, 
protein kinase B) and the tuberous sclerosis complex (TSC1/TSC2)2. Activated AKT 
phosphorylates TSC2, which lead to the dissociation of TSC1/TSC2 complex, thus inhibiting 
the ability of TSC2 to act as a GTPase activating protein. This allows Rheb, a small G-
protein, to remain in a GTP bound state and to activate mTORC1. AKT can also activate 
mTORC1 by PRAS40 phosphorylation, thereby relieving the PRAS40-mediated inhibition of 
mTORC14, 5.  
mTORC2 (mTOR complex 2) is activated through a currently unknown mechanism, possibly 
by receptor tyrosine kinase (RTK) signaling 4. It has been suggested that mTORC2 
phosphorylates and activates a different pool of AKT, that is not upstream of mTORC1. 
PHLPP phosphatase plays a role of a negative regulator. mTORC2 is rapamycin insensitive 
and is required for the organization of the actin cytoskeleton 3.  
 
mTORC1-mediated signaling is subject to modulation by the macrocyclic lactone rapamycin 
and its derivatives, such as Everolimus Once these agents bind to the 12 kDa cytosolic 
FK506-binding protein immunophilin FKBP12, the resulting rapamycin-FKBP12 complexes 
bind to a specific site near the catalytic domain of mTORC1 and inhibit phosphorylation of 
mTOR substrates. As a consequence, downstream signaling events involved in regulation of 
the G1 to S-phase transition are inhibited. This mechanism is thought to be responsible for the 
immunosuppressive effects of rapamycin as well as its putative antineoplastic activity 6. As 
many cancers are characterized by dysregulation of G1 transit (for example, overexpression of 
cyclin or cyclin-dependent kinases), inhibition of mTOR becomes an intriguing target for 
inducing cytostasis 2. Studies using leukemic cells have also demonstrated that temsirolimus 
and everolimus block the mTORC2 complex which could be cell type or dose dependent 7. 
 


 
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1.1.2 
Preclinical studies 
Pre-clinical investigations have demonstrated that Everolimus is a potent inhibitor of the 
proliferation of a range of human tumor cell lines in-vitro with IC50s ranging from sub/low 
nM to µM concentrations, concentrations capable of being reached in patients at the doses 
used in clinical trials.  
Everolimus was shown to have activity in human tumor cell lines originating from lung, 
breast, prostate, colon, kidney, melanoma and glioblastoma. Everolimus was also shown to 
have activity in human pancreatic neuroendocrine cells, where induction of apoptosis was 
reported 8, as well as in acute myeloid leukemia cells 7, adult T-cell leukemia cells 9, diffuse 
large B cell lymphoma cells [DLBCL; 10], pancreatic tumor cells 11, ovarian cancer cells 12, 13 
and hepatocellular carcinoma cells 14.  
As a single agent, Everolimus inhibited proliferation in three mantle cell lymphoma cell lines 
(Jeko1, SP49 and NCEB1) approximately 40–65% compared to control cells. This was 
associated with G1 cell-cycle arrest and reduced phosphorylation of the mTOR downstream 
target, 4E-BP1 15.  
In a clonogenic assay using cells derived from 81 patient-derived tumor xenografts never 
cultured in vitro (11 human tumor types with 3 to 24 tumors each: bladder, colon, gastric, 
NSCLC [adeno, squamous epithelium and large cell], SCLC, breast, ovary, pancreatic, renal, 
melanoma, and pleuramesothelioma), Everolimus inhibited colony formation in a 
concentration-dependent manner. In addition, normal hematopoetic stem cells were 
insensitive to Everolimus, with an IC50 about 15 fold higher than the tumor lines.  
Everolimus also inhibits the proliferation of human umbilical vein endothelial cells 
(HUVECS), with particular potency against VEGF-induced proliferation. The inhibition of 
endothelial proliferation and antiangiogenic activity of Everolimus was confirmed in vivo, as 
Everolimus selectively inhibited VEGF-dependent angiogenic response. Mice with primary 
and metastatic tumors treated with Everolimus showed a significant reduction in blood vessel 
density when compared to controls at well tolerated doses. Additionally, activity in a VEGF-
impregnated s.c. implant model of angiogenesis and reduced vascularity (vessel density) of 
Everolimus -treated tumors (murine melanoma) provided evidence of in vivo effects of 
angiogenesis. 
Everolimus also inhibits tumor growth in-vivo in xenografted, syngeneic and orthotopic 
animal models, residing longer in tumor tissue than in plasma and demonstrating high tumor 
penetration in a rat pancreatic tumor model. These effects occurred within the dose range of 
2.5 to 10 mg/kg p.o. daily. Typically, the antitumor activity of Everolimus monotherapy was 
that of reduction of tumor growth rates rather than producing regressions or stable disease. 
Everolimus administred p.o., was a potent inhibitor of tumor growth and well tolerated in: 
 s.c. mouse xenograft model, established from a variety of tumor cell lines of diverse 
histotypes (NSCLC, pancreatic, colon, melanoma, epidermoid), including a Pgp170 
overexpressing multi-drug resistant tumor line  
 in a series of low-passage tumor xenografts established directly from human tumor 
material, maintained only in vivo and considered highly predictive of therapeutic outcome 
in patients. These included breast (5 lines), colorectal (9 lines), gastric (3 lines), lung (22 


 
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lines including adenocarcinomas, epidermoid cell, large cell and small cell histotypes), 
melanoma (6 lines), ovarian (4 lines), pancreatic (3 lines) and renal (6 lines) 
 in two syngeneic models (CA20948 rat pancreatic, B16/Bl6 mouse orthotopic melanoma) 
Taken together, these data indicate the broad antiproliferative potential of Everolimus. 
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. PTEN status alone may not be predictive of Everolimus relative in 
vitro sensitivity, however in some cases (i.e., GBM) there is also a correlation with PTEN 
status. 
In preclinical models, the administration of Everolimus is associated with reduction of protein 
phosphorylation in target proteins downstream of mTOR, notably phosphorylated S6 (pS6) 
and p4E-BP1, and occasionally with an increase in phosphorylation AKT (pAKT).  
Pre-clinical safety 
In safety pharmacology studies, Everolimus was devoid of relevant effects on vital functions 
including the cardiovascular, respiratory and nervous systems. Everolimus had no influence 
on QT interval prolongation. Furthermore, Everolimus showed no antigenic potential. 
Although Everolimus passes the blood-brain barrier, there was no indication of relevant 
changes in the behavior of rodents, even after single oral doses up to 2000mg/kg or after 
repeated administration at up to 40 mg/kg/day. Based on these findings, the potential of 
Everolimus to affect vital functions in patients is considered to be low. 
Everolimus is considered to have no genotoxicity or carcinogenicity potential. All significant 
adverse events observed in preclinical toxicology studies with Everolimus in mice, rats, 
monkeys and minipigs were consistent with its anticipated pharmacologic action as an 
antiproliferative 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. Ocular effects (lenticular disorders) observed in rats were not observed in any other 
species and are considered to be a species-specific disorder. 
More pre-clinical information is provided in the Investigator’s Brochure. 
1.1.3 
Clinical experience 
1.1.3.1 
Everolimus Pharmacokinetics 
Everolimus is rapidly absorbed with a median tmax of 1-2 hours. The bioavailability of the 
drug is believed to be 11% or greater. The AUC0-τ is dose-proportional over the dose range 
between 5 to 70 mg in the weekly regimen and 5 and 10 mg in the daily regimen. Cmax is 
dose-proportional between 5 and 10 mg for both the weekly and daily regimens. At doses of 
20 mg/week and higher, the increase in Cmax is less than dose-proportional. The coefficient of 
variation between patients is approximately 50%.  
Trough levels (24 hour post-dose) correlate well with AUC0-τ at steady-state during daily 
administration. 


 
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In whole blood, at a daily dose of 10 mg, about 20% of Everolimus is confined in plasma with 
26% being unbound. The remaining 80% is sequestered in blood cells.  
Everolimus is extensively metabolized in the liver and eliminated in the bile. Major 
metabolites are inactive. Elimination half-life is approximately 30 hours. The clearance of 
Everolimus is approximately halved in patients with mild-moderate hepatic impairment 
(Child-Pugh Class A or B), while renal impairment has little or no impact on the 
pharmacokinetics of Everolimus. 
Age, weight and gender in the adult population do not affect the pharmacokinetics of 
Everolimus to a clinically relevant extent. The clearance of Everolimus is reduced in children. 
Pharmacokinetic characteristics are not notably different between Caucasian and Japanese 
subjects, whereas in Black patients’ population pharmacokinetic studies have shown an 
average 20% higher clearance. 
A high-fat meal altered the absorption of Everolimus with 1.3 hour delay in tmax, a 60% 
reduction in Cmax and a 16% reduction in AUC. 
Everolimus is a substrate of CYP3A4 and a substrate and a moderate inhibitor of the multi-
drug efflux pump P-glycoprotein (P-gP, MDR1, ABCB1). Hence, its metabolism is sensitive 
to drugs which modify these enzymes (substrates, inducers, or inhibitors of these enzymes). 
Competitive inhibition could occur when Everolimus is combined with drugs which are also 
CYP3A4 or P-glycoprotein substrates 
Table 3-3 (Section 3.3.3) lists examples of clinically relevant CYP3A inhibitors and inducers. 
Please refer to Section 3.3.3 for more information on the concomitant use of CYP3A4 
inhibitors/inducers and other medications. 
More information on Everolimus pharmacokinetics is provided in the Investigator’s Brochure. 
1.1.3.2 
Everolimus Pharmacodynamic studies 
Pharmacokinetic/pharmacodynamic modeling based on inhibition of the biomarker p70S6 
kinase 1 [S6K1] in peripheral blood mononuclear cells [PBMC]) suggests that 5-10 mg daily 
should be an adequate dose to produce a high-degree of sustained target inhibition {[Study 
C2101] / [Study 2102], 16}. Furthermore, molecular pharmacodynamic (MPD) studies, using 
immunocytochemistry (IHC) in biopsied tumor tissue, assessed the degree of inhibition and 
its duration for pS6, p4E-BP1 and pAKT expression with the daily and weekly dosing. There 
was high inhibition of the downstream markers S6K1 and 4E-BP1 at 5mg/day, which was 
complete at 10 mg/day, while preliminary results suggest increase in pAKT expression with 
maximal effect at 10 mg daily {[Study C2107], 17}. 
More information is provided in the Investigator’s Brochure. 
1.1.3.3 
Clinical experience with Everolimus  
Everolimus has been investigated as a component of multi-drug immunosuppression in solid 
organ transplantation since 1996 and was approved for the indication of prophylaxis of organ 
rejection in adult patients receiving an allogeneic renal or cardiac transplant on 8 Jul 2003 by 
the European Union under the trade name of Certican®. The most frequent adverse drug 


 
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reactions in this context are highly specific to the transplant context. However, certain events 
are generalizable, most notably myelosuppression, skin disorders and increases in blood lipid 
levels. 
Everolimus has been in development for patients with cancer since 2002. Approximately 2586 
patients with various malignancies have been treated in either Novartis sponsored or non-
Novartis sponsored clinical studies as of 31 Aug 2007. Overall, Novartis sponsored a total of 
22 studies of Everolimus administered either as single-agent (n=848), or in combination with 
other anti-tumor agents (n=663). Ongoing or completed Investigator sponsored studies also 
enrolled over 1000 patients globally. 
Eight single-agent Novartis sponsored trials have or are being conducted in various advanced 
malignancies. Five Phase I studies evaluated several escalating doses with either weekly or 
daily administration (Studies C2101/02, C2106, C2107, C1101) of Everolimus with the  
objective to identify an optimal regimen and dosage, based on safety, pharmacokinetics and 
knowledge of the drug’s molecular effects on various tumors. The 10 mg/day and 50-70 
mg/week dosages were proposed for further studies, when using Everolimus as a single agent, 
and as a target maximum dose in combination studies. In addition the Phase I studies, 
conducted in prostate cancer (Study C2106) and in Japanese patients with advanced cancers 
(Study C1101), evaluated the safety and the molecular changes in tumor, associated with the 
administration of Everolimus.  
Two Phase II monotherapy studies were designed to evaluate the safety and efficacy of a 
single dose of 10 mg administered daily including Study C2235 in advanced NSCLC (n=81) 
and Study C2239 in advanced pancreatic neuroendocrine tumors (n=160). 
Everolimus has shown activity in patients whose metastatic renal cell cancer has progressed 
despite treatment with VEGF-R inhibitors in a phase 2 study 18. A Phase III, randomized, 
double blind, placebo controlled study in patients with mRCC who progressed on a VEGFR 
TKI demonstrated that everolimus, administered daily at an oral dose of 10 mg provides 
positive clinical benefit 19. Median progression free survival (PFS) was prolonged from 1.87 
months for patients receiving placebo to 4.01 months for everolimus treated patients, assessed 
by central independent review blinded to clinical data (hazard ratio 0.30, 95% CI 0.22-0.40, 
p<0·0001). 
 
Overall, the most frequent mild-moderate Grade 1/2 adverse effects have been rash, 
stomatitis, fatigue, neutropenia and to a lesser extent gastrointestinal disorders (nausea, 
anorexia, diarrhea, vomiting), and headache. The primary DLT has been severe (Grade 3) 
stomatitis, and occasionally fatigue, hyperglycemia, and neutropenia. Reduced blood counts, 
hyperlipidemia (mainly hypercholesterolemia) and hyperglycemia are relatively frequent 
laboratory findings. Infections have not been notably frequent or severe. Non-infectious low-
Grade (Grade 1/2) pneumonitis has led to development of treatment guidelines for the 
disorder (Table 3-2). Preliminary indications of anti-tumor activity are encouraging. 
For more information on known undesirable effects of Everolimus refer to Section 3.2.5.  
Further detailed information regarding Everolimus clinical development, safety and efficacy 
is provided in the Investigator’s Brochure. 


 
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1.1.4 
Study Rationale 
1.1.4.1 
Squamous Cell Carcinoma of the Head and Neck (SCCHN) 
Approximately 40,000 new cases of head and neck cancer are diagnosed annually in the 
United States.  Of these patients, two-thirds present with locoregionally advanced disease 
(American Joint Committee on Caner [AJCC] stage III or IV) and one-third with early stage 
disease (AJCC stage I or II).  At presentation, 10% of patients may be found to have 
involvement of distant organs, most commonly the lung.  In addition, 20% of patients will 
develop clinically detected distant metastases over the course of their disease. In autopsy 
series up to 50% of patients with head and neck cancer are found to have metastases.  It is 
likely that with improvements in the rate of locoregional control, the risk of distant failure will 
become predominant, and that systemic therapy, if efficacious, will have a major impact on 
outcome.  Approximately 95% of all head and neck malignancies are squamous cell 
carcinomas and this histological type is the focus of this review and study protocol.  Also, it 
should be noted that even though head and neck malignancies are usually examined in one 
group, they represent a heterogeneous group of diseases, with variability in biologic behavior 
and natural history, prognosis, and considerations in management.  Disease sites such as the 
hypopharynx and the base of tongue have a worse prognosis compared to the larynx or 
nasopharynx, and may require more aggressive treatment strategies.  The vast majority of 
head and neck malignancies can be attributed to the use of tobacco and alcohol.  These 
carcinogens are synergistic, and may damage the entire aerodigestive epithelium.  Due to their 
frequent history of exposure to tobacco and alcohol patients with head and neck cancer are at 
high risk for the development of second primary tumors, synchronous or metachronous, that 
may involve the head and neck region as well as other organs, predominantly the lung. 
 
For patients with resectable locally advanced head and neck cancer (AJCC stage III or IV), 
surgery and postoperative radiation have been traditionally considered the mainstay of 
treatment, whereas radiation therapy alone has been offered to patients with unresectable 
tumors.  It is important to recognize that the distinction between resectable and unresectable 
disease lacks clear definition.  With the exception of a few widely accepted signs of 
unresectability, such as involvement of the carotid artery, in most cases the assessment is 
subjective and relates to the experience of the surgeon and the availability of reconstructive 
strategies.  Despite aggressive locoregional treatment with surgical resection and 
postoperative radiotherapy, locoregionally advanced disease has a poor prognosis with 5-year 
survival of less than 30%. The most common site of failure remains locoregional, whereas 
distant failure occurs in 20-30% of patients. 
 
Localized treatment modalities have been considered as standard care. For patients with Stage 
I or II disease either surgery or radiation, are used as single treatment modalities with curative 
intent.  Cure is achieved in the majority of cases (60-80%, depending on the exact stage and 
anatomic location) and, in this group of patients, the development of a second malignancy is a 
greater long-term risk than a recurrence of their primary disease.  
 


 
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For patients with locoregionally advanced disease (Stage III or IV) surgery and radiation have 
been used in sequence (unless the patient is medically inoperable or has unresectable disease).  
Despite this aggressive bimodality treatment approach, cure is achieved in only a minority of 
patients.  Most patients die of locoregional persistence or recurrence of disease; some specific 
patient subgroups (e.g., laryngeal, nasopharyngeal disease) may have a better prognosis. In 
patients with stage III and IV disease, the addition of chemotherapy to the overall treatment 
plan has been studied intensively over the last 3 decades.  Research strategies, generally, have 
included the use of induction (neoadjuvant) or adjuvant chemotherapy, as well as concomitant 
chemoradiotherapy. The primary goal of such research is to improve local control and 
survival.   
 
After completion of curative intent local therapy there are no standard approaches to reduce 
the risk of SCCHN recurrence. Secondary prevention efforts have been attempted in the past 
but have either proven ineffective, too toxic, or both20. Surveillance for local or distant failure 
is standard practice but the frequency of examinations and radiographic assessments is not 
well defined in an asymptomatic patient. Therefore, routine management of patients at risk of 
recurrence of SCCHN currently does not include any active therapeutic intervention. 
1.1.4.2 
Adjuvant Therapy with an mTOR Inhibitor  
The Akt/mTOR pathway is activated in the great majority of SCCHN. Expression of eIF4E is 
functionally active in SCCHN through activation of the Akt/mTOR signaling pathway21, 22. 
Moreover, activation of eIF4E in histologically tumor-free surgical margins appears to be an 
independent predictor of recurrence21, 22. Patients with advanced stage SCCHN have a high 
rate of recurrence after curative intent therapy. In a preclinical model of minimal residual 
SCCHN, mTOR inhibitors have been shown to inhibit tumor formation and increase 
survival23. An exploratory biomarker trial with temsirolimus in newly diagnosed advanced 
stage SCCHN patients showed inhibition of the Akt/mTOR pathway in tumors and PBMCs 
(surrogate markers) and proapoptotic activity of temsirolimus in patients with head and neck 
tumors.  
 
There are data regarding long term toxicities of mTOR inhibitors.  Analysis of special 
populations such as renal transplant patients and patients with tuberous sclerosis suggests that 
sirolimus and its analogues are well tolerated 24. Studies in renal-transplant patients have 
always administered sirolimus in combination with cyclosporine and/or corticosteroids 
making interpretation of these data regarding single agent sirolimus difficult. Nonetheless, the 
studies suggest that adding sirolimus to allograft rejection prophylaxis regimens is safe and 
does not increase immunosuppression or rate of second malignancies 25.   Moreover, no 
increased incidence of immunosuppression has been observed in multiple trials of single-
agent rapamycin or rapamycin analogues in cancer patients 26, 27. However, the most relevant 
experience to this study is a trial in patients with tuberous sclerosis or sporadic 
lymphangioleiomyomatosis who received single-agent sirolimus for one year and had serum 
drug levels equal to or exceeding those in transplant patients 24. The most common adverse 
events attributable to sirolimus included aphthous ulcers and diarrhea. Twenty-five subjects 
entered the study and 20 were able to complete 1 year of therapy. Of the 5 subjects that 


 
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withdrew prior to completing planned therapy, only 1 did so secondary to adverse effects of 
sirolimus. 
Therefore, the Akt/mTOR pathway is active in SCCHN, mTOR inhibitors display biologic 
activity in preclinical and clinical SCCHN models, and currently available oral mTOR 
inhibitors appear to be well tolerated even for prolonged periods of time. Taken together and 
given the ability to identify patients who have no evidence of disease after therapy but a high 
risk of recurrence, we propose studying everolimus as adjuvant therapy in this setting. 


 
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2 
Study objectives 
Primary 
Two-year progression-free survival (PFS) probability in subjects treated with everolimus 
versus placebo after definitive local therapy 
 
Secondary 
 Toxicity of everolimus versus placebo as adjuvant therapy 
 Site of disease progression (locoregional vs. distant) in subjects treated with everolimus 
versus placebo 
 Incidence of second primary tumors in subjects treated with everolimus versus placebo  
 Prevalence of Akt/mTOR pathway activation in locally advanced SCCHN  
 Determine correlation between progression free survival (PFS) and the degree of 
activation of the Akt/mTOR pathway biomarkers in tumors and adjacent mucosa treated 
with everolimus versus placebo  
 Determine if PTEN status is predictive marker of Everolimus sensitivity 
3 
Investigational plan 
3.1 
Overall study design 
This is a randomized, double-blind, phase 2 study of everolimus versus placebo. 
Randomization will be stratified for disease stage and type of local therapy (IVa surgical vs. 
IVa non-surgical vs. IVb) as well as treating institution. Eight to 16 weeks after completion of 
definitive, curative-intent therapy for locally advanced SCCHN, potentially eligible subjects 
will be consented and randomized to receive either everolimus or placebo for a maximum of 1 
year. Subjects will be evaluated prior to starting therapy; 4, 16, 32 and 52 weeks after starting 
therapy; and then at least every 4 months for a minimum of 2 years (those enrolled early will 
be followed for 3 years).  
 
Radiographic assessments (CT, PET-CT, PET and/or MRI) will be conducted prior to 
initiating therapy and every 4-6 months for 2 years then every 6 months in year 3.  Not all 
patients will be followed for 3 years at end of study. Minimum radiographic follow-up will be 
2 years for all patients. For those subjects enrolled early, longer follow-up will determine 
secondary endpoints such as PFS and OS. 
3.2 
Study population 
3.2.1 
Patient population 
160 subjects (80 per arm, everolimus vs. placebo) 


 
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3.2.2 
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. 
Inclusion criteria  
 Squamous cell carcinoma of the head and neck that is pathologically confirmed 
 Patients must have no evidence of disease (NED) within 16 weeks after receiving curative 
intent therapy for locally advanced squamous cell carcinoma of the head and neck 
(SCCHN). 
 NED is defined as ANY of the following: 
 Biopsy demonstrating no cancer cells 
 Radiographic studies (CT, MRI, or PET) demonstrating complete response or 
absence of cancer as judged by the investigator 
 Clinical assessment including direct visualization by nasopharyngolarygoscopy 
demonstrating complete response 
 Initial TNM stage IVa or IVb (AJCC 6th edition) 
 Tumor tissue available for correlative analyses (see Section 3.4.7). Patient can be 
registered, randomized, and start therapy prior to specimen shipment. 
 Primary tumor site is oral cavity, oropharynx, hypopharynx, or larynx (including 
supraglottis and subglottis) 
 For oropharynx cancer patients only:  
 Human papilloma virus negative by in-situ hybridization, polymerase chain reaction, or 
negative p16 immunohistochemistry 
 Human papilloma virus positive with a history of tobacco use. Minimal tobacco 
exposure must be 10 pack years (pack years = average number of packs smoked per 
day multiplied by number of years smoked) 
 Age ≥ 18 years 
 Karnofsky performance status > 70% 
 Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, 
Hb >9 g/dL 
 Adequate liver function as shown by: 
 serum bilirubin ≤ 1.5 x ULN 
 ALT and AST ≤ 2.5x ULN  
 INR and PTT ≤1.5.  (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of 
warfarin or on a stable dose of LMW heparin for >2 weeks at time of randomization.) 
 Adequate renal function: serum creatinine ≤ 1.5 x ULN 


 
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 Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 
x 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 and confirmation of 
lipid levels within acceptable criteria. 
 Signed informed consent 
 
Exclusion criteria 
 Patients currently receiving anticancer therapies or who have received anticancer therapies 
within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, 
antibody based therapy, etc.) 
 Patients, who have had a major surgery or significant traumatic injury within 4 weeks of 
start of study drug, patients who have not recovered from the side effects of any major 
surgery (defined as requiring general anesthesia) 
 Patients with acute radiotherapy related mucositis and dermatitis > grade 1 (all other acute 
radiotherapy related toxicities > grade 1 may be eligible per sponsor discretion) 
 Prior treatment with any investigational drug within the preceding 4 weeks 
 Patients receiving chronic, systemic treatment with corticosteroids or another 
immunosuppressive agent. Topical or inhaled corticosteroids are allowed. 
 Patients should not receive immunization with attenuated live vaccines within one week of 
study entry or during study period.  
 Lip, nasopharynx, nasal cavity, paranasal sinus, salivary gland, skin, or thyroid primary 
tumors 
 Evidence of metastatic disease 
 Other malignancies within the past 3 years except for adequately treated CIS of the cervix 
or basal or squamous cell carcinomas of the skin 
 Patients who have any severe and/or uncontrolled medical conditions or other conditions 
that could affect their participation in the study such as: 
 Symptomatic congestive heart failure of New York heart Association Class III or 
IV  
 unstable angina pectoris, symptomatic congestive heart failure, myocardial 
infarction within 6 months of start of study drug, serious uncontrolled cardiac 
arrhythmia or any other clinically significant cardiac disease 
 severely impaired lung function – if suspected, pulmonary function tests should be 
performed with severely impaired function defined as spirometry and DLCO that 
is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest 
on room air 
 uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN 
 active (acute or chronic) or uncontrolled severe infections (Note: Optimal glycemic 
control should be achieved before starting trial therapy.) 
 liver disease such as cirrhosis, or severe hepatic impairment (Child-Pugh class C). 


 
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 Chronic or active hepatitis B or C. Note: A detailed assessment of Hepatitis B/C 
medical history and risk factors must be done at screening for all patients.  HBV 
DNA and HCV RNA PCR testing are required at screening for all patients with a 
positive medical history based on risk factors and/or confirmation of prior 
HBV/HCV infection (see Section 4.6.1.2).  
 A known history of HIV seropositivity 
 Impairment of gastrointestinal function or gastrointestinal disease that may significantly 
alter the absorption of Everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome or small bowel resection) 
 N.B.: patients are allowed to administer everolimus through a feeding tube (see 
Appendix A) 
 Patients with an active, bleeding diathesis 
 Female patients who are pregnant or breast feeding, or adults of reproductive potential 
who are not using effective birth control methods. Adequate contraception must be used 
throughout the trial by both sexes and for at least 8 weeks after the last dose of study drug, 
by both sexes. Hormonal contraceptives are not acceptable as a sole method of 
contraception.  (Women of childbearing potential must have a negative urine or serum 
pregnancy test within 7 days prior to administration of Everolimus) 
 Male patient 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 
 Patients who have received prior treatment with an mTOR inhibitor (sirolimus, 
temsirolimus, everolimus). 
 Patients with a known hypersensitivity to Everolimus or other rapamycin analogues 
(sirolimus, temsirolimus) or to its excipients 
 History of noncompliance to medical regimens 
 Patients unwilling to or unable to comply with the protocol 
3.2.3 
Interruption or discontinuation of treatment 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the patient on study drug. If administration of 
Everolimus must be interrupted because of unacceptable toxicity, drug dosing will be 
interrupted or modified according to rules described in Table 3-1. Toxicity will be assessed 
using the NIH-NCI Common Terminology Criteria for Adverse Events, version 4.0 
(CTCAEv4.0,(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf)). 
 


 
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Table 3.0   Everolimus dose level modification guidelines 
Dose level 
Dose and schedule 
0 (starting dose) 
10 mg daily 
-1 
5 mg daily 
-2 
5 mg every other day 
 
 


 
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Table 3-1 
Criteria for dose-modification in case of suspected Everolimus 
Everolimus toxicity and re-initiation of Everolimus treatment 
Toxicity 
Actions 
Non-hematological toxicity 
 
Grade 2  
(except pneumonitis – refer to Table 3-2) 
If the toxicity is tolerable to the patient, maintain the same 
dose. If the toxicity is intolerable to patient, interrupt 
Everolimus until recovery to grade 1. Then reintroduce 
Everolimus at same dose. 
If event returns to grade 2, then interrupt Everolimus 
until recovery to grade 1. Then reintroduce Everolimus 
at the lower dose level. 
Grade 3 
(except hyperlipidemia*) 
(except pneumonitis – refer to Table 3-2) 
Interrupt Everolimus until recovery to grade 1. Then 
reintroduce Everolimus at the lower dose level. For 
pneumonitis consider the use of a short course of 
corticosteroids. 
Grade 4 
Discontinue Everolimus. 
Hematological toxicity 
 
Grade 2 Thrombocytopenia (platelets <75, ≥ 50x109/L)  
Interrupt Everolimus until recovery to grade 1 (>75 
x109/L). Then reintroduce Everolimus at initial dose. 
If thrombocytopenia again returns to grade 2, interrupt 
Everolimus until recovery to grade 1. Then reintroduce 
Everolimus at the lower dose level.  
Grade 3 Thrombocytopenia (platelets <50, ≥ 25 x10 9/L) 
Interrupt Everolimus until recovery to grade ≤1 (platelets 
≥ 75 x109/L).  Then resume Everolimus at one dose level 
lower.  If grade 3 thrombocytopenia recurs, discontinue 
Everolimus. 
Grade 4 Thrombocytopenia (platelets < 25 x109/L)  
Discontinue Everolimus. 
Grade 3 Neutropenia (neutrophils <1, ≥0.5 x109/L) 
Interrupt Everolimus until recovery to grade 1 ( 
neutrophils ≥ 1.5 x 109/L). Then resume Everolimus at the 
initial dose.  If ANC again returns to Grade 3, hold 
Everolimus until the ANC ≥ 1.5 x 109/L.  Then resume 
Everolimus dosing at the lower dose level.  Discontinue 
patient from study therapy for a third episode of grade 3 
neutropenia. 
Grade 4 Neutropenia (neutrophils < 0.5 x109/L) 
Interrupt Everolimus until recovery to grade  1  
(neutrophils ≥ 1.5 x 109/L). Then resume Everolimus at the 
lower dose level. If grade 3 or grade 4 neutropenia occurs 
despite this dose reduction, discontinue Everolimus. 
Grade 3 febrile neutropenia (not life-threatening) 
Interrupt Everolimus until resolution of fever and 
neutropenia to grade ≤ 1. Hold further Everolimus until 
the ANC ≥ 1,500/mm3 and fever has resolved. Then 
resume Everolimus at the lower dose level. If febrile 
neutropenia recurs, discontinue Everolimus. 
Grade 4 febrile neutropenia (life-threatening) 
Discontinue Everolimus. 
Any hematological or non-hematological toxicity requiring interruption for 
≥ 3 weeks 
Discontinue Everolimus.  
*Grade 3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should be 
managed using medical therapies (see Sec. 3.2.5.2). 
 
Subjects who require anticoagulation after randomization should be treated according to their 
physician’s discretion and can continue on study. Since everolimus can interact with warfarin, 
the use of low-molecular weight heparins or non-coumarin containing anticoagulants is 
encouraged. If warfain is administered, close monitoring of INR is warranted.  


 
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3.2.4 Monitoring of Everolimus suspected toxicities  
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or abnormal laboratory value suspected to be related to Everolimus must be followed at least 
weekly until the adverse event or abnormal laboratory resolves or returns to grade 1. If a 
patient requires a dose delay of > 21 days from the intended day of the next scheduled dose, 
then the patient must be discontinued from the study. 
3.2.5 Known Undesirable Side Effects of Everolimus  
The data described below reflect exposure to everolimus (n=274) and placebo (n=137) in a 
randomized phase III study for the treatment of metastatic renal cell carcinoma. In total, 165 
patients were exposed to everolimus 10 mg/day for ≥4 months. The median age of patients 
was 61 years (range 27 to 85). The most common adverse reactions (incidence ≥10%) were 
stomatitis, rash, fatigue, asthenia, diarrhea, anorexia, nausea, mucosal inflammation, 
vomiting, cough, peripheral edema, infections, dry skin, epistaxis, pruritus, and dyspnoea. The 
most common grade 3-4 adverse reactions (incidence ≥2%) were infections, stomatitis, 
fatigue, and pneumonitis. 
The median duration of blinded study treatment was 141 days (range 19 to 451) for patients 
receiving everolimus and 60 days (range 21 to 295) for those receiving placebo. The rates of 
treatment-emergent adverse reactions resulting in permanent discontinuation were 7% and 0% 
for the everolimus and placebo treatment groups, respectively. Most treatment-emergent 
adverse reactions were grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse 
reactions were reported in 39% versus 7% of patients receiving everolimus and placebo, 
respectively. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal 
failure (0.4%) were observed on the everolimus arm. 
Everolimus has immunosuppressive properties and may predispose patients to bacterial, 
fungal, viral or protozoan infections, including infections with opportunistic pathogens. 
Localized and systemic infections, including pneumonia, other bacterial infections, invasive 
fungal infections, such as aspergillosis or candidiasis and viral infections including 
reactivation of hepatitis B virus, have been described in patients taking everolimus. Some of 
these infections have been severe (e.g. leading to respiratory or hepatic failure) and 
occasionally have had a fatal outcome. 
Physicians and patients should be aware of the increased risk of infection with everolimus. 
Treat pre-existing infections prior to starting treatment with everolimus. While taking 
everolimus, be vigilant for symptoms and signs of infection; if a diagnosis of infection is 
made, institute appropriate treatment promptly and consider interruption or discontinuation of 
everolimus. If a diagnosis of invasive systemic fungal infection is made, discontinue 
everolimus and treat with appropriate antifungal therapy. 
 
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving 
chemotherapy (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 


 
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be done for all patients at screening, with testing performed prior to the first dose of 
everolimus.  
Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, 
dyspnea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or 
without respiratory impairment) have been observed with everolimus. 
Hyperglycemia has been reported in clinical trials. Monitoring of fasting serum glucose is 
recommended prior to the start of everolimus therapy and periodically thereafter. Optimal 
glycemic control should be achieved before starting a patient on everolimus. Mouth ulcers, 
stomatitis and oral mucositis have been seen in patients treated with everolimus. In such cases 
topical treatments are recommended, but alcohol- or peroxide-containing 
Elevations of serum creatinine, usually mild, have been reported in clinical trials. Monitoring 
of renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, 
is recommended prior to the start of everolimus therapy and periodically thereafter. 
Decreased hemoglobin, lymphocytes, platelets and neutrophils have been reported in clinical 
trials. Monitoring of complete blood count is recommended prior to the start of everolimus 
therapy and periodically thereafter. 
Everolimus is not recommended in patients with severe hepatic impairment, (Child-Pugh class 
C). 
The use of live vaccines and close contact with those who have received live vaccines should 
be avoided during treatment with everolimus. Close contact with those who have received 
attenuated live vaccines should be avoided during treatment with everolimus. Examples 
of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, 
yellow fever, varicella and TY21a typhoid vaccines. 
Hypophosphatemia, hypomagnesemia, hyponatremia and hypocalcemia have been reported as 
serious adverse reactions. Electrolytes should be monitored in patients treated with 
Everolimus. 
Table 3-1 provides general recommendations for the management of patients, with suspected 
drug toxicities while on treatment with Everolimus as single-agent therapy. 
More detailed information regarding Everolimus reported suspected toxicities and individual 
cases is provided in the Investigator’s Brochure. 
3.2.5.1 Management of stomatitis/oral mucositis/mouth ulcers 
Stomatitis/oral mucositis/mouth ulcers due to Everolimus should be treated using local 
supportive care. Please note that investigators in earlier trials have described the oral toxicities 
associated with Everolimus as mouth ulcers, rather than mucositis or stomatitis. If your 
examination reveals mouth ulcers rather than a more general inflammation of the mouth, 
please classify the adverse event as such. Please follow the paradigm below for treatment of 
stomatitis/oral mucositis/mouth ulcers: 
1. For mild toxicity (Grade 1), use conservative measures such as non-alcoholic mouth 
wash or salt water (0.9%) 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 


 
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adequate oral alimentation), the suggested treatments are topical analgesic mouth 
treatments (i.e., local anesthetics such as benzocaine, butyl aminobenzoate, tetracaine 
hydrochloride, menthol, or phenol) with or without topical corticosteroids, such as 
triamcinolone oral paste 0.1% (Kenalog in Orabase®). 
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives (e.g. Thymol) may 
tend to worsen mouth ulcers. It is preferable to avoid these agents. 
4. Antifungal agents must be avoided unless a fungal infection is diagnosed. In particular, 
systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) 
should be avoided in all patients due to their strong inhibition of Everolimus metabolism, 
thereby leading to higher Everolimus exposures. Therefore, topical antifungal agents are 
preferred if an infection is diagnosed. Similarly, antiviral agents such as acyclovir should 
be avoided unless a viral infection is diagnosed. 
Note:  Stomatitis/oral mucositis should be appropriately graded using the functional grading 
given on the NCI-CTC for adverse events, version 3.0. 
3.2.5.2  Management of hyperlipidemia and hyperglycemia  
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary 
habits. Blood tests to monitor hyperlipidemia must be taken in the fasting state. Treatment of 
hyperlipidemia should take into account the pre-treatment status and dietary habits. Blood 
tests to monitor hyperlipidemia must be taken in the fasting state.. Hyperlipidemia and 
hypertriglyceridemia should be treated according to local best clinical practice. Patients 
should be monitored clinically and through serum chemistry for the development of 
rhabdomyolysis and other adverse events as required in the product label/data sheets for 
HMG-CoA reductase inhibitors. 
Hyperglycemia has been reported in clinical trials. Monitoring of fasting serum glucose is 
recommended prior to the start of everolimus therapy and periodically thereafter. Optimal 
glycemic control should be achieved before starting trial therapy. 
  
3.2.5.3  Management of non-infectious pneumonitis 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious 
pneumonitis (including interstitial lung disease) have also been described in patients taking 
everolimus (see Section 5 Adverse drug reactions). 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 
dyspnoea, and in whom infectious, neoplastic and other non-medicinal causes have been 
excluded by means of appropriate investigations. Patients should be advised to report 
promptly any new or worsening respiratory symptoms.  
Patients who develop radiological changes suggestive of non-infectious pneumonitis and have 
few or no symptoms may continue everolimus therapy without dose alteration. If symptoms 
are moderate (Grade 2), consideration should be given to interruption of therapy until 


 
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symptoms improve. The use of corticosteroids may be indicated. Everolimus may be 
reintroduced at a reduced dose until recovery to Grade 1 or better.  
For cases where symptoms of non-infectious pneumonitis are severe (Grade 3), everolimus 
therapy should be discontinued and the use of corticosteroids may be indicated until clinical 
symptoms resolve. Therapy with everolimus may be re-initiated at a reduced dose depending 
on the individual clinical circumstances. 
Table 3-5 
Management of non-infectious pneumonitis 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis  
Everolimus Dose Adjustment 
Grade 1 
CT scans with lung windows and 
pulmonary function testing 
including: spirometry, DLCO, and 
room air O2 saturation at rest. 
Repeat chest x-ray/CT scan every 2 
Cycles until return to baseline. 
No specific therapy is 
required 
Administer 100% of Everolimus dose. 
Grade 2 
CT scan with lung windows and 
pulmonary function testing 
including: spirometry, DLCO, and 
room air O2 saturation at rest. 
Repeat each subsequent Cycle until 
return to baseline. Consider 
bronchoscopy *  
Symptomatic only. 
Prescribe 
corticosteroids if 
cough is troublesome. 
Reduce Everolimus dose until recovery to ≤ 
Grade 1. Everolimus may also be 
interrupted if symptoms are troublesome. 
Patients will be withdrawn from the study if 
they fail to recover to ≤ Grade 1 within 3 
weeks. 
Grade 3 
CT scan with lung windows and 
pulmonary function testing 
including: spirometry, DLCO, and 
room air O2 saturation at rest; 
Repeat each subsequent Cycle until 
return to baseline. Bronchoscopy is 
recommended * 
Prescribe 
corticosteroids if 
infective origin is ruled 
out. Taper as 
medically indicated. 
Hold treatment until recovery to ≤ Grade 1. 
May restart protocol treatment within 3 
weeks at a reduced dose (by one level) if 
evidence of clinical benefit. Patients will be 
withdrawn from the study if they fail to 
recover to ≤ Grade 1 within 3 weeks. 
Grade 4 
CT scan with lung windows and 
required pulmonary function 
testing includes: spirometry, DLCO, 
and room air O2 saturation at rest. 
Repeat each subsequent Cycle until 
return to baseline. Bronchoscopy is 
recommended *. 
Prescribe 
corticosteroids if 
infective origin is ruled 
out. Taper as 
medically indicated. 
Discontinue treatment. 
*A bronchoscopy with biopsy and/or bronchoalveolar lavage is recommended. 
 
All interruptions or changes to study drug administration must be recorded. 
 
It will be documented whether or not each patient completed the clinical study. If for any 
patient either study treatment or observations were discontinued the reason will be recorded. 
Reasons that a patient may discontinue participation in a clinical study are considered to 
constitute one of the following: 
1. adverse event(s) 
2. abnormal laboratory value(s) 
3. abnormal test procedure result(s) 
4. disease progression 
5. protocol violation 
6. subject withdrew consent 


 
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Study No.  
 
7. lost to follow-up 
8. administrative problems 
9. death 
3.3 
Treatments 
3.3.1 
Everolimus Administration 
The study drug Everolimus or placebo will be self-administered (by the patients themselves). 
The investigator will instruct the patient to take the study drug exactly as specified in the 
protocol. Everolimus /placebo will be administered orally as once daily dose of 10 mg (two 5 
mg tablets) continuously from study day 1 until progression of disease, unacceptable toxicity, 
or 1 year from start of therapy. Patients will be instructed to take Everolimus /placebo in the 
morning, at the same time each day. Everolimus /placebo can be taken with or without food (a 
low-fat meal is recommended). Dietary habits around the time of Everolimus /placebo intake 
should be as consistent as possible throughout the study. If vomiting occurs, no attempt 
should be made to replace the vomited dose. All dosages prescribed and dispensed to the 
patient and all dose changes during the study must be recorded. 
Medication labels will comply with US legal requirements and be printed in English. They 
will supply no information about the patient. The storage conditions for study drug will be 
described on the medication label. 
 
For this trial, Everolimus and placebo are supplied, by Novartis, 10 tablets per card. Tablets 
should be opened only at the time of administration as drug is both hygroscopic and light-
sensitive. Drug request forms will be provided to use when ordering Everolimus and placebo. 
Everolimus will only be shipped once all required regulatory documents are received. 
3.3.2 
Treatment assignment 
 8-16 weeks after completion of curative intent therapy for locally advanced squamous 
cell carcinoma of the head and neck patients will be randomized to receive everolimus 
10 mg or placebo 
 Treatment assignment will be double-blinded. Unblinding will occur at the conclusion 
of the study (approximately 2 years after completion of accrual) or if required for 
patient safety  
 Expected treatment duration is 1 year from day 1 of everolimus or placebo 
administration 
 Randomization will be stratified for disease stage and type of local therapy (IVa 
surgical vs. IVa non-surgical vs. IVb) as well as treating institution. 
 A secure online registration interface has been developed to register patients, and is 
integrated with the randomization component, as well as data collection and storage 
system.  This type of an interface has been used successfully in other Head and Neck 
cancer clinical trials at the University of Chicago (e.g. DeCIDE). 


 
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 Stratified randomization sequences will be generated using the method of permuted 
blocks.  At the time of patient registeration an electronic notification will be sent to 
the study pharmacist. To randomize this patient, the pharmacist will login into the 
registration system, which will provide the randomized treatment assignment. Only 
the pharmacisist will have access to the treatment assignment to maintain the 
blinding. 
3.3.3 
Concomitant therapy 
Patients will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without prior consultation with the investigator. At 
each visit, the investigator will ask the patient about any new medications he/she is or has 
taken after the start of the study drug. 
All Concomitant medications/Significant non-drug therapies taken ≤ 30 days prior to start and 
after start of study drug, including physical therapy and blood transfusions, should be 
recorded. 
The following restrictions apply during the entire duration of the study: 
 No other investigational therapy should be given to patients. 
 No anticancer agents other than the study medication should be given to patients. If such 
agents are required for a patient then the patient must first be withdrawn from the study. 
 Oral contraceptives in preclinical and clinical data have shown everolimus to have 
CYP3A4 inhibitory activity rather than induction activity, induction of metabolism of 
contraceptive hormones by everolimus is unlikely. Consequently, administration of 
everolimus should not reduce the efficacy of oral contraceptives. 
 Growth factors (e.g.G-CSF, GM-CSF, erythropoietin, platelets growth factors etc.) are not 
to be administered prophylactically but may be prescribed by the investigator for rescue 
from severe hematologic events, if this is thought to be appropriate. 
 Concurrent administration of Everolimus and strong CYP3A4 inhibitors (such as 
ketoconazole, itraconazole, ritonavir) and inducers (such as rifampin, rifabutin) should be 
avoided. Provided there is no alternative treatment available, patients should be closely 
monitored for potential toxicities. 
 Concurrent administration of Everolimus and moderate CYP3A4 inhibitors (such as 
erythromycin, fluconazole, calcium channel blockers, benzodiazepines) and moderate 
CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin) should also be avoided 
if possible, or used subject to caution (e.g. increased frequency of safety monitoring, 
temporary interruption of Everolimus). 
 Competitive inhibition could occur when Everolimus is combined with drugs which are 
also CYP3A4 substrates. Therefore caution should be exercised in such cases. 
 Co-administration with substrates, inducers, or inhibitors of P-glycoprotein should be 
avoided, if possible, or used subject to caution (e.g. increased frequency of safety 
monitoring, temporary interruption of Everolimus).  
 Grapefruit and grapefruit juice affect cytochrome P450 and P-glycoprotein activity and 
should therefore be avoided.  


 
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Study No.  
 
 In addition, patients should avoid Seville oranges and star fruit, as well as the juice of 
these fruits, which are potent CYP3A4-inhibitors.  
 No chronic treatment with systemic steroids or another immunosuppressive agent. Topical 
or inhaled corticosteroids are allowed. 
 Everolimus may affect the response to vaccinations making the response to the 
vaccination less effective. Live vaccines should be avoided while a patient is treated with 
Everolimus. 
Inhibitors of CYP3A4 and/or PgP 
Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
ritonavir) or P-glycoprotein (PgP) should be avoided. 
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or PgP 
inhibitors should be used with caution.  If patient requires co-administration of moderate 
CYP3A4 inhibitors or PgP inhibitors, reduce the dose of everolimus to half the currently used 
dose. 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. 
Seville orange, star fruit, grapefruit and their juices affect P450 and PgP activity. Concomitant 
use should be avoided. 
Inducers of CYP3A4 and/or PgP 
Avoid the use of strong CYP3A4 inducers. If patient requires co-administration of strong 
CYP3A4 inducers (i.e., phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. 
John’s wort), an increase in the dose of everolimus up to twice the currently used daily dose 
should be considered, using 2.5mg - 5mg increments. Enzyme induction usually occurs within 
7-10 days, therefore everolimus dose should be increased by one increment 7 days after the 
start of the inducer therapy.  If no safety concerns are seen within the next 7 days, the dose 
can be increased again one additional increment up to a maximum of twice the daily dose 
used prior to initiation of the strong CYP3A4 inducer.   
This dose adjustment of everolimus is intended to achieve similar AUC to the range observed 
without inducers.  However, there are no clinical data with this dose adjustment in patients 
receiving strong CYP3A4 inducers.  If the strong inducer is discontinued the everolimus dose 
should be returned to the dose used prior to initiation of the strong CYP3A4/PgP inducer. 
 


 
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Study No.  
 
Table 3-6 Examples of clinically relevant drug interaction: substrates, inducers and 
inhibitors of isoenzyme CYP3A.  
Substrates (competitive inhibition) 
 
Antibiotics1: 
 
clarithromycin* 
 
erythromycin  
 
telithromycin* 
Anti-arrhythmics: 
 
quinidine 
Benzodiazepines: 
 
alprazolam 
 
diazepam 
 
midazolam 
 
triazolam 
Immune Modulators: 
 
cyclosporine 
 
tacrolimus (FK506) 
HIV Protease Inhibitors: 
 
indinavir* 
 
ritonavir* 
 
saquinavir* 
Prokinetic: 
 
cisapride 
Antihistamines: 
 
astemizole 
 
chlorpheniramine30 
Calcium Channel Blockers: 
 
amlodipine 
 
diltiazem 
 
felodipine 
 
nifedipine 
 
nisoldipine 
 
nitrendipine 
 
verapamil 
HMG CoA Reductase Inhibitors2:  
 
atorvastatin 
 
cerivastatin 
 
lovastatin 
 
simvastatin 
Miscellaneous: 
 
aprepitant 
 
buspirone 
 
haloperidol 
 
methadone 
 
pimozide  
 
quinine 
 
sildenafil 
 
tamoxifen 
 
trazodone 
 
vincristine 
Inducers 
Carbamazepine 
Phenobarbital 
Phenytoin* 
Rifabutin* 
Rifampin* 
St John’s wort 
Troglitazone 
Inhibitors 
Amiodarone 
Cimetidine 
Clarithromycin 
Delaviridine 
Diltiazem 
Erythromycin 
Fluvoxamine* 
Grapefruit juice 
Sevilla orange 
Indinavir 
Itraconazole* 
Ketoconazole* 
Voriconazole* 
Posaconazole* 
Mibefradil 
Nefazodone* 
Nelfinavir* 
Troleandomycin 
Verapamil 
Based on: Ingelman-Sundberg M, Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms, Naunyn 
Schmiedebergs Arch Pharmacol. 2004 Jan;369(1):89-104.  and [http://www.medicine.iupui.edu/flockhart/clinlist.htm as of July 13, 2006] 
* asterisk denotes strong inhibition/ induction  
Please note: 
- 
strong inhibitor implies that it can cause ≥5-fold increase in AUC or ≥80% decrease in clearance of sensitive CYP substrates 
- 
moderate inhibitor implies that it can cause 2 to 5-fold increase in AUC values or 50-80% decrease in clearance  of sensitive 
CYP substrates. 
(Distinction is not always categorical as interaction can vary according to conditions). 
1. Macrolide antibiotics: 
Azithromycin is not a CYP3A substrate. It may therefore be employed where antibiotherapy with a 
macrolide is desirable in a patient being treated with Everolimus  
2. Statins: Atorvastatin and pravastatin may be administered with Everolimus, since a PK interaction study has shown that there is no 
relevant PK interaction.  
 Seville orange, star fruit, grapefruit and their juices affect P450 and PgP activity. 
Concomitant use should be avoided 


 
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Study No.  
 
 No chronic treatment with systemic steroids (at a dose equivalent of greater than 20 mg 
prednisone per day) or other immunosuppressive agents. Topical or inhaled corticosteroids 
are allowed. 
 The use of live vaccines and close contact with those who have received live vaccines 
should be avoided during treatment with everolimus. Examples of live vaccines include 
intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and 
TY21a typhoid vaccines. 
Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no interaction with 
everolimus is expected. However, drug-drug interaction studies between macrolide antibiotics 
and warfarin have produced mixed outcomes and the disparity in these findings has led to the 
conclusion that multiple factors may alter the clearance of warfarin. The coadministration of 
everolimus and oral anticoagulants is possible but should be subject to verification of 
coagulation (INR) once steady state is reached (after one week’s treatment). 
Examples are provided in Table 3-5 (CYP3A4 inhibitors/inducers) and Table 3-6 (Drug 
interactions mediated by P-glycoprotein). A comprehensive list of cytochrome P450 
isoenzymes and CYP3A4 inhibitors, inducers, and substrates can be found at 
http://medicine.iupui.edu/flockhart.  This website is continually revised and should be 
checked frequently for updates. 
 
3.3.4 
Treatment compliance 
Records of study medication used, dosages administered, and intervals between visits will be 
recorded during the study. Drug accountability will be noted and patients will be asked to 
return all unused study medication. A drug diary should be given to each patient to complete 
(see Appendix B) 
 
3.3.5 
Definition of Curative Intent Therapy for Locally Advanced Squamous Cell 
Carcinoma of the Head and Neck 
Specific curative intent therapy is left to the discretion of investigators but the following 
criteria should be met for patients to be considered to have received curative intent therapy for 
locally advanced SCCHN and to be eligible for study: 
 Acceptable chemoradiotherapy regimens: 
o Cisplatin or carboplatin based regimens 
o 5FU/hydroxyurea based regimens 
o Cetuximab based regimens 
 Radiotherapy dose to gross disease must be > 58 Gy if treated post-operatively and > 
64Gy if treated with primary chemoradiotherapy or radiotherapy alone 
 Neoadjuvant or induction chemotherapy is permitted 


 
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Study No.  
 
 Any questions regarding the acceptability of curative intent therapy should be directed to 
Cherie-Ann Nathan (318 675 6262) or Ezra Cohen (773 702 4137) 
3.4 
Visit schedule and assessments 
3.4.1 
Pre-study Procedures 
 All patients must have completed curative intent therapy for locally advanced SCCHN 8-
16 weeks prior to randomization (as defined in 3.3.5 AND be NED as defined in 3.2.2). 
 Tissue must have been collected PRIOR to starting curative intent therapy on all patients 
(see Section 3.4.7) 
 A detailed assessment of hepatitis B/C medical history and risk factors must be done for 
all patients at screening.   
Testing for hepatitis B viral load and serologic markers: HBV-DNA, HBsAg, HBs Ab, and 
HBc Ab and HCV RNA PCR are required at screening for all patients in the following risk 
categories:  
o 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/2010/chapter-2/hepatitis-b.aspx#849 ] 
o 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 
abdomen pain. 
o Additional patients at the discretion of the investigator  
Testing for hepatitis C should be performed using quantitative RNA-PCR at screening for all 
patients in the following risk categories: 
o known or suspected past hepatitis C infection (including patients with past interferon 
‘curative’ treatment),  
o blood transfusions prior to 1990,  
o current or prior IV drug users,  
o current or prior dialysis,  
o household contact of hepatitis C infected patient(s),  
o current or prior high-risk sexual activity,  
o body piercing or tattoos,  


 
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Study No.  
 
o At the discretion of the investigator, additional patients may also be tested for 
hepatitis C.   
 
3.4.2 
Visit schedule 
Table 3-4  Evaluation and visit schedule 
Examination 
Screening/ 
Baseline 
Week 
 
 
4 
16 
32 
52 
64 
80 
96 
112 
128 
144 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
No Evidence of Disease1 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Tissue Biopsy2 
X 
 
 
 
 
 
 
 
 
 
 
 
Radiographic assessment3 
X 
Every 4-6 months in years 1 and 2 then every 6 months in year 3 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory test4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Research Blood Draw5 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
HBV-DNA, HbsAg, HBs Ab, HBs Ab, HCV-RNA-
PCR 6 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient Questionnaire7 
X 
 
 
 
 
 
 
 
 
 
 
 
Follow Up Form8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1See Section 3.2.2 
2See Section 3.4.7; Tissue biopsy must have been obtained PRIOR to curative intent therapy 
3Baseline radiographic assessment (CT, PET-CT, PET and/or MRI as appropriate) must be 
preformed within 12 weeks of starting everolimus. CT, PET-CT, PET and/or MRI as 
appropriate should be performed at least every 4-6 months in years 1 and 2 then every 6 
months in year 3. 
4Baseline assessments must be performed within 7 days of starting everolimus. Hemoglobin, 
platelets, total white blood cell count (WBC), and differential; sodium, potassium, chloride, 
bicarbonate, calcium, glucose, creatinine, blood urea nitrogen, albumin, total protein, SGOT 
(AST), SGPT (ALT), total bilirubin, alkaline phosphatase, uric acid, phosphorus, serum lipid 
profile (triglycerides, total cholesterol, HDL and LDL); PT (INR) evaluation only at baseline 
unless otherwise indicated. Patients should be fasting at the time of the blood sampling.  
5Blood draw for serum, whole blood and optional PBMC isolation (see Section 3.4.7). Serum 
will be drawn at screening, weeks 4, 16 and 52.  Whole blood will be drawn at weeks 4, 16 
and 52.  Optional PBMC will be drawn at screening and week 4. 
6All patients should be screened for hepatitis risk factors and any past illnesses of hepatitis B 
and hepatitis C infection. If the patient has any of the risk factors outlined in section 3.4.1 then 
serologic testing must be done.   


 
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Study No.  
 
7All patients should fill out the Patient Questionnaire prior to first dose.  See the Study 
Procedures manual. 
8See the Study Procedures Manual 
 
3.4.3 
Efficacy assessments 
The primary study endpoint is progression-free survival. Disease progression will be 
evaluated by clinical and radiographic methods and date of progression will be recorded. If in 
question, disease progression should be confirmed pathologically. Site of disease progression 
will be classified as local (progression at primary tumor site), regional (progression in cervical 
lymph nodes), and/or distant (metastatic disease). 
 
A diagnosis of second primary tumor must be confirmed pathologically. Deaths on study 
should be classified as disease (SCCHN), non-disease, or study treatment related. 
3.4.4 
Safety assessments 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology, blood chemistry and urine values, 
regular measurement of vital signs and the performance of physical examinations. 
These assessments should be performed within ±2 days of the scheduled day of assessment 
except for adverse events that will be evaluated continuously through the study. Safety and 
tolerability 
will 
be 
assessed 
according 
to 
the 
NIH/NCI 
CTC 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. 
3.4.4.1 
Adverse events 
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. 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not considered to 
be related to study drug. Medical conditions/diseases present before starting study drug are 
only considered adverse events if they worsen after starting study drug. Abnormal laboratory 
values or test results constitute adverse events only if they induce clinical signs or symptoms, 
are considered clinically significant, or require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments. As far as possible, each adverse event should be evaluated to determine: 
1. the severity grade (mild, moderate, severe) or (grade 1-4) 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 


 
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4. action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization) 
5. whether it constitutes a serious adverse event (SAE) 
Grading for all adverse events will utilize NCI CTCAE v4.0.  
CTCAE version 4.0 is available at: http://ctep.cancer.gov/reporting/ctc.html 
 
All adverse events should be treated appropriately. Such treatment may include changes in 
study drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or 
any other medically required intervention. Once an adverse event is detected, it should be 
followed until its resolution, and assessment should be made at each visit (or more frequently, 
if necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigators’ Brochure. This information should be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
3.4.4.2 
Serious adverse events 
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: 
 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 
 Pregnancy 
To ensure patient safety, the principal investigator has the obligation to report all serious 
adverse events to the FDA, IRB, and Novartis, regardless of suspected causality, occurring: 
 after the patient has provided informed consent and until 30 days after the patient has 
stopped study treatment/participation 


 
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 after the patient is randomized and until 30 days after the patient has stopped study 
treatment/participation 
 after the patient begins taking study drug and until 30 days after the patient has stopped 
study treatment/participation 
 after protocol-specified procedures begin (e.g., placebo run-in, washout period, double-
blind treatment, etc.) and until 30 days after the patient has stopped study 
treatment/participation 
 after the start of any period in which the study protocol interferes with the standard 
medical treatment given to a patient (e.g., treatment withdrawal during washout period, 
change in treatment to a fixed dose of concomitant medication) and until 30 days after the 
patient has stopped study treatment/participation  
 
SAEs must be reported to Novartis within 24 hours of learning of its occurrence. Any SAEs 
experienced after this 30 day period should only be reported to Novartis if the investigator 
suspects a causal relationship to the Novartis study drug. Recurrent episodes, complications, 
or progression of the initial SAE must be reported as follow-up to the original episode within 
24 hours of the investigator receiving the follow-up information. 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. 
The investigator must assess and record the relationship of each SAE to each specific study 
drug (if there is more than one study drug), complete the SAE Report in English, and send the 
completed, signed form by fax as specified in Section 4.6. The original copy of the SAE 
Report and the fax confirmation sheet must be kept within the Trial Master File at the study 
site. 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of 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 (if applicable), and 
whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study drug, a Clinical Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN), to inform all investigators involved in any study with the same drug that 
this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will 
be collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries. 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 
3500A (MedWatch Form).  Reporting guidelines are provided in the following table: 


 
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Study No.  
 
 
UNEXPECTED EVENT 
EXPECTED EVENT 
 
GRADES 2 – 3 
Attribution of Possible, 
Probable or Definite 
 
GRADES 4 and 5 
Regardless of Attribution 
GRADES 1 - 3 
GRADES 4 and 5  
Regardless of Attribution 
 
Written report within 10 
working days. 
 
(Grade 1 SAE Reporting 
NOT required.) 
Any pregnancy should 
be reported as specified 
under Unexpected Grade 
4 and 5 events. 
 
Report by phone to 
University of Chicago 
Study Coordinator and 
University of Chicago 
Cancer Clinical Trials 
Office within 24 hours.  
Information will be 
distributed to Principal 
Investigators, University of 
Chicago IRB, and Novartis 
within 24 hrs.  Written 
report to follow within 5 
calendar days. 
 
This includes all deaths 
within 30 days of the last 
dose of treatment 
regardless of attribution. 
 
Any late death attributed to 
the agent (possible, 
probable, or definite) 
should be reported within 5 
calendar days. 
Adverse Event 
Expedited Reporting 
NOT required. 
Written report, within 10 
working days except for 
deaths within 30 days of 
the last dose of treatment 
regardless of attribution, 
which must be reported 
within 5 calendar days. 
 
Any late death attributed to 
the agent (possible, 
probable, or definite) 
should be reported within 5 
calendar days. 
 
 
 
3.4.5 
Laboratory Evaluations 
Hematology 
Hematology must include hemoglobin, hematocrit, platelets, total white blood cell count 
(WBC) and differential. PT (INR) evaluation will be included for baseline evaluations. 
Blood chemistry 
Blood chemistry must include sodium, potassium, chloride, bicarbonate, calcium, glucose, 
creatinine, blood urea nitrogen, albumin, total protein, SGOT (AST), SGPT (ALT), total 
bilirubin, alkaline phosphatase, uric acid, phosphorus, serum lipid profile (triglycerides, total 
cholesterol, HDL and LDL). 
Because accurate serum glucose and lipid measurements are required, patients should be 
fasting at the time of the blood sampling. 
3.4.6 
Vital signs 
Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, 
temperature and weight. 


 
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3.4.6.1 
Physical examination 
Physical examination will be performed which must comprise a total body examination 
(general appearance, skin, neck, including thyroid, eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities and basic nervous system). 
Significant findings made after the start of study drug which meet the definition of an Adverse 
Event must be recorded. 
3.4.6.2 
ECG 
A standard 12 lead ECG is to be performed (during screening only to confirm I/E criteria) and 
significant findings must be recorded. 
3.4.6.3 
Performance status 
Performance status will be assessed using the Karnofsky scale 
3.4.7 
Research tests 
Tissue obtained (PRIOR to curative intent therapy) from the diagnostic biopsy/panendoscopy 
and/or during surgical resection, PBMC, serum and whole blood samples will be used for the 
correlative studies. The studies will be performed in Dr. Cherie-Ann Nathan’s research 
laboratory (LSUHSC, Shreveport, LA) and at the University of Chicago. 
The tumor suppressor gene PTEN is an important regulator of the Akt/mTOR pathway and 
often found to be mutated in HNSCC patients29. Hence we will evaluate PTEN status by FISH 
and mutation analysis in all patients. Correlation between PTEN status and the sensitivity to 
Everolimus will be determined. 
We will determine the correlation of the Akt/mTOR pathway activation [pAkt(S473), 
pmTOR(S2448), pS6(S235/236), p4EBP1(T37/46) and eIF4E] by IHC and/or western blot 
(when available) analysis in tumors and adjacent normal mucosa. The Kaplan-Meier method 
with logrank test and/or Cox Regression model will be used to compare PFS between HNSCC 
patients with different degree of biomarker upregulation in tumors but more importantly in the 
normal surrounding mucosa as previous studies have shown that patients with mTOR 
activation in the margins are at a higher risk for recurrence.  
Upregulation of the Akt/mTOR pathway is associated with an increased survival of cancer 
cells and their decreased sensitivity to chemo- and radiotherapy30, 31. Also it was shown for 
some types of cancer that tumors with heightened Akt activation are more sensitive to mTOR 
inhibition30, 31. Based on these evidences we hypothesize that the risk of disease recurrence 
correlates with the degree of activation of the Akt/mTOR pathway biomarkers and that the 
patients with heightened Akt activation will benefit the most from adjuvant therapy with 
everolimus. Thus we will test the hypothesis that either the adjacent normal mucosa or tumor 
tissue or both from SCCHN patients who recurred after treatment will have higher 
pAkt/pmTOR expression as compared to the tissue samples from the SCCHN patients who 
did not recur after treatment. 
Tissue Sample:  


 
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Diagnostic tumor biopsy should be preferably obtained from advancing edge of the tumor. 
Normal mucosa should be biopsied at least 1 cm away from the tumor. 
At the minimum, 10 slides of the tumor/biopsy and 10 slides of all the histologically tumor 
free surgical resection margins/adjacent normal mucosa from the paraffin embedded blocks 
should be mounted on positively charged slides.  Slides should be labeled with institution, 
protocol number, patient initials, patient registration number, and the date of biopsy. If tissue 
blocks are available these are preferable to the slides.   
If frozen tissue obtained (PRIOR to curative intent therapy) from the diagnostic 
biopsy/panendoscopy and/or during surgical resection  is available, resected tumor tissue and 
adjacent normal mucosa measuring minimum 1 cm x 5 mm should be placed in cryovials and 
clearly labeled with appropriate study identifiers. These samples should be stored at -80C 
until shipment and they will be used for western blot biomarker analysis. 
All tumor tissue should be accompanied by a de-identified pathology report and be shipped to 
LSUHSC in Shreveport for correlative studies at the address indicated below with 
accompanying Notification of Correlative Study Samples Shipment form (Appendix C). 
Peripheral Blood Mononuclear Cells (PBMC) (optional procedure based on the sites 
ability to process sample): 
Venous blood sample will be collected prior to therapy and at week 4 in 1 blue and black tiger 
top tube (~8 cc).  See Appendix D for PBMC isolation protocol.  Sample should be labeled 
with institution, protocol number, patient initials, patient registration number, and the date and 
time of draw.  PBMC sample should be stored at -80C till shipment. PBMC sample should 
be shipped with accompanying Sample Shipping Form and Notification of Correlative Study 
Samples Shipment form (Appendix C) to LSUHSC in Shreveport for correlative studies at the 
address indicated below. (As this is an adjuvant trial, patients will not have any post-treatment 
tumor tissue. Hence, biomarker changes in PBMC can be used as surrogate marker of tumor 
response.) 
Serum and whole blood: 
Serum samples will be collected prior to therapy on all patients and at weeks 4, 16 and 52 in 
three 7-10 cc gold top tubes. Blood in the serum collection tube should be allowed to clot for 
60 minutes and then centrifuged to separate serum. Serum should be stored in 2 mL cryovial 
tubes (Nalgene Cat# 5000-0020) in 410uL aliquots. Samples should be labeled with 
institution, protocol number, patient initials, patient registration number, and the date and time 
of draw.  Serum samples should be stored at -80C till shipment. Serum samples collected 
from two gold top tubes should be shipped with a copy of accompanying Sample Shipping 
Form and Notification of Correlative Study Samples Shipment form (Appendix C) to 
LSUHSC in Shreveport for correlative studies at the address indicated below. Serum samples 
collected from one gold top tube should be shipped with accompanying Sample Shipping 
Form (Appendix C) to the University of Chicago at the address indicated below.  
Whole blood samples will be collected on all patients at weeks 4, 16 and 52 in 1 lavender top 
tube (10 cc).  The tube will be inverted several times to mix contents of the tube immediately 
after collection of the blood sample. Samples should be labeled with institution, protocol 
number, patient initials, patient registration number, and the date and time of draw.  Freeze at 


 
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-80°C within 60 minutes of draw until shipment. Whole blood samples collected from one 
lavender top tube should be shipped with accompanying Sample Shipping Form (Appendix C) 
to the University of Chicago at the address indicated below. 
We may store all samples until publication of the study results to potentially address 
reviewers concerns. It is not expected that any study samples will remain at the conclusion of 
the study as we have proposed an extensive number of biomarkers to analyze. 
 
Sample Shipping: 
All the tissue, PBMC, whole blood and serum samples will be packaged and transported by 
carrier service in batched samples following the government regulation 42 CFR Part 72 – 
“Interstate Shipment of Etiologic Agents,” which describes the requirements for the proper 
packaging and shipping of infectious substances and other biomedical material. All the 
samples will be packaged and delivered in such a way that the contents will not leak and will 
arrive in good condition. The tissue, PBMC, whole blood and serum samples will be 
transported in the packages with the biohazard label on the front to Dr. Nathan’s laboratory or 
to Leslie Martin at the University of Chicago. Frozen tissue samples, PBMCs whole blood 
and serum samples should be shipped on dry ice. Paraffin-embedded tissue sections mounted 
on positively charged slides and paraffin-embedded tissue blocks should be shipped at 
ambient temperature. All institutional requirements for safety and confidentiality will be met 
during specimen transmittance. All samples must be accompanied by a Sample Shipping 
Form (Appendix C).  
 
Correlative study investigator: (tissue, PBMC, 2 
serum samples) 
Research samples: (1 serum sample, whole 
blood) 
Dr. Cherie-Ann O. Nathan, M.D., F.A.C.S.,  
Leslie Martin  
Department of Otolaryngology/HNS,  
University of Chicago 
Louisiana State University Health Sciences 
Center 
5841 S. Maryland Ave. 
Building: Medical School; Room #9-203  
Room P-616A  
1501 Kings Highway, Shreveport, LA 71130  
Chicago, IL 60637-1470 
Tel: (318)-675-6262; Fax: (318)-675-6260  
Phone: 773-834-8392  
See Appendix C for further shipping instructions. 
 
4 
Regulatory Procedures 
4.1 
New Protocol Distribution and IRB Submission 
Once final Novartis and University of Chicago (U of C) IRB approval is received, the 
protocol and consent form will be distributed to the participating affiliate institutions 
electronically.  Upon receipt of the email, the affiliate institution is expected to do the 
following:   


 
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 The affiliate must reply to the email indicating that the protocol was received by the 
institution.   
 The affiliate institution is expected to submit the protocol to their IRB as soon as 
possible after receipt. 
 The U of C version date must appear on the affiliate consent form and on the 
affiliate IRB approval letter.  The version dates can be found on the footer of every 
page of the protocol and consent form. 
 When the protocol and consent receive IRB approval at the affiliate institution a copy 
of the IRB approval letter, the IRB approved protocol and the IRB approved 
consent form must be faxed or emailed to the Regulatory Coordinator, Kurombi 
Wade-Oliver at (773) 702-1561, kwadeoli@medicine.bsd.uchicago.edu. 
4.2 
Amendment Distribution and IRB Submission 
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, 
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. 
All modifications to the protocol, or consent form will be submitted to the University of 
Chicago IRB for review and approval.  A list of the proposed modifications or amendments to 
the protocol and an explanation of the need of these modifications will be submitted, along 
with a revised protocol incorporating the modifications.  Only the P.I. at the central institution 
can authorize any modifications, amendments, or termination of the protocol.   Once a 
protocol amendment has been approved by the U of C IRB, the Regulatory Coordinator will 
send the amended protocol and consent form to the affiliate institutions electronically.  Upon 
receipt of the packet the affiliate institution is expected to do the following:  


 
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 The affiliate must reply to the email from the Regulatory Affairs Administrator 
indicating that the amendment was received by the institution and that it will be 
submitted to the local IRB. 
 The amendment should be submitted to the affiliate institution’s IRB as soon as 
possible after receipt.  The amendment must be IRB approved by the institution 
within 3 months from the date that it was received.   
 The U of C version date and/or amendment number must appear on the affiliate 
consent form and on the affiliate IRB approval letter.  The version dates can be 
found on the footer of every page of the protocol and consent form.  The amendment 
number can be found on the U of C IRB amendment approval letter that is sent with 
the protocol/amendment mailing. 
 The IRB approval for the amendment and the amended consent form (if amended 
consent is necessary) for the affiliate institution must be faxed or emailed to the 
Regulatory Affairs Administrator. 
4.3 
Annual IRB Renewals, Continuing Review and Final Reports 
A continuing review of the protocol will be completed by the University of Chicago IRB and 
the affiliates’ IRBs at least once a year for the duration of the study. The annual IRB renewals 
for the affiliate institution should be faxed promptly to the Regulatory Affairs Administrator.  
If the institution’s IRB requires a new version of the consent form with the annual renewal the 
consent form should be included with the renewal letter.   
Continuing review reports will include the following:  the number of subjects accrued; a 
description of any adverse events or unanticipated problems involving risks to subjects or 
others and of any withdrawal of subjects from the research or complaints about the research; a 
summary of research literature, findings obtained thus far, amendments or modifications since 
the last review, reports of multi-center trials and any other relevant information, especially 
information about the risks associated with the research; and a copy of the current informed 
consent document.   
4.4 
Departure from the Protocol 
An investigator cannot modify the protocol without satisfying procedures in 4.2.  Any 
changes in research activity, except those necessary to remove an apparent, immediate hazard 
to the study subject, must be reviewed and approved by the local IRB.  When a variation from 
the protocol is deemed necessary for an individual subject, the principal investigator must be 
contacted 
by 
phone 
or 
email 
(Ezra 
Cohen, 
773 
702 
4137, 
ecohen@medicine.bsd.uchicago.edu).  Such contact must be made as soon as possible to 
permit a decision as to whether or not the subject is to continue in the study.   
The principal investigator must be informed of all intentional or unintentional departures from 
the protocol and will decide whether or not the subject is to continue in the study (Ezra 
Cohen, 773 702 4137, ecohen@medicine.bsd.uchicago.edu). All departures from the protocol, 
intentional and unintentional, along with the decision of the principal investigator will be 
submitted in a written report to the local and University of Chicago IRB. 


 
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4.5 
Registration 
All patients must be registered with the University of Chicago Study Coordinator at least 48 
hours prior to the commencement of treatment.  Confirm all selection criteria listed in Section 
3.2.2, and then call the Study Coordinator at 773-702-1679 with the following information: 
 
Provider of information 
Study # and Institution 
Treating Physician 
Patient name and hospital ID number 
Patient's zip code of residence 
Date of signed informed consent 
Race, gender, date of birth of patient 
Diagnosis and date of initial diagnosis 
The Study Coordinator will issue a confirmation of registration.  The Study Coordinator will 
ensure that all necessary supporting documents have been received and that the potential 
patient is eligible to start treatment on schedule.  Photocopies of the appropriate pages of the 
protocol will be used to determine eligibility.  If there are questions about eligibility, the 
Study Coordinator will question the principal investigator, who will be responsible for any 
final decisions on eligibility.  The date the patient is registered will be considered the patient’s 
“On-Study Date.”  Patients that sign consent and do not go “On-Study” will be recorded in the 
database with the date that they signed consent and the reason for not going “On-Study” 
(either Ineligible or Withdrawn Consent).  The treatment start date will also be tracked.   
At the time of registration, the registering institution will: 
 Confirm that their institution has IRB approval of the correct version of 
protocol/consent and has an annual update on file. 
 Fax or email all required forms (see data submission Section 5) and source 
documentation for the protocol required eligibility criteria and pre-study procedures, 
including labs, radiology, pathology reports, and signed consent form to the Study 
Coordinator’s attention. 
 Communicate with the Study Coordinator to ensure that all necessary supporting 
documents have been received and that the potential patient is eligible to start 
treatment on schedule. 
4.6 
Reporting of Adverse Events 
 
Serious Adverse Events that require phone reporting within 24 hrs per section 3.4.4.2 should 
be phoned and emailed to the University Of Chicago Cancer Clinical Trials Office (CCTO) at 
773-702-5149 and faxed to Novartis Clinical Safety and Epidemiology Department. (888-
299-4565) by the end of the business day during which the investigator becomes aware of the 
event or by 12 noon the following day if the event occurs after normal business hours. 
The following information is required when calling in the event:  
- 
Reporter’s Name and Telephone Number 


 
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- 
Patient Initials 
- 
Patient Medical Record Number 
- 
IRB Protocol Number 
- 
PI of Study 
- 
Attending Physician 
- 
Date of Event 
- 
Description of Event (including grade of the event and if the event required  
hospitalization) 
 
Upon receipt of the 24-hour notification, the CCTO will send an e-mail to the research nurse, 
attending physician, all PI’s, and to Novartis Pharmaceuticals CS&E Department FAX (888-
299-4565).    
All serious adverse events, except those exempted from reporting per section 3.4.4.2, must be 
reported to the University of Chicago Cancer Center Clinical Trials Office in writing within 
10 calendar days of event occurrence (5 calendar days for an unexpected grade 4 or 5 
event, or death within 30 days of discontinuing investigational therapy).  MedWatch form 
(FDA form 3500A) should be utilized. Report should also be submitted to the affiliate 
institution’s local IRB according to institutional guidelines.  Reports should be sent to the 
address or fax number below with any appropriate source documentation. 
 
Quality Assurance Coordinator 
Cancer Clinical Trials Office 
University of Chicago, MC 1140 
5841 S. Maryland Ave. 
Chicago, IL  60637-1470 
Fax: 773-702-8855 
Email: qaccto@bsd.uchicago.edu 
 
Adverse Events will be recorded and followed until the adverse event has subsided and 
abnormal findings have returned to normal or stabilized. In addition, any events with a 
suspected causal relationship to Novartis study drug will be reported as AEs or SAEs (as 
applicable) throughout follow-up. 
The sponsor will stop the study at any time if new knowledge is obtained indicating that: 
 Safety for all participating patients can no longer be assumed; and/or 
 The risk-benefit ratio is no longer acceptable for the participating patients. 
New adverse events for patients who discontinue the study will not be recorded past their date 
of discontinuation but events that are ongoing will be followed, if feasible, until they resolve.  
All patients will be followed for survival. 
A weekly report of delinquent or pending documents will be forwarded to Denise Friesema, 
RN (U of C Events Only). All delinquent reporting (greater than 10 days from event 
occurrence) must include documentation of reason for delinquency and may require 
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SAEs that have not resolved at the time of reporting should have a follow up written report 
within 10 calendar days of resolution. This includes any pregnancies in which the outcome, 
including spontaneous or voluntary termination, details of birth, and the presence or absence 
of any birth defects, congenital abnormalities or maternal and newborn complications should 
be reported. 
Once the appropriate SAE documents have been received, the University of Chicago Cancer 
Center Clinical Trials office forwards these to the Principal Investigator.  The Principal 
Investigator should comment on the outcomes of the event or problem including likely 
relationship to study drug.  The Principal Investigator should also indicate whether he/she 
concurs with the details of the report provided by the study investigator and provide any 
recommendations for actions to be taken in response to the SAE.   
Once the University of Chicago Cancer Center Clinical Trials Office receives the Principal 
Investigator’s report, they will forward all documents to the IRB, research nurse, all 
participating institutional PI’s, the FDA, and Novartis FAX (888-299-4565). 
 
4.6.1 
Novartis instructions for rapid notification of serious adverse events 
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). 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 
3500A (MedWatch Form).  
All events must be reported, by FAX (888-299-4565), to Novartis Pharmaceuticals 
DS&E Department within 24 hours of learning of its occurrence. This includes serious, 
related, labeled (expected) and serious, related, unlabeled (unexpected) adverse experiences. 
All deaths during treatment or within 30 days following completion of active protocol therapy 
must be reported within 5 working days. 
Any serious adverse event occurring after the patient has provided informed consent and until 
4 weeks after the patient has stopped study participation must be reported. This includes the 
period in which the study protocol interferes with the standard medical treatment given to a 
patient (e.g. treatment withdrawal during washout period, change in treatment to a fixed dose 
of concomitant medication). 
Serious adverse events occurring more than 4 weeks after study discontinuation need only be 
reported if a relationship to the Novartis study drug (or therapy) is suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
 
4.6.1.1 
Pregnancies 
Any pregnancy that occurs during study participation should be reported. To ensure patient 
safety each pregnancy must also be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including 


 
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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. 
 
4.6.1.2 
Testing for Hepatitis 
Hepatitis B Virus testing 
Prior to randomization the categories of patients listed in Section 3.2 should be tested for 
hepatitis B serologic markers and viral load: HBV-DNA HBsAg, HBc Ab, and HBs Ab.  
Hepatitis C Virus testing 
Patients with hepatitis C risk factors and additional patients at the discretion of the 
investigator should be tested for HCV RNA-PCR test at baseline. For a list of hepatitis C risk 
factors, refer to Section 3.2.5.  
Note – serologic testing is not mandatory for all subjects. Rather, each subject needs to 
be screened by history taking for risk factors and ONLY if they are at risk for HBV or 
HCV should serologic testing be performed. 
4.7 
Data and Safety Monitoring 
Subject accrual and all reported serious adverse events will be monitored at the University of 
Chicago during the weekly Phase 2 Conference. This meeting will include study investigators, 
independent investigators, and study coordinators. Quarterly reports of completed and missing 
Case Report Forms will be generated and reviewed by the principal investigators. 
 
A Data and Safety Monitoring Board (DSMB) will be convened to review toxicity and 
efficacy data. The DSMB will consist of a statistician and two experts in SCCHN. DSMB 
members cannot be investigators or co-investigators involved in the clinical trial. After the 
annual meeting of the DSMB a report to the principal investigators will be issued 
recommending study continuation/discontinuation or proposed changes to the protocol. 
 
Toxicity will be reviewed annually, with the first review approximately coinciding with the 
first 30 patients being enrolled and on-treatment for at least 3 months.  A single formal 
interim analysis will take place after 36 events have occurred, which corresponds to 50% of 
the expected number of on-study events. The DSMB may be convened more often should 
significant toxicities be observed. The guideline to stop early for futility will be if the 
conditional power at the interim look is less than 10% using the stochastic curtailment 
approach (as described in Jennison and Turnbull).  Based on this approach, the effect of 
adding the interim look on overall power will be negligible (Jennison C, Turnbull BW. Group 
Sequential Methods: Applications to Clinical Trials. 1999. Chapman & Hall/ CRC). 
  


 
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5 
Data management 
5.1 
Data collection 
Investigators must record the information required by the protocol. Case Report Forms (CRF) 
will be made available for all data elements required by the study. CRFs should be faxed or 
emailed to the Study Coordinator at (773) 834-2058.  
6 
Statistical methods 
6.1 
Statistical methods 
This is a multicenter, randomized, placebo-controlled, double-blind Phase II clinical trial of 
adjuvant Everolimus vs. placebo.  Patients will be randomized 8-16 weeks after the 
completion of curative intent therapy.  The primary endpoint is 2-year progression-free 
survival (PFS) rate. Progression-free survival will be estimated using the method of Kaplan-
Meier, and compared between the two treatment arms using the stratified logrank test. 
Multivariate regression models will be used to compare treatment effect between treatment 
groups adjusting for other important prognostic factors. Adverse event rates will be 
summarized and compared between treatment groups using Chi-squared or Fisher's exact test. 
Continuous variables will be compared between groups using t-test or Wilcoxon rank sum test 
as appropriate, and categorical variables will be compared using Cox Regression Analysis. 
Regression models will be used as part of exploratory analysis to explore treatment effects 
adjusting for other important prognostic factors.  The guideline to stop early for futility will be 
if the conditional power at the interim look (Section 4.7) is less than 10% using the stochastic 
curtailment approach (as described in Jennison and Turnbull). 
Sample Size  
Assuming uniform 3-year accrual and 2-year follow-up, a two-sided logrank test with a 
sample size of 132 (66 patients per treatment arm) will achieve 80% power at =0.05 to 
detect a difference between 50% and 70% progression free survival at 2 years.  This 
difference corresponds to median survival times of 24 months and 46.6 months, respectively, 
and a hazard ratio HR=1.94, assuming exponential survival distribution (The HR is based on a 
2-year PFS that would be clinically meaningful – 50% to 70%, the preclinical animal data, 
and the hazard ratio associated with activated mTOR in patient samples. As no historical data 
exists for this type of trial these assumptions are rational given what information is available). 
Assuming 20% loss to follow-up, N=160 patients (80 per arm) will be enrolled.  
The stratified logrank test will also be used for the analysis of secondary endpoints, 
specifically comparing PFS in patients with evidence of Akt/mTOR pathway activation 
(mTOR+ vs. mTOR-) in the adjacent normal mucosa.  Whereas progression-free survival is 
expected to be similar among mTOR+ and mTOR- patients in the everolimus arm, mTOR+ 
patients on placebo are expected to do worse than mTOR- patients.  Assuming 50% mTOR+ 
prevalence in each arm (n=33/arm), a two-sided logrank test will have 80% power and  
=0.05 to detect a difference in 2-year PFS of 70% vs. 40.7%, which corresponds to median 
time to progression or death of 46.6 and 18.5 months, and a hazard ratio HR=2.5.  Similarly, 
assuming 40% prevalence of upregulated Akt/mTOR pathway (n=26/arm), a two-sided 
logrank test will achieve 80% power at =0.05 to detect a difference between 70% vs. 36.4% 


 
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2-year PFS, which corresponds to median time to progression or death of 46.6 and 16.5 
months, and HR=2.8.  While the detectable differences are quite large, they are comparable to 
those observed in other studies – for example, patients with FOE+ and FOE- in the 
retrospective study (Nathan et al, 1999) had median PFS of 82 and 31.5, which corresponds to 
HR=2.6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7 
References 
 
1. 
Boulay A, Lane HA. The mammalian target of rapamycin kinase and tumor growth 
inhibition. Recent Results Cancer Res 2007;172:99-124. 
2. 
Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev 
Cancer 2004;4:335-48. 
3. 
Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 
2006;124:471-84. 


 
Confidential 
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Study No.  
 
4. 
Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 
2007;129:1261-74. 
5. 
Wang L, Harris TE, Roth RA, Lawrence JC, Jr. PRAS40 regulates mTORC1 kinase 
activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 
2007;282:20036-44. 
6. 
Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of single-agent temsirolimus 
(CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005;23:5347-56. 
7. 
Zeng Z, Sarbassov dos D, Samudio IJ, et al. Rapamycin derivatives reduce mTORC2 
signaling and inhibit AKT activation in AML. Blood 2007;109:3509-12. 
8. 
Zitzmann K, De Toni EN, Brand S, et al. The novel mTOR inhibitor RAD001 
(everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells. 
Neuroendocrinology 2007;85:54-60. 
9. 
Ikezoe T, Nishioka C, Bandobashi K, et al. Longitudinal inhibition of 
PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell 
leukemia cells. Leuk Res 2007;31:673-82. 
10. 
Wanner K, Hipp S, Oelsner M, et al. Mammalian target of rapamycin inhibition 
induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises 
DLBCL cells to rituximab. Br J Haematol 2006;134:475-84. 
11. 
Tuncyurek P, Mayer JM, Klug F, et al. Everolimus and mycophenolate mofetil 
sensitize human pancreatic cancer cells to gemcitabine in vitro: a novel adjunct to standard 
chemotherapy? Eur Surg Res 2007;39:380-7. 
12. 
Mabuchi S, Altomare DA, Cheung M, et al. RAD001 inhibits human ovarian cancer 
cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian 
cancer model. Clin Cancer Res 2007;13:4261-70. 
13. 
Treeck O, Wackwitz B, Haus U, Ortmann O. Effects of a combined treatment with 
mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human cancer 
cells. Gynecol Oncol 2006;102:292-9. 
14. 
Sieghart W, Fuereder T, Schmid K, et al. Mammalian target of rapamycin pathway 
activity in hepatocellular carcinomas of patients undergoing liver transplantation. 
Transplantation 2007;83:425-32. 
15. 
Haritunians T, Mori A, O'Kelly J, Luong QT, Giles FJ, Koeffler HP. Antiproliferative 
activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle 
cell lymphoma. Leukemia 2007;21:333-9. 
16. 
Lane H, Tanaka C, Kovarik J, et al. Preclinical and clinical 
pharmacokinetic/pharmacodynamic (PK/PD) modeling to help define an optimal biological 
dose for the oral mTOR inhibitor, RAD001, in oncology J Clin Oncol 2003;22:237A. 
17. 
Tabernero J, Rojo F, Casado E, et. al. A phase 1 study with tumor molecular 
pharmacodynamic evaluation of dose and schedule of the oral mTOR inhibitor everlolimus 
(RAD001) in patients with advanced solid tumors. J Clin Oncol 2005;23:16S. 
18. 
Jac J, Amato RJ, Giessinger S, Saxena S, Willis JP. A phase II study with a daily 
regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic renal 
cell carcinoma which has progressed on tyrosine kinase inhibition therapy. J Clin Oncol 
2008;26. 
19. 
Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell 
carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 
2008;372:449-56. 


 
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20. 
Lippman SM, Hawk ET. Cancer prevention: from 1727 to milestones of the past 100 
years. Cancer Res 2009;69:5269-84. 
21. 
Nathan CO, Franklin S, Abreo FW, Nassar R, De Benedetti A, Glass J. Analysis of 
surgical margins with the molecular marker eIF4E: a prognostic factor in patients with head 
and neck cancer. J Clin Oncol 1999;17:2909-14. 
22. 
Nathan CO, Amirghahari N, Abreo F, et al. Overexpressed eIF4E is functionally 
active in surgical margins of head and neck cancer patients via activation of the 
Akt/mammalian target of rapamycin pathway. Clin Cancer Res 2004;10:5820-7. 
23. 
Nathan CO, Amirghahari N, Rong X, et al. Mammalian target of rapamycin inhibitors 
as possible adjuvant therapy for microscopic residual disease in head and neck squamous cell 
cancer. Cancer Res 2007;67:2160-8. 
24. 
Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in 
tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008;358:140-51. 
25. 
Kauffman HM, Cherikh WS, Cheng Y, Hanto DW, Kahan BD. Maintenance 
immunosuppression with target-of-rapamycin inhibitors is associated with a reduced 
incidence of de novo malignancies. Transplantation 2005;80:883-9. 
26. 
O'Donnell A, Faivre S, Burris HA, 3rd, et al. Phase I pharmacokinetic and 
pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in 
patients with advanced solid tumors. J Clin Oncol 2008;26:1588-95. 
27. 
Hidalgo M, Buckner JC, Erlichman C, et al. A phase I and pharmacokinetic study of 
temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients 
with advanced cancer. Clin Cancer Res 2006;12:5755-63. 
28. 
Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple 
dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients 
with advanced refractory renal cell carcinoma. J Clin Oncol 2004;22:909-18. 
29. 
Keniry M, Parsons R. The role of PTEN signaling perturbations in cancer and in 
targeted therapy. Oncogene 2008;27:5477-85. 
30. 
Amornphimoltham P, Patel V, Sodhi A, et al. Mammalian target of rapamycin, a 
molecular target in squamous cell carcinomas of the head and neck. Cancer Research 
2005;65:9953-61. 
31. 
Amornphimoltham P, Sriuranpong V, Patel V, et al. Persistent activation of the Akt 
pathway in head and neck squamous cell carcinoma: a potential target for UCN-01. Clin 
Cancer Res 2004;10:4029-37. 


 
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8 
Procedures and instructions 
8.1.1 
Publication of results 
Any formal presentation or publication of data from this trial may be published after review 
and comment by Novartis and prior to any outside submission.  Novartis must receive copies 
of any intended communication in advance of publication (at least fifteen working days for 
presentational materials and abstracts and thirty working days for manuscripts).   These 
requirements acknowledge Novartis’ responsibility to provide peer input regarding the 
scientific content and conclusions of such publications or presentations.  Principal 
Investigation/Institution shall have the final authority to determine the scope and content of its 
publications, provided such authority shall be exercised with reasonable regard for the 
interests of Novartis and, in accord with the trial contract and shall not permit disclosure of 
Novartis confidential or proprietary information. 
8.1.2 
Disclosure and confidentiality 
The investigator agrees to keep all information provided by Novartis in strict confidence and 
to request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents 
provided by Novartis (investigators' brochures and other material) will be stored appropriately 
to ensure their confidentiality. The information provided by Novartis to the investigator may 
not be disclosed to others without direct written authorization from Novartis, except to the 
extent necessary to obtain informed consent from patients who wish to participate in the trial. 
8.1.3 
Discontinuation of study 
Novartis reserves the right to discontinue any study under the conditions specified in the 
clinical trial agreement. 
8.2 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in Novartis standard operating procedures and: 
1. 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 
91/507/EEC, The Rules Governing Medicinal Products in the European Community. 
2. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations). 
3. 
Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects). 
The investigator agrees to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of Good Clinical Practice that it conforms to. 


 
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8.2.1 
Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB). A signed and 
dated statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB must be given to Novartis before study initiation. Any amendments to the 
protocol, other than administrative ones, must be reviewed by Novartis approved by this 
committee. 
8.2.2 
Informed consent 
The investigator must explain to each subject (or legally authorized representative) the nature 
of the study, its purpose, the procedures involved, the expected duration, the potential risks 
and benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any 
time and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before signing 
and dating it, and should be given a copy of the signed document. If the subject cannot read or 
sign the documents, oral presentation may be made or signature given by the subject’s legally 
appointed representative, if witnessed by a person not involved in the study, mentioning that 
the patient could not read or sign the documents. No patient can enter the study before his/her 
informed consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by 
the investigator with it for IRB/IEC/REB approval. 
8.2.3 
Declaration of Helsinki 
The investigator must conduct the trial in accordance with the principles of the Declaration of 
Helsinki. Copies of the Declaration of Helsinki and amendments will be provided upon 
request or can be accessed via the website of the World Medical Association at 
http://www.wma.net/e/policy/17-c_e.html. 
 
 
 
 
 
 
 
 
 
 


 
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9 
Appendices 
 
9.1 
Appendix A - Procedure for Administration of Everolimus in Water via 
Gastrostomy Tube 
 
In cases where tablets cannot be swallowed, the tablets should be dissolved in water just prior 
to administration. Approximately 30 ml of water should be put into a glass. The tablets should 
then be added and the contents stirred gently (for a maximum of 7 minutes) until the tablets 
are disintegrated. The contents should then be swallowed by the patient. Afterwards, the glass 
should be rinsed with an additional 30 ml of liquid and drunk by the patient. 
 
In cases where the patient cannot swallow, follow the same procedure as above and 
administer the water with dissolved tablets via gastrostomy tube. After administration flush 
gastrostomy tube with at least 30ml of liquid.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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9.2 
Appendix B - Patient’s Medication Diary 
Name: Last ____________________ First ___________________ MI ___ 
Patient’s Study ID: __ __ __ __ __ - __ __ __  
 
Instructions:  
1. For each dose of the study medication, please record the time and the number of tablets you took.  
Write “0” if you missed a dose.  Please complete this diary every day.   
2. If you experience any health/medical complaints, please record this information on the back of this 
form. 
3. Please bring your diary and study medication blister packs (empty packs and packs containing 
any unused medication) to EACH appointment with the research nurse.  
DATE 
TIME OF DOSE 
# OF 
TABLETS
 
DATE 
TIME OF DOSE 
# OF 
TABLETS
01 Mar 2010 __ __ : __ __   
am 
pm 
  
 
17 Mar 2010
__ __ : __ __   
am 
pm 
  
02 Mar 2010 __ __ : __ __   
am 
pm 
  
 
18 Mar 2010
__ __ : __ __   
am 
pm 
  
03 Mar 2010 __ __ : __ __   
am 
pm 
  
 
19 Mar 2010
__ __ : __ __   
am 
pm 
  
04 Mar 2010 __ __ : __ __   
am 
pm 
  
 
20 Mar 2010
__ __ : __ __   
am 
pm 
  
05 Mar 2010 __ __ : __ __   
am 
pm 
  
 
21 Mar 2010
__ __ : __ __   
am 
pm 
  
06 Mar 2010 __ __ : __ __   
am 
pm 
  
 
22 Mar 2010
__ __ : __ __   
am 
pm 
  
07 Mar 2010 __ __ : __ __   
am 
pm 
  
 
23 Mar 2010
__ __ : __ __   
am 
pm 
  
08 Mar 2010 __ __ : __ __   
am 
pm 
  
 
24 Mar 2010
__ __ : __ __   
am 
pm 
  
09 Mar 2010 __ __ : __ __   
am 
pm 
  
 
25 Mar 2010
__ __ : __ __   
am 
pm 
  
10 Mar 2010 __ __ : __ __   
am 
pm 
  
 
26 Mar 2010
__ __ : __ __   
am 
pm 
  
11 Mar 2010 __ __ : __ __   
am 
pm 
  
 
27 Mar 2010
__ __ : __ __   
am 
pm 
  
12 Mar 2010 __ __ : __ __   
am 
pm 
  
 
28 Mar 2010
__ __ : __ __   
am 
pm 
  
Randomized Double-Blind Phase II Trial of Everolimus vs. 
Placebo as Adjuvant Therapy in Patients with  
Locally Advanced Squamous Cell Cancer of the Head and Neck 
Rev. 0 


 
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13 Mar 2010 __ __ : __ __   
am 
pm 
  
 
29 Mar 2010
__ __ : __ __   
am 
pm 
  
14 Mar 2010 __ __ : __ __   
am 
pm 
  
 
30 Mar 2010
__ __ : __ __   
am 
pm 
  
15 Mar 2010 __ __ : __ __   
am 
pm 
  
 
31 Mar 2010
__ __ : __ __   
am 
pm 
  
16 Mar 2010 __ __ : __ __   
am 
pm 
  
 
 
 
  
 
Health or Medical Complaints 
Please record any medical or health complaints. Please use an extra sheet of paper if you need more 
space. 
Please describe what you experienced 
Date started 
Dated stopped 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other Medication 
Please record only non-study medication (prescription and/or over-the counter, including herbal 
medications and vitamins).  Please use an extra sheet of paper if you need more space.  
Name of Medication 
Why did you take the medication? 
Date started 
Date Stopped 
 
 
 
 
 
 
 
 


 
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9.3 
Appendix C - Tissue and Blood Sample Collection Forms 
 
See separate form. 
 
9.4 
 Appendix D - PBMC isolation protocol 
 
Specimen 
 
Venous blood (8ml) in one BD Vacutainer CPT® (8 mL blue & black tiger top) tube.  
Required Materials and Equipment 
 Vacutainer-CPT (Blue Tiger tops) (BD Scientific, Cat. #362761) 
 Class II Biological Safety Cabinet 
 A timer regulated centrifuge with swinging bucket style rotor capable of maintaining a 
spin rate of 1500 x g for 20 minutes 
 Table-top centrifuge 
 Vacuum pump with trap flask 
 –80 °C freezer 
 Dry Ice 
 Dulbecco’s Phosphate-Buffered Saline (PBS); Sterile; Store at room temperature 
 Red Blood Cells Lysis Buffer (Pure Gene Gentra RBC Lysis Solution, Cat. #D-5001) 
 Adjustable, automatic micropipette (P1000) 
 P1000 aerosol tips 
 Pipette aid 
 10 ml pipettes 
 15 ml polyproylene centrifuge tubes  
 1.5 ml eppendorf tubes to store PBMC pellets 
 
For each tube / sample received: 
 
Testing procedure must be performed in a class II Biological Safety Cabinet.   Powder-free 
gloves must be worn at all steps.  All disposables and reagents must be sterile.  Any pipette or 
tip that comes in contact with a specimen must be disposed of after use and a new, sterile one 
used for the next specimen or reagent. All reagents must be at room temperature before use. 
 
 
1. Invert the tube gently 8 times. 
2. Centrifuge the tube at room temperature in a horizontal swinging bucket rotor at 1500 x g 
for 20 minutes, no brake.  
Check that loaded buckets swing freely. 
Check that bucket inserts are lined up, so that tubes are seated at the bottom. 
Carefully remove tubes after spinning; avoid shaking 
3. After centrifugation there are four different layers visible in the tube:  


 
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a top layer of approximately 4 mL of plasma 
a white buffy coat of PBMCs (just underneath the serum) 
a solid agar gel barrier 
and red blood cells (below the agar barrier) 
4. Remove and discard plasma layer. 
5. Add 5 ml sterile PBS (room temperature) to the cell layer in the CPT tube. 
6. Cap and invert tube gently 8 times. 
7. Transfer the cell suspension (all the liquid above the agar gel barrier) into a labeled 15mL 
polypropylene centrifuge tube. 
8. Add another 3ml of sterile PBS back to the CPT vacutainer tube to wash remaining cells. 
9. Cap the tube again and invert gently 8 times. 
10. Transfer the cell suspension into the same labeled 15mL polypropylene centrifuge tube. 
11. Centrifuge the tube at 450 x g for 5 minutes, with brake.   
12. Aspirate the supernatant, being careful not to disturb the cell pellet. 
13. Re-suspend PBMC pellet in 3 ml of PBS. Re-suspend thoroughly by aspirating up and 
down using a pipette aid with serological pipette. 
14. Centrifuge in the 15 ml conical tube at room temperature at 450 x g 5 min, with brake. 
15. After centrifugation, aspirate the supernatant.  Do not disturb the cell pellet. 
16. Add RBC Lysis Buffer 1:3 cell pellet:buffer ratio. 
17. Incubate at room temperature 5 min. 
18. Transfer the cell suspension into a 1.5 ml eppendorf tube. 
19. Centrifuge at room temperature in a table-top centrifuge at 6,000 rpm for 3 min. 
20. Aspirate supernatant. 
21. Add 1 ml of PBS to the cell pellet. Re-suspend thoroughly. 
22. Centrifuge at room temperature in a table-top centrifuge at 6,000 rpm for 5 minutes. 
23. Aspirate the supernatant using an aspirating pipette and unfiltered micropipette tip 
attached to a vacuum pump. Do not disturb the cell pellet.  Store eppendorf tubes with 
PBMC pellets at -80°C until shipment.