Clinical trial NCT02352844
Conditions: Solid Malignancy Solid Tumor
Sponsor: Washington University School of Medicine
Start date: 2015-10-07; Completion date: 2017-08-15
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this research study is to look at participants with solid tumor malignancies and specific mutations respond to treatment with everolimus.

Detailed description:
Cancer is a molecularly heterogeneous disease comprised of complex genomic alterations in common and overlapping pathways. Somatic inactivating mutations in tuberous sclerosis complex 1 (TSC1) gene were recently identified as potential markers of response to mTOR therapy. Everolimus is an oral derivative of rapamycin. At the cellular and molecular level, everolimus acts as a signal transduction inhibitor, and selectively inhibits mTOR. We hypothesize that everolimus will exhibit clinical activity in solid malignancies harboring TSC1, TSC2, NF1, NF2, or STK11 mutations.

Arms: arm 1: Everolimus is an oral drug which will be administered on an outpatient basis at a dose of 10 mg daily on a 28-day cycle.
Interventions: intervention 1: Everolimus
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version: 02/15/17 
 
Page 1 of 53 
 
 
 
Phase II Study of Everolimus in Patients with Advanced Solid Malignancies with TSC1, 
TSC2, NF1, NF2, or STK11 Mutations 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol#: 201502067  
Version Date: 02/15/17 
 
Principal Investigator: 
Saiama Waqar, M.D. 
Phone:  (314) 362-5737 
E-mail:  saiamawaqar@wustl.edu 
 
Sub-Investigators 
 
 
 
Modality 
Ramaswamy Govindan, M.D. 
 
Medical Oncology 
Maria Q. Baggstrom, M.D. 
 
 
Medical Oncology 
Daniel Morgensztern, M.D.  
 
Medical Oncology 
Feng Gao, Ph.D. 
 
 
 
Biostatistics 
 
 
Study Drug(s): 
 
Everolimus (RAD001, Afinitor / Votubia) 
 
IND#: 
125661 EXEMPT 
Clinical Trials.gov# 
NCT02352844 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 


Protocol Version: 02/15/17 
 
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Phase II Study of Everolimus in Patients with Advanced Solid Malignancies with TSC1, 
TSC2, NF1, NF2 or STK11 Mutations 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
05/04/2015 
Amendment #1 Version 
 
 
 
 
 
 
09/10/2015 
Amendment #2 Version 
 
 
 
 
 
 
12/15/2015 
Amendment #3 Version 
 
 
 
 
 
 
04/25/2016 
Amendment #4 Version 
 
 
 
 
 
 
02/15/2017 


Protocol Version: 02/15/17 
 
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Phase II Study of Everolimus in Patients with Advanced Solid Malignancies with TSC1, 
TSC2, NF1, NF2, or STK11 Mutations 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Everolimus 10 mg orally once 
daily 
Follow-up CT 8 weeks later and 
then every 2 months for disease 
assessment 
Discontinue everolimus at time 
of progression 
Follow-up biopsy of accessible 
lesions that clearly show 
progression 


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Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
ASH 
American Society of Hematology 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
B-HCG 
Beta human chorionic gonadotropin  
BM 
Bone marrow 
BMT 
Bone marrow transplant 
BUN 
Blood urea nitrogen 
CALGB 
Cancer and Leukemia Group B 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CMML 
Chronic Myelomonocytic Leukemia 
CNS 
Central nervous system 
CR 
Complete remission 
CRc 
Cytogenetic complete remission 
CRi 
Complete remission incomplete 
CRm 
Morphologic complete remission 
CRF 
Case report form 
CST 
Central standard time 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLTs 
Dose Limiting Toxicities 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
DSMC 
Data Safety Monitoring Committee 
DTIC 
Dacarbazine 
EC 
Ethics Committee 
ECG (or EKG) 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
EE 
Efficacy-Evaluable 
EFS 
Event free survival 
EMEA 
European Agency for Evaluation of Medicinal Products 
FAB 
French-American-British classification 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 
FWA 
Federal wide assurance 


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GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony stimulating factor, filgrastim (Neupogen) 
GM-CSF 
Granulocyte/macrophage colony stimulating factor, sargramostim, (Leukine, Prokine) 
HDACs 
Histone deacetylases 
HHS 
Department of Health and Human Services’ 
HI 
Hematologic improvement 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
ICH 
International Conference on Harmonization 
IFN 
Interferon 
IL-2 
Interleukin-2 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous (i.v.) 
IVRS 
Interactive Voice Response System 
IWG 
International Working Group 
LD 
Longest diameter 
LDH 
Lactate dehydrogenase 
LPS 
lipopolysaccharide 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCL 
Mantle cell lymphoma 
MCV 
Mean corpuscular volume 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activity 
MM 
Multiple myeloma 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCCN 
National Cancer Center Network 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NK 
Natural killer cell 
NSCLC 
Non-small cell lung cancer 
OHRP 
Office of Human Research Protections  
ORR 
Overall response rate 
OS 
Overall survival 
PB 
Peripheral blood 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PI 
Principal investigator 


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PR 
Partial response (Partial remission) 
PSA 
Prostate-specific antigen 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RAEB 
Refractory anemia with excess blasts 
RAEB-t 
Refractory anemia with excess blasts in transformation 
RARS 
Refractory anemia with ringed sideroblasts 
RBC 
Red blood cell (count) 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RFS 
Relapse free survival 
RR 
Response rate 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SCT 
Stem cell transplant 
SD 
Stable disease 
TF 
Treatment failure 
TPP 
Therapeutics Product Programme 
TRAIL 
TNF-related apoptosis-inducing ligand 
TSH 
Thyroid stimulating hormone 
TTP 
Time to progression 
UPN 
Unique patient number 
US 
Ultrasound 
VEGF 
Vascular endothelial growth factor 
VPA 
Valproic acid 
WBC 
White blood cell (count) 
FCBP 
Females of child bearing potential 
WHO 
World Health Organization 
 
 


Protocol Version: 02/15/17 
 
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Table of Contents 
SCHEMA ........................................................................................................................................ 3 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 9 
1.1 
The Mammalian Target of Rapamycin (mTOR) Pathway ............................................... 9 
1.2 
Everolimus ....................................................................................................................... 9 
1.3 
Next Generation Sequencing .......................................................................................... 14 
1.4 
Study Rationale .............................................................................................................. 14 
2.0 
OBJECTIVES .................................................................................................................... 15 
2.1 
Primary Objectives ......................................................................................................... 15 
2.2 
Secondary Objectives ..................................................................................................... 15 
3.0 
PATIENT SELECTION .................................................................................................... 15 
3.1 
Inclusion Criteria ............................................................................................................ 15 
3.2 
Exclusion Criteria ........................................................................................................... 16 
3.3 
Inclusion of Women and Minorities............................................................................... 17 
4.0 
REGISTRATION PROCEDURES ................................................................................... 17 
4.1 
Confirmation of Patient Eligibility ................................................................................. 18 
4.2 
Patient Registration in the Siteman Cancer Center Oncore Database ............................ 18 
4.3 
Assignment of UPN ....................................................................................................... 18 
5.0 
TREATMENT PLAN ........................................................................................................ 18 
5.1 
Agent Administration ..................................................................................................... 18 
5.2 
Supportive Care Guidelines ........................................................................................... 19 
5.3 
Concomitant Medications .............................................................................................. 26 
5.4 
Women of Childbearing Potential .................................................................................. 29 
5.5 
Duration of Therapy ....................................................................................................... 30 
5.6 
Duration of Follow-up .................................................................................................... 31 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 31 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 33 
7.1 
Definitions ...................................................................................................................... 33 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
………………………………………………………………………………………….35 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 35 
7.4 
Reporting to Novartis ..................................................................................................... 36 
7.5 
Timeframe for Reporting Required Events .................................................................... 37 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 37 
8.1 
Everolimus ..................................................................................................................... 37 
9.0 
CORRELATIVE STUDIES .............................................................................................. 40 
9.1 
Archived Tumor Tissue .................................................................................................. 40 
9.2 
Fresh Tumor Biopsy ....................................................................................................... 40 
10.0 STUDY CALENDAR ....................................................................................................... 41 
11.0 DATA SUBMISSION SCHEDULE ................................................................................. 42 
12.0 MEASUREMENT OF EFFECT........................................................................................ 42 
12.1 Antitumor Effect – Solid Tumors................................................................................... 42 
12.2 Disease Parameters ......................................................................................................... 42 
12.3 Methods for Evaluation of Measurable Disease ............................................................ 43 
12.4 Response Criteria ........................................................................................................... 46 


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13.0 DATA AND SAFETY MONITORING ............................................................................ 48 
14.0 STATISTICAL CONSIDERATIONS............................................................................... 49 
14.1 Study Design .................................................................................................................. 49 
14.2 Data Analysis ................................................................................................................. 49 
15.0 REFERENCES .................................................................................................................. 51 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 52 
APPENDIX B: PATIENT’S MEDICATION DIARY ................................................................. 53 
 
 


Protocol Version: 02/15/17 
 
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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
The Mammalian Target of Rapamycin (mTOR) Pathway 
 
Activation of the mammalian target of rapamycin (mTOR) pathway has been implicated 
in the development of several malignancies.1,2 A member of the phosphatidylinositol 3-
kinase (PI3K)-related family of kinases, mTOR is a 289-kDa protein serine/threonine 
kinase that was first identified as the cellular target of rapamycin and is involved in 
checkpoint regulation of the cell cycle regulation. Additionally, the mTOR pathway is 
responsible for upregulating downstream signaling of hypoxia inducible factor-1-α (HIF1-
α) which promotes angiogenesis and cell proliferation.3 mTOR is represented by two 
structurally and functionally distinct multiprotein signaling complexes, the rapamycin 
sensitive mTOR complex 1 (mTORC1), and rapamycin insensitive mTOR complex 2 
(mTORC2). mTORC 1 is mainly activated via the PI3K pathway through AKT and the 
tuberous sclerosis complex (TSC1/TSC2). Activated AKT phosphorylates TSC2, which 
leads to 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. Another regulator of the mTOR pathway is NF1. 
 
1.2 
Everolimus 
 
Everolimus is a novel oral derivative of rapamycin.  At the cellular and molecular level, 
everolimus acts as a signal transduction inhibitor, and selectively inhibits mTOR. 
Everolimus has been in clinical development since 1996 as an immunosuppressant in solid 
organ transplantation and has been in development for patients with various malignancies 
since 2002. It has been demonstrated to have activity in several human solid tumor cell 
lines, as well as in mouse xenograft models.4-7  Everolimus was first approved by the U.S. 
Food and Drug Administration (FDA) for the treatment of patients with advanced renal 
cell carcinoma (RCC) in 2009.  It recently received approval for use in patients with 
advanced pancreatic neuroendocrine tumors as well.  The FDA approved dose of 
everolimus is 10 mg daily by mouth. Everolimus is extensively metabolized in the liver 
and eliminated by bile. It is a substrate of CYP3A4 and substrate and inhibitor of P-
glycoprotein. It well tolerated, with the most common adverse reactions being stomatitis, 
fatigue, nausea, diarrhea. Grade 3-4 adverse reactions (≥2%) include infections, stomatitis, 
fatigue and pneumonitis. The most common laboratory abnormalities are anemia, 
hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia and increased 
creatinine.8 
 
Somatic mutations in tuberous sclerosis complex 1 (TSC1) and NF2 genes were recently 
identified as potential markers of response to mTOR therapy.  In a phase II study 
(NCT00805129) of patients with bladder cancer treated with everolimus, 13 patients had 
tumor tissue available for molecular analysis. Of these, 8 patients were wild type for TSC1 
and all had progressive disease. Five of those patients had TSC1 mutations: 1 had CR of 
greater than 2 years (also had NF2 inactivation), 2 had minor response (24% and 17%), 1 
had stable disease, and 1 had progressive disease. Since mTORC 1 is mainly activated via 


Protocol Version: 02/15/17 
 
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the PI3K pathway through AKT and the tuberous sclerosis complex (TSC1/TSC2), we 
hypothesis that in a similar manner TSC2 mutation would also predict for response to 
everolimus. Inactivating somatic mutations of STK11 (LKB1) reported in 34% of lung 
adenocarcinomas and 19% of squamous cell carcinomas could potentially identify patients 
likely to respond to temsirolimus given the sensitivity of a cell line with loss of STK11 to 
rapamycin.10-12 
 
1.2.1 Overview of Everolimus 
 
Everolimus is a derivative of rapamycin which acts as a signal transduction 
inhibitor (Table 1-1, Figure 1-1). Everolimus selectively inhibits mTOR 
(mammalian target of rapamycin), specifically targeting the mTOR-raptor signal 
transduction complex. mTOR is a key serine-threonine kinase in the PI3K/AKT 
signaling cascade, which is known to be dysregulated in a wide spectrum of human 
cancers (Boulay and Lane 2007). 
 
Everolimus is being investigated as an anticancer agent based on its potential to act 
 directly on the tumor cells by inhibiting tumor cell growth and proliferation; 
 indirectly by inhibiting angiogenesis leading to reduced tumor vascularity 
(via potent inhibition of tumor cell VEGF (vascular endothelial growth 
factor) production and VEGF-induced proliferation of endothelial cells). 
 
Table 1.0-1 
Everolimus - Drug substance 
Chemical name 
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,
32S,35R)-1,18-dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-
hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-
19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-
dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-
tetraene-2,3,10,14,20-pentaone 
International non-
proprietary name 
Everolimus 
 
Figure 1.0-1 Chemical structure of Everolimus 
 


Protocol Version: 02/15/17 
 
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1.2.2 mTOR Pathway and Cancer 
 
At the cellular and molecular level, everolimus acts as a signal transduction 
inhibitor. It selectively inhibits mTOR (mammalian target of rapamycin), a key 
protein kinase which regulates cell growth, proliferation and survival. The mTOR 
kinase is mainly activated via the phosphatidylinositol 3-kinase (PI3-Kinase) 
pathway through AKT/PKB and the tuberous sclerosis complex (TSC1/2). 
Mutations in these components or in PTEN, a negative regulator of PI3-kinase, may 
result in their dysregulation. Abnormal functioning of various components of the 
signaling pathways contributes to the pathophysiology of numerous human cancers. 
Various preclinical models have confirmed the role of this pathway in tumor 
development (Cohen et al 2005). 
 
The main known functions of mTOR include the following (Bjornsti and Houghton 
2004): 
 mTOR functions as a sensor of mitogens, growth factors and energy and 
nutrient levels; 
 Facilitating cell-cycle progression from G1-S phase in appropriate growth 
conditions; 
 The PI3K/mTOR pathway itself is frequently dysregulated in many human 
cancers, and oncogenic transformation may sensitize tumor cells to mTOR 
inhibitors; 
 PI3-kinase mutations have been reported in the primary tumor in 10-20% 
of human colorectal cancers (Frattini 2005, Velho 2005); 
 The loss of PTEN protein, either through gene deletion or functional 
silencing (promoter hypermethylation), is reported in approximately 60% 
of primary human colorectal cancers (Goel et al 2004); 
 The mTOR pathway is involved in the production of pro-angiogenic factors 
(i.e., VEGF) and inhibition of endothelial cell growth and proliferation; 
 Through inactivating eukaryotic initiation factor 4E binding proteins and 
activating the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates 
protein translation, including the HIF-1 proteins. Inhibition of mTOR is 
expected to lead to decreased expression of HIF-1. 
 
1.2.3 Non-clinical Experience 
 
Everolimus inhibits the proliferation of a range of human tumor cell lines in vitro 
including lines originating from lung, breast, prostate, colon, melanoma and 
glioblastoma. IC50s range from sub/low nM to µM. Everolimus also inhibits the 
proliferation of human umbilical vein endothelial cells (HUVECS) in vitro, with 
particular potency against VEGF-induced proliferation suggesting that everolimus 
may also act as an anti-angiogenic agent. The anti-angiogenic activity of 
everolimus was confirmed in vivo. Everolimus selectively inhibited VEGF-
dependent angiogenic response at well tolerated doses. Mice with primary and 


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metastatic tumors treated with everolimus showed a significant reduction in blood 
vessel density when compared to controls. 
 
The potential of everolimus as an anti-cancer agent was shown in rodent models. 
Everolimus is orally bioavailable, residing longer in tumor tissue than in plasma in 
a subcutaneous mouse xenograft model, and demonstrating high tumor penetration 
in a rat pancreatic tumor model. The pharmacokinetic profile of everolimus 
indicates sufficient tumor penetration, above that needed to inhibit the proliferation 
of endothelial cells and tumor cell lines deemed sensitive to everolimus in vitro. 
 
Everolimus administered orally daily was a potent inhibitor of tumor growth, at 
well tolerated doses, in 11 different mouse xenograft models (including pancreatic, 
colon, epidermoid, lung and melanoma) and two syngeneic models (rat pancreatic, 
mouse orthotopic melanoma). These models included tumor lines considered 
sensitive and “relatively resistant” in vitro. In general, everolimus was better 
tolerated in mouse xenograft models than standard cytotoxic agents (i.e., 
doxorubicin and 5-fluorouracil), while possessing similar anti-tumor activity. 
Additionally, activity in a VEGF-impregnated subcutaneous implant model of 
angiogenesis and reduced vascularity (vessel density) of everolimus-treated tumors 
(murine melanoma) provided evidence of in vivo effects of angiogenesis. 
 
It is not clear which molecular determinants predict responsiveness of tumor cells 
to everolimus. Molecular analysis has revealed that relative sensitivity to 
everolimus in vitro correlates with the degree of phosphorylation (activation) of the 
AKT/PKB protein kinase and the S6 ribosomal protein; in some cases (i.e., 
glioblastoma) there is also a correlation with PTEN status. 
 
In vivo studies investigating the anti-tumor activity of everolimus in experimental 
animal tumor models showed that everolimus monotherapy typically reduced 
tumor cell growth rates rather than produced regressions. These effects occurred 
within the dose range of 2.5 mg to 10 mg/kg, orally once a day. 
 
In preclinical models, the administration of everolimus is associated with reduction 
of protein phosphorylation in target proteins downstream of mTOR, notably 
phosphorylated S6 (p-S6) and p-4E-BP1, and occasionally with an increase in 
phosphorylated AKT, a protein upstream of mTOR signaling pathway. 
All significant adverse events observed in toxicology studies with everolimus in 
mice, rats, monkeys and mini-pigs were consistent with its anticipated 
pharmacological action as an anti-proliferative and immunosuppressant and at least 
in part reversible after a 2 or 4-week recovery period with the exception of the 
changes in male reproductive organs, most notably testes. 
 
In vitro genotoxicity studies covering relevant genotoxicity end-points showed no 
evidence of clastogenic or mutagenic activity. 
 
In male fertility studies in rats, testicular morphology was affected at 0.5 mg/kg and 


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above, and sperm motility, sperm head count and plasma testosterone levels were 
diminished at 5 mg/kg which corresponded to 0.7 times the estimated clinical 
exposure at 10 mg/day, and caused a decrease in male fertility. There was evidence 
of reversibility. Female fertility was not affected, but everolimus caused an increase 
of pre-implantation loss in female rats at doses > 0.1 mg/kg, suggesting it could 
also potentially impact fertility in females.  Everolimus crossed the placenta and 
was toxic to the conceptus. In rats, everolimus caused embryo/fetotoxicity at 
systemic exposure below the planned therapeutic level comprising mortality and 
reduced fetal weight. The incidence of skeletal variations and malformations at 0.3 
and 0.9 mg/kg (e.g. sternal cleft) was increased. In rabbits, embryo toxicity was 
evident by an increase in late resorptions. Effects of everolimus on the pre- and 
postnatal development of rats were limited to slightly affected body weight and 
survival in the F1-generation at ≥0.1 mg/kg, and did not indicate a specific toxic 
potential.  
 
The potential reproductive risk for humans is unknown. However, due to the 
observed malformations in rats, everolimus should be considered potentially 
teratogenic. Everolimus should not be given to pregnant women unless the potential 
benefit outweighs the potential risk for the fetus. Women of childbearing potential 
should be advised to use highly effective contraception methods while they are 
receiving everolimus and up to 8 weeks after treatment has been stopped. It is not 
known whether everolimus is excreted in human milk. In animal studies, 
everolimus and/or its metabolites were readily transferred into the milk of lactating 
rats. Therefore women who are taking everolimus should not breastfeed. 
 
Further details can be found in the Everolimus Investigator’s Brochure. 
 
 


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1.3 
Next Generation Sequencing 
 
TSC1,TSC2, NF1 NF2, and STK11 mutational analysis will be performed as part of a 
larger panel of genomic testing to aid in treatment of patients with cancer as standard of 
care and will not be billed to Novartis. This screening will identify potential patients for 
this study. Provided they meet other eligibility criteria, they will be consented to participate 
in the study.  
 
Genes to be sequenced include TSC1,TSC2, NF1, NF2 and STK11. The technology 
employed will permit detection of single nucleotide variants, small insertions, deletions, 
and complex indels, as well as amplifications and large deletions across the coding regions 
of all sequenced genes. Tumor-derived DNA obtained from formalin fixed, paraffin 
embedded tissue will serve as the source of input material for the assay.  Sensitive and 
specific methods to call variants and other genomic alterations will be performed using a 
clinical grade data analysis pipeline including a software package allowing for 
interpretation and reporting of such findings. 
 
1.4 
Study Rationale 
 
Cancer is a molecularly heterogeneous disease comprised of complex genomic alterations 
in common and overlapping pathways.  Complicating the heterogeneous nature of cancer 
is the clonal evolution that occurs within a tumor 10.  The molecular landscape of the tumor 
at time of diagnosis may differ significantly from the molecular profile at the time of 
disease progression 11.  It is critical that tumor samples are obtained at the time of diagnosis 
and following disease progression.  Key alterations in the tumor biology can be identified 
efficiently through use of routine next generation sequencing.  It is important to identify 
predictive biomarkers for response to molecularly targeted agents; however, it is also 
important to investigate biomarkers that confer resistance to specific therapies.  As an 
example, 10% of non small cell lung cancers (NCSLC) carry activating mutations in the 
epidermal growth factor receptor tyrosine kinase (EGFR TK).12  Although tyrosine kinase 
inhibitors such as erlotinib have demonstrated response rates of approximately 70-90% 
13,14, drug resistance eventually develops as a consequence of an emergence of a population 
of tumor cells harboring a new mutation in the EGFR TK domain or amplification in the 
MET oncogene 15.  As a result, clinical studies are underway targeting EGFR mutations in 
combination with MET inhibitors to target the genomic alterations that are occurring at the 
time of progression on an EGFR inhibitor.  Using a similar model, mutations in the 
mTOR/PI3K pathway and potential mechanisms of resistance to everolimus can be 
identified using routine next generation sequencing at the time of diagnosis and at time of 
disease progression.  
 
 
 


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2.0 
OBJECTIVES 
 
2.1 
Primary Objectives 
 
To assess the response rate of patients with solid malignancies whose tumors carry 
mutations in TSC1, TSC2, NF1, NF2, or STK11 to everolimus. 
 
2.2 
Secondary Objectives 
 
1. To correlate mutations in the mTOR pathway with therapeutic response to everolimus. 
2. To investigate the genetic changes associated with disease progression following 
treatment with everolimus. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Histologically confirmed diagnosis of advanced (metastatic, recurrent, or unresectable) 
cancer with mutations in any of the following genes: TSC1,TSC2, NF1, NF2 or STK11 
 
2. Must have failed at least 1 standard of care systemic therapy for their malignancy.  
 
3. Measurable disease defined as lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >10 mm with CT scan, as >20 mm by 
chest x-ray, or >10 mm with calipers by clinical exam. 
 
4. Prior therapy (chemotherapy, radiation therapy, and surgery) is allowed if completed 
at least 2 weeks prior to registration and if all treatment-related toxicities are resolved 
to ≤ CTCAE grade 1, with the exception of alopecia and hematologic values otherwise 
meeting the bone marrow function criteria specified below. 
 
5. At least 18 years of age. 
 
6. ECOG performance status < 2 (see Appendix A). 
 
7. Normal bone marrow and organ function as defined below: 
a. Leukocytes > 3,000/mcL 
b. Absolute neutrophil count > 1,500/mcL 
c. Platelets > 100,000/mcL 
d. Hemoglobin > 9.0 g/dL 
e. Total serum bilirubin ≤ 2.0 x IULN 
f. AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN (≤ 5.0 x IULN in patients with liver 
metastases) 


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g. Serum creatinine ≤ 1.5 x IULN OR creatinine clearance > 45 mL/min/1.73 m2 for 
patients with creatinine levels above institutional normal 
h. Fasting cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 
2.5 x IULN.  NOTE: In case one or both of these thresholds are exceeded, the 
patient can only be included after initiation of appropriate lipid lowering medication 
 
8. Able to swallow tablets. 
 
9. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, must use highly effective methods of contraception (please refer 
to Section 5.4) during the study and for 8 weeks after.  Women are considered post-
menopausal and not of childbearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, 
history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or 
without hysterectomy) or tubal ligation at least six weeks prior to randomization.  In 
the case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow-up hormone level assessment is she considered not of 
childbearing potential. 
 
10. Male patients whose sexual partner(s) are women of childbearing potential must agree 
to use adequate contraception during the study and for 8 weeks after the end of 
treatment. 
 
11. Able to understand and willing to sign an IRB approved written informed consent 
document (or that of legally authorized representative, if applicable) 
 
3.2 
Exclusion Criteria 
 
1. A history of other malignancy ≤ 3 years previous with the exception of basal cell or 
squamous cell carcinoma of the skin which were treated with local resection only or 
carcinoma in situ of the cervix. 
 
2. Taking an investigational agent within 4 weeks of initiation of everolimus. 
 
3. Symptomatic brain metastases.  Known brain metastases are allowed if asymptomatic 
and previously treated. 
 
4. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to everolimus or other agents used in the study. 
 
5. Known impairment of GI function or GI disease that may significantly alter the 
absorption of oral everolimus. 
 
6. Currently taking CYP3A4 inhibitors or inducers (such as the antiepileptic drugs 
phenytoin, carbamazepine, or phenobarbital; cyclosporine; grapefruit or its juice; 
Seville oranges; starfruit; or St. John’s wort) (refer to Section 5.3). 


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7. Chronic treatment with corticosteroids or other immunosuppressive agents.  Topical or 
inhaled corticosteroids are allowed. 
 
8. Received live attenuated vaccine within 1 week of start of everolimus (i.e. intranasal 
influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and 
TY21a typhoid vaccines). 
 
9. Uncontrolled diabetes mellitus defined as HbA1c > 8% despite adequate therapy.  
Patients with a known history of impaired fasting glucose or diabetes mellitus may be 
included; however, blood glucose and antidiabetic treatment must be monitored closely 
throughout the trial and adjusted as necessary. 
 
10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure of NYHA class III or IV, active 
coronary artery disease, unstable angina pectoris, cardiac arrhythmia, myocardia 
infraction ≤ 6 months prior to start of everolimus, uncontrolled hypertension (systolic 
pressure > 150 mmHg or diastolic pressure > 90 mmHg), uncontrolled seizure disorder, 
liver disease such as cirrhosis, decompensated liver disease, active and chronic 
hepatitis, known severely impaired lung function (spirometry and DLCO 50% or less 
of normal and 02 saturation 88% or less at rest on room air), active bleeding diathesis, 
or psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
11. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
pregnancy test within 14 days of study entry. 
 
12. Known HIV-positivity on combination antiretroviral therapy because of the potential 
for pharmacokinetic interactions with everolimus.  In addition, these patients are at 
increased risk of lethal infections when treated with marrow-suppressive therapy.  
Appropriate studies will be undertaken in patients receiving combination antiretroviral 
therapy when indicated. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 


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2. Registration of patient in the Siteman Cancer Center Oncore database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center Oncore Database 
 
All patients must be registered through the Siteman Cancer Center. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
This is an open label, single-arm phase II trial focusing on the response rate of everolimus.  The 
study treatment plan is as follows: 
 
1. Everolimus 10 mg orally, once daily 
2. Follow-up CT scan 8 weeks later and then every two months for disease assessment 
3. Discontinue everolimus at the time of progression as defined by RECIST 1.1  criteria 
4. Follow up biopsy (of accessible lesions that clearly showed progression) 
 
5.1 
Agent Administration 
 
Everolimus is an oral drug which will be administered on an outpatient basis at a dose of 
10 mg daily on a 28-day cycle.  Patients should take everolimus at approximately the same 
time every day, either consistently with or consistently without food.  The tablets should 
be swallowed whole with a glass of water and should not be chewed or crushed.  The glass 
should be rinsed with the same volume of water and the rinse completely swallowed to 
ensure the entire dose is administered.  If vomiting occurs, no attempt should be made to 
replace the vomited dose.  If a patient misses a dose, the patient should be instructed not to 
take or make up that dose and to resume dosing with the next scheduled dose.  Patients will 
be instructed to bring all unused tablets and their medication diary (see Appendix B) to 
each study visit for assessment of compliance.   


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5.2 
Supportive Care Guidelines 
 
Overall, safety data available from completed, controlled and uncontrolled studies indicate 
that everolimus is generally well tolerated at weekly or daily dose schedules. The safety 
profile is characterized by manageable adverse events (AEs). These AEs are generally 
reversible and non-cumulative. 
 
Adverse events most frequently observed with everolimus are stomatitis, rash, diarrhea, 
fatigue, infections, asthenia, nausea, peripheral edema, decreased appetite, headache, 
dysgeusia, epistaxis, mucosal inflammation, pneumonitis, weight decreased, vomiting, 
pruritus, cough, dyspnea, dry skin, nail disorder, and pyrexia. Overall, the most frequently 
observed laboratory abnormalities include decreased hematology parameters including 
hemoglobin, lymphocytes, platelets, and neutrophils (or collectively as pancytopenia).; 
increased clinical chemistry parameters including cholesterol, triglycerides, glucose, 
aspartate transaminases, creatinine, alanine transaminases, and bilirubin; and decreased 
clinical chemistry parameters including phosphate and potassium. The majority of these 
AEs have been of mild to moderate severity (NCI CTC grade 1-2).  
 
5.2.1 Management of infections 
 
Everolimus has immunosuppressive properties and may predispose patients to 
bacterial, fungal, viral or protozoal infections, including infections with 
opportunistic pathogens. Localized and systemic infections, including pneumonia, 
other bacterial infections, invasive fungal infections, such as aspergillosis or 
candidiasis and viral infections including reactivation of hepatitis B virus, have 
been described in patients taking everolimus. Some of these infections have been 
severe (e.g. leading to sepsis, respiratory or hepatic failure) and occasionally have 
had a fatal outcome. 
 
Physicians and patients should be aware of the increased risk of infection with 
everolimus. Treat pre-existing infections prior to starting treatment with 
everolimus. While taking everolimus, be vigilant for symptoms and signs of 
infection; if a diagnosis of infection is made, institute appropriate treatment 
promptly and consider interruption or discontinuation of everolimus. 
 
If a diagnosis of invasive systemic fungal infection is made, discontinue everolimus 
and treat with appropriate antifungal therapy. 
 
Cases of pneumocystis jirovecii pneumonia (PJP), some with a fatal outcome, have 
been reported in patients who received everolimus. PJP may be associated with 
concomitant use of corticosteroids or other immunosuppressive agents.  
Prophylaxis for PJP should be considered when concomitant use of corticosteroids 
or other immunosuppressive agents are required. 
 
5.2.2 Management of skin toxicity 


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For patients with grade 1 toxicity, no specific supportive care is usually needed or 
indicated. Rash must be reported as an AE. Patients with grade 2 or higher toxicity 
may be treated with the following suggested supportive measures at the discretion 
of the investigator: oral minocycline, topical tetracycline, topical clindamycin, 
topical silver sulfadiazine, diphenhydramine, oral prednisolone (short course), 
topical corticosteroids, or pimecrolimus. 
 
5.2.3 Management of hypersensitivity reactions 
 
Hypersensitivity reactions manifested by symptoms including, but not limited to, 
anaphylaxis, dyspnea, flushing, chest pain or angioedema (e.g. swelling of the 
airways or tongue, with or without respiratory impairment) have been observed 
with everolimus. 
 
5.2.4 Angioedema with concomitant use of angiotensin-converting enzyme 
(ACE) inhibitors 
 
Patients taking concomitant ACE inhibitor therapy may be at increased risk for 
angioedema (e.g. swelling of the airways or tongue, with or without respiratory 
impairment). 
 
5.2.5 Renal Failure Events 
 
Cases of renal failure (including acute renal failure), some with fatal outcome, 
occurred in patients treated with everolimus. Renal function of patients should be 
monitored particularly where patients have additional risk factors that may further 
impair renal function. 
 
Elevations of serum creatinine, usually mild, and proteinuria have been reported in 
patients taking everolimus. Monitoring of renal function, including measurement 
of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is 
recommended prior to the start of everolimus therapy and periodically thereafter. 
 
 


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5.2.6 Management of stomatitis / oral mucositis / mouth ulcers 
 
Severity 
Everolimus Dose Adjustment and Management Recommendations 
Grade 1 
(Minimal 
symtpoms, 
normal diet) 
No dose adjustment required.  
Manage with non-alcoholic or salt water (0.9%) mouth wash severaltimes a 
day. 
Grade 2 
(Symptomatic 
but can eat and 
swallow 
modified diet) 
Temporary dose interruption until recovery to grade ≤1.  
Re-initiate everolimus at the same dose. 
If stomatitis recurs at grade 2, interrupt dose until recovery to grade ≤1. Re-
initiate everolimus at a lower dose. 
Manage with topical analgesic mouth treatments (e.g. benzocaine,butyl 
aminobenzoate, tetracaine hydrochloride, menthol or phenol)with or without 
topical corticosteroids (i.e. triamcinolone oral paste)*. 
Grade 3 
(Symptomatic 
and unable to 
adequately eat 
or hydrate 
orally) 
Temporary dose interruption until recovery to grade ≤1.  
Re-initiate everolimus at lower dose. 
Manage with topical analgesic mouth treatments (i.e. benzocaine,butyl 
aminobenzoate, tetracaine hydrochloride, menthol or phenol) with or 
without topical corticosteroids (i.e. triamcinolone oral paste)* 
Grade 4 
(Symptoms 
associated with 
life-threatening 
consequences) 
Discontinue everolimus and treat with appropriate medical therapy. 
* using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in management of 
stomatitis as they may worsen mouth ulcers. 
 
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with 
gastrointestinal morbidity associated with mouth/dental infections, irritation of 
esophageal mucosa e.g. gastroesophageal reflux disease (GERD) and pre-existing 
stomatitis/mucositis must be monitored even more closely. Patients should be 
instructed to report the first onset of buccal mucosa irritation/reddening to their 
study physician immediately. 
 
Stomatitis/oral mucositis/mouth ulcers due to everolimus should be treated using 
local supportive care. Please note that investigators in earlier trials have described 
the oral toxicities associated with everolimus as mouth ulcers, rather than mucositis 
or stomatitis. If your examination reveals mouth ulcers rather than a more general 
inflammation of the mouth, please classify the adverse event as such. The suggested 
paradigm for treatment of stomatitis/oral mucositis/mouth ulcers is as follows: 
 
1. For mild toxicity (grade 1), no dose adjustment required. Manage with non-
alcoholic mouth wash or salt water (0.9%) mouth wash several times a day 
until resolution. 
2. For more severe toxicity (grade 2 in which case patients have pain but are 
able to maintain adequate oral alimentation, or grade 3 in which case 
patients cannot maintain adequate oral alimentation), the suggested 
treatments are topical analgesic mouth treatments (i.e., local anesthetics 
such as, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 


Protocol Version: 02/15/17 
 
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menthol, or phenol) with or without topical corticosteroids, such as 
triamcinolone oral paste 0.1% (Kenalog in Orabase®). 
3. Agents containing alcohol, hydrogen peroxide, iodine, and thyme 
derivatives may tend to worsen mouth ulcers.  These agents should be 
avoided. 
4. Antifungal agents should be avoided unless a fungal infection is diagnosed. 
In particular, systemic imidazole antifungal agents (ketoconazole, 
fluconazole, itraconazole, etc.) should be avoided in all patients due to their 
strong inhibition of everolimus metabolism, therefore leading to higher 
everolimus exposures. Therefore, topical antifungal agents are preferred if 
an infection is diagnosed.  
 
5.2.7 Management of diarrhea 
 
Appearance of grade 1-2 diarrhea attributed to study drug toxicity may be treated 
with supportive care such as loperamide, initiated at the earliest onset (for example 
4 mg orally followed by 2 mg orally every 2 hours until resolution of diarrhea). 
 
5.2.8 Management of hyperlipidemia and hyperglycemia 
 
Severity 
Everolimus Dose Adjustment and Management Recommendations 
Grade 1 
No dose adjustment required. 
Initiate appropriate medical therapy and monitor. 
Grade 2 
No dose adjustment required. 
Manage with appropriate medical therapy and monitor. 
Grade 3 
Temporary dose interruption. 
Re-initiate everolimus at lower dose. 
Manage with appropriate medical therapy and monitor. 
Grade 4 
Discontinue everolimus and treat with appropriate medical therapy. 
 
Treatment of hyperlipidemia should take into account the pre-treatment status and 
dietary habits of the patient. Grade 2 or higher hypercholesterolemia (>300 mg/dL 
or 7.75 mmol/L) or grade 2 hypertriglyceridemia or higher (>2.5x upper normal 
limit) should be treated with a 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase 
inhibitor (e.g. atorvastatin, pravastatin, fluvastatin) or appropriate triglyceride-
lowering medication, in addition to diet. 
 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is 
associated with an increased risk of a rare but serious skeletal muscle toxicity 
manifested by rhabdomyolysis, markedly elevated creatine phosphokinase (CPK) 
levels and myoglobinuria, acute renal failure and sometimes death. The risk versus 
benefit of using this therapy should be determined for individual patients based on 
their risk of cardiovascular complications of hyperlipidemia. 
 
Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been 
reported in patients taking everolimus.  Monitoring of blood cholesterol and 
triglycerides prior to the start of everolimus therapy and periodically thereafter as 
well as management with appropriate medical therapy is recommended. 


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Hyperglycemia has been reported in patients taking everolimus. Monitoring of 
fasting serum glucose is recommended prior to the start of everolimus and 
periodically thereafter. More frequent monitoring is recommended when 
everolimus is co-administered with other drugs that may induce hyperglycemia. 
Optimal glycemic control should be achieved before starting a patient on 
everolimus. 
 
5.2.9 Management of non-infectious pneumonitis 
 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of 
non-infectious pneumonitis (including interstitial lung disease) have also been 
described in patients taking everolimus. Some of these have been severe and on 
rare occasions, a fatal outcome was observed. 
 
 A diagnosis of non-infectious pneumonitis should be considered in patients 
presenting with non-specific respiratory signs and symptoms such as 
hypoxia, pleural effusion, cough or dyspnea, and in whom infectious, 
neoplastic and other non-medicinal causes have been excluded by means of 
appropriate investigations. Opportunistic infections such as PJP should be 
ruled out in the differential diagnosis of non-infectious pneumonitis. 
Patients should be advised to report promptly any new or worsening 
respiratory symptoms. 
 
Patients who develop radiological changes suggestive of non-infectious 
pneumonitis and have few or no symptoms may continue everolimus therapy 
without dose alteration. 
 
If symptoms are moderate (grade 2), consideration should be given to interruption 
of therapy until symptoms improve.  The use of corticosteroids may be indicated.  
Everolimus may be reintroduced at a daily dose approximately 50% lower than the 
dose previously administered. 
 
For cases of grade 3 non-infectious pneumonitis, interrupt everolimus until 
resolution to less than or equal to grade 1.  Everolimus may be re-initiated at a daily 
dose approximately 50% lower than the dose previously administered depending 
on the individual clinical circumstances.  If toxicity recurs at grade 3, consider 
discontinuation of everolimus.  For cases of grade 4 non-infectious pneumonitis, 
everolimus therapy should be discontinued.  Corticosteroids may be indicated until 
clinical symptoms resolve. 
 
For patients who require use of corticosteroids for treatment of non-infectious 
pneumonitis, prophylaxis for pneumocystis jirovecii pneumonia (PJP) may be 
considered. The two compounds studied most extensively for prophylaxis against 
PJP have been trimethoprim-sulfamethoxazole, given orally, and pentamidine, 
given as an aerosol. 


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If non-infectious pneumonitis develops, the guidelines in the table below should be 
followed. Consultation with a pulmonologist is recommended for any case of 
pneumonitis that develops during the study. 
Management of non-infectious pneumonitis 
Worst grade 
pneumonitis 
Suggested investigations 
Management of 
pneumonitis 
Everolimus dose adjustment 
Grade 1 
(Asymptomatic, 
radiographic 
findings only) 
CT scans with lung windows. 
No specific therapy 
is required 
No dose adjustment required.  
Initiate appropriate monitoring. 
Grade 2 
(Symptomatic, 
not interering 
with Activities 
of Daily Living) 
CT scan with lung windows. Consider 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Consider a 
bronchoscopy with biopsy and/or BAL. 
Monitoring at each visit until return to ≤ 
grade 1. Return to initial monitoring 
frequency if no recurrence. 
Symptomatic only. 
Consider 
corticosteroids 
and/or other 
supportive therapy if 
symptoms are 
troublesome. 
Rule out infection and consider 
interruption of Everolimus until 
symptoms improve to Grade ≤ 1. 
Re-initiate Everolimus at one dose 
level lower.  
Discontinue Everolimus if failure to 
recover within ≤ 28 days. 
Grade 3 
(Symptomatic, 
Interfering with 
Activities of 
Daily Living. 
O2 indicated 
CT scan with lung windows and 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Monitoring at each 
visit until return to ≤ grade 1. Return to 
initial monitoring frequency if no 
recurrence. Bronchoscopy with biopsy 
and/or BAL is recommended. 
Consider 
corticosteroids 
if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Rule out infection and interrupt 
Everolimus until symptoms improve 
to Grade ≤ 1. 
Consider re-initiating Everolimus at 
one dose level lower (approximately 
50% lower than the dose previously 
administered depending on individual 
clinical circumstances) 
Discontinue Everolimus if failure to 
recover within ≤ 28 days.If toxicity 
recurs at Grade 3, consider 
discontinuation 
Grade 4 (Life-
threatening, 
ventlatory 
support 
indicated) 
CT scan with lung windows and required 
pulmonary function testing, if possible, 
includes: spirometry, DLCO, and room 
air O2 saturation at rest. Monitoring at 
each visit until return to ≤ grade 1. 
Return to initial monitoring frequency if 
no 
recurrence. 
Bronchoscopy 
with 
biopsy and/or BAL is recommended if 
possible. 
Consider 
corticosteroids 
if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Rule out infection and discontinue 
Everolimus. 
 
5.2.10 Management of hepatitis reactivation / flare 
 
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer 
receiving chemotherapy (Yeo 2004). Sporadic cases of Hepatitis B reactivation 
have also been seen in this setting with everolimus. Use of antivirals during anti-
cancer therapy has been shown to reduce the risk of Hepatitis B virus reactivation 
and associated morbidity and mortality (Loomba 2008). A detailed assessment of 
Hepatitis B/C medical history and risk factors must be done for all patients at 
screening, with testing performed prior to the first dose of everolimus. 
  
Monitoring and prophylactic treatment for hepatitis B reactivation 
The table below provides detail of monitoring and prophylactic therapy according 
to the screening results of viral load and serologic markers testing. 


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Action to be taken based on screening hepatitis B results 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBsAb 
+ or - 
+ or - 
+ 
and no prior HBV 
vaccination 
+ or - 
- 
or + with prior 
HBV vaccination 
HBcAb 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendation 
Prophylaxis treatment should 
be started 1-2 weeks prior to 
first dose of Everolimus 
 
Monitor HBV-DNA 
approximately every 4-8 
weeks 
No prophylaxis 
 
Monitor HBV-DNA 
approximately every 3-4 weeks  
No specific action 
 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of 
everolimus. For HBV reactivation definition and management guidelines, see the 
table below. 
 
Guidelines for the management of hepatitis B reactivation 
HBV reactivation (with or without clinical signs and symptoms)* 
For patients with baseline 
results:  
Positive HBV-DNA 
OR 
positive HBsAg 
-------------------------------------- 
reactivation is defined as: 
[Increase of 1 log in HBV-DNA 
relative to baseline HBV-DNA 
value OR new appearance of 
measurable HBV-DNA] 
 
Treat: Start a second antiviral medication 
AND 
Interrupt Everolimus administration until resolution:  
 
≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days, Everolimus should be re-
started at one dose lower, if available. If the patient is already 
receiving the lowest dose of Everolimus according to the protocol, 
the patient should restart at the same dose after resolution. Both 
antiviral therapies should continue at least 4 weeks after last dose of 
Everolimus.  
If resolution occurs > 28 days Patients should discontinue 
Everolimus but continue both antiviral therapies at least 4 weeks 
after last dose of Everolimus. 
For patients with baseline 
results: 
Negative HBV-DNA and HBsAg 
AND 
[Positive HBsAb (with no prior 
history of vaccination against 
HBV), OR positive HBcAb] 
------------------------------------- 
Reactivation is defined as: 
New appearance of measurable 
HBV-DNA 
Treat : Start first antiviral medication 
AND 
Interrupt Everolimus administration until resolution: 
 
≤ undetectable (negative) HBV-DNA levels 
If resolution occurs within ≤ 28 days, Everolimus should be re-
started at one dose lower, if available. If the patient is already 
receiving the lowest dose of Everolimus according to the protocol, 
the patient should restart at the same dose after resolution. Antiviral 
therapy should continue at least 4 weeks after last dose of 
Everolimus. 
If resolution occurs > 28 days Patients should discontinue 
Everolimus but continue antiviral therapy at least 4 weeks after last 
dose of Everolimus. 
* All reactivations of HBV are to be recorded as grade 3 (e.g. CTCAE Version 3.0 - Investigations/Other: 
Viral Reactivation), unless considered life threatening by the investigator, in which case they should be 
recorded as grade 4. Date of viral reactivation is the date on which the rise or reappearance of HBV-DNA 
was recorded. 


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Monitoring for hepatitis C flare 
The following two categories of patients should be monitored every 4–8 weeks for 
HCV flare: 
 Patients with detectable HCV RNA-PCR test at screening. 
 Patients known to have a history of HCV infection, despite a negative viral 
load test at screening (including those that were treated and are considered 
‘cured’) 
For definitions of HCV flare and actions to be taken in the event of a flare, please 
refer to the table below. 
 
Guidelines for the management of hepatitis C flare 
Baseline results 
HCV flare definition* 
HCV flare 
management 
Detectable HCV-RNA 
 
> 2 log10 IU/mL increase in HCV-RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher. 
Discontinue 
everolimus 
Knowledge of past 
hepatitis C infection with 
no detectable HCV-RNA 
New appearance of detectable HCV-RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher. 
Discontinue 
everolimus 
* All flares of HCV are to be recorded as grade 3 (e.g. CTCAE Version 3.0 - Investigations - 
Other: Viral Flare), unless considered life threatening by the investigator; in which case they 
should be recorded as grade 4. Date of viral flare is the date on which both the clinical criteria 
described above were met. (e.g., for a patient whose HCV-RNA increased by 2 logs on 01 JAN 
2011 and whose ALT reached > 5 x ULN on 22 JAN 2011, the date of viral flare is 22 JAN 
2011). 
 
5.3 
Concomitant Medications 
 
Patients must be instructed not to take any medications (over-the-counter or other products) 
during the protocol treatment period without prior consultation with the investigator. The 
investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of study drug. All medications (other than study drug) and 
significant non-drug therapies (including physical therapy and blood transfusions) taken 
within 28 days of starting study treatment through the 30-day safety follow up visit should 
be reported on the CRF. 
 
5.3.1 Cytochrome P450 and P-glycoprotein inhibitors/inducers/substrates 
 
Co-administration with strong inhibitors of CYP3A4 or PgP should be avoided; and 
may cause increased everolimus concentrations. For a current table of Substrates, 
Inhibitors and Inducers please access the following website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources
/DrugInteractionsLabeling/ucm093664.htm  
 


Protocol Version: 02/15/17 
 
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Everolimus is metabolized by CYP3A4 in the liver and to some extent in the 
intestinal wall. 
 
Therefore, the following are recommended: 
 Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, 
itraconazole, ritonavir) or P-glycoprotein (PgP) inhibitor should be avoided. 
 Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, 
fluconazole) or PgP inhibitors should be used with caution. If a patient 
requires co-administration of moderate CYP3A4 inhibitors or PgP 
inhibitors, reduce the dose of everolimus by approximately 50%. Additional 
dose reductions to every other day may be required to manage toxicities. If 
the inhibitor is discontinued, the everolimus dose should be returned to the 
dose used prior to initiation of the moderate CYP3A4/PgP inhibitor after a 
washout period of 2 to 3 days. 
 TSC with SEGA: Everolimus trough concentrations should be assessed 
approximately 2 weeks after the addition of a moderate CYP3A4/PgP 
inhibitor. If the inhibitor is discontinued the everolimus dose should be 
returned to the dose used prior to initiation of the inhibitor and the 
everolimus trough concentration should be re-assessed approximately 2 
weeks later. 
 
Grapefruit, Seville oranges, and starfruit affect P450 and PgP activity. 
Concomitant use should be avoided. 
 If patients require co-administration of a strong CYP3A4 inducer, consider 
doubling the daily dose of everolimus (based on pharmacokinetic data), 
using increments of 5 mg or less. This dose of everolimus is predicted to 
adjust the 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, consider a washout 
period of at least 3 to 5 days (reasonable time for significant enzyme de-
induction), before the everolimus dose is returned to the dose used prior to 
initiation of the strong CYP3A4 inducer. 
 TSC with SEGA Patients receiving concomitant strong CYP3A4 
inducers (e.g., the enzyme inducing antiepileptic drugs carbamazepine, 
phenobarbital, and phenytoin) may require an increased everolimus 
dose to attain trough concentrations of 3 to 15 ng/mL. Double the daily 
dose of everolimus and assess tolerability. Assess the everolimus trough 
level two weeks after doubling the dose. Further adjust the dose if 
necessary to maintain the trough within the 3 to 15 ng/mL range. If the 
strong inducer is discontinued, the everolimus dose should be returned 
to the dose used prior to initiation of the strong CYP3A4 inducer and 
the everolimus trough concentrations should be assessed approximately 
2 weeks later. 
 This dose adjustment of everolimus is intended to achieve similar AUC to 
the range observed without inducers. However, there are no clinical data 
with this dose adjustment in patients receiving strong CYP3A4 inducers. If 


Protocol Version: 02/15/17 
 
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the strong inducer is discontinued the everolimus dose should be returned 
to the dose used prior to initiation of the strong CYP3A4/PgP inducer. 
 
Please refer to the tables below listing relevant inducers and inhibitors of CYP3A 
and relevant substrates, inducers, and inhibitors of PgP. 
 
5.3.2 Everolimus and drugs influencing CYP3A4 enzyme 
 
Everolimus is a substrate of CYP3A4, and a substrate and moderate inhibitor of the 
multidrug efflux pump, PgP (PgP, MDR1, and ABCB1). Therefore, extent of 
absorption and subsequent elimination of systemically absorbed everolimus may 
be influenced by products that are substrates, inhibitors, or inducers of CYP3A4 
and/or PgP. Concurrent treatment with strong CYP3A4-inhibitors should be 
avoided. Refer to Table 6-2 in section 6 for a comprehensive list of inducers and 
inhibitors of CYP3A4 and Table 6-3 ]for a list of relevant substrates, inducers and 
inhibitors of PgP. Inhibitors of PgP may decrease the efflux of everolimus from 
brain or tumor and therefore increase everolimus concentrations in these tissues. In 
vitro studies showed that everolimus is a competitive inhibitor of CYP3A4 and of 
CYP2D6, potentially increasing the concentrations of products eliminated by these 
enzymes. Thus, caution should be exercised when co-administering everolimus 
with CYP3A4 and CYP2D6 substrates with a narrow therapeutic index. Clinical 
studies have been conducted in healthy subjects to assess pharmacokinetic drug 
interactions between everolimus and potential CYP3A modifiers (ketoconazole, 
verapamil, erythromycin, rifampin, midazolam, and HMGCoA reductase inhibitors 
(statins). Please refer to http://medicine.iupui.edu/clinpharm/ddis/main-table/ and 
the tables below. 
 
Clinically relevant drug interactions: inducers, and inhibitors of isoenzyme 
CYP3A 
Inducers 
Strong inducers: 
avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, 
rifampin (rifampicin), St. John's wort (hypericum perforatum) 
Moderate inducers: 
bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, ritonavir, 
[talviraline], thioridazine, tipranavir 
Weak inducers: 
amprenavir, aprepitant, armodafinil (R-modafinil), bexarotene, clobazam, 
danshen, dexamethasone, Echinacea, garlic (allium sativum), gingko (ginkgo 
biloba), 
glycyrrhizin, 
methylprednisolone, 
nevirapine, 
oxcarbazepine, 
pioglitazone, prednisone, [pleconaril], primidone, raltegravir, rufinamide, 
sorafenib, telaprevir, terbinafine, topiramate, [troglitazone] , vinblastine 


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Inhibitors 
Strong inhibitors: 
boceprevir, clarithromycin, cobicistat, conivaptan, elvitegravir, indinavir, 
itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, 
posaconazole (Krishna et al 2009), ritonavir, saquinavir, telaprevir, 
telithromycin, tipranavir, troleandamycin, voriconazole 
Moderate inhibitors: 
Amprenavir, aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, 
cyclosporine, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, 
fosamprenavir, grapefruit juice (citrus parasidi fruit juice), imatinib, schisandra 
sphenanthera, tofisopam, verapamil 
 
Clinically relevant drug interactions: substrates, inducers, inhibitors of PgP and 
PgP/CYP3A dual inhibitors 
Substrates 
colchicine, digoxin, fexofenadine, indinavir, paclitaxel, talinolol, topotecan, 
vincristine, everolimus 
Inducers 
rifampin, St John’s wort 
PgP Inhibitors and PgP/CYP3A Dual Inhibitors 
amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, 
diltiazem, dronedarone, elacridar, erythromycin, felodipine, fexofenadine, 
fluvoxamine, ginkgo (ginkgo biloba), indinavir, itraconazole, lopinavir, 
mibefradil, milk thistle (silybum marianum), nelfinavir, nifedipine, nitrendipine, 
paroxetine, quercetin, quinidine, ranolazine, rifampin, ritonavir, saquinavir, 
Schisandra chinensis, St John’s wort (hypericum perforatum), talinolol, 
Telaprevir, telmisartan, ticagrelor, tipranavir, tolvaptan, valspodar, verapamil 
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, 
updated Oct. 2, 2011,29-Oct-2012 which summarizes DDI data from three 
sources including the FDA’s “Guidance for Industry, Drug Interaction Studies”, 
the University of Washington’s Drug Interaction Database, and Indiana 
University School of Medicine's Drug Interaction Table. 
 
5.3.3 Vaccinations 
 
Immunosuppressants may affect the response to vaccination and vaccination during 
treatment with everolimus may therefore be less effective. The use of live vaccines 
should be avoided during treatment with everolimus. For pediatric patients with 
SEGA that do not require immediate treatment, complete the recommended 
childhood series of live virus vaccinations prior to the start of therapy according to 
local treatment guidelines. Examples of live vaccines are: intranasal influenza, 
measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a 
typhoid vaccines. 
 
5.4 
Women of Childbearing Potential 
 


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Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative serum pregnancy test within 14 days prior to the first dose of everolimus.   
 
Female and male patients (along with their female partners) are required to use highly 
effective contraception during participation in the study and for 8 weeks following the last 
dose of everolimus.  Highly effective contraception methods include a combination of any 
two of the following: 
 Use of oral, injected, or implanted hormonal methods of contraception 
 Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
 Barrier methods such as condom or occlusive cap (diaphragm or cervical/vault cap) 
with spermicidal foam/gel/film/cream/vaginal suppository 
 Total abstinence 
 Male/female sterilization 
 
If a patient is suspected to be pregnant, everolimus should be immediately discontinued.  
In addition a positive urine test must be confirmed by a serum pregnancy test.  If it is 
confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 8 weeks after the last dose of everolimus, the investigator must be notified in order 
to facilitate outcome follow-up. 
 
5.5 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue 
indefinitely until one of the following criteria applies: 
 
 Documented and confirmed disease progression 
 Death 
 Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
 General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 Suspected pregnancy 
 Serious noncompliance with the study protocol 
 Lost to follow-up 
 Patient withdraws consent 
 Investigator removes the patient from study 
 The Siteman Cancer Center decides to close the study 


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Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.6 
Duration of Follow-up 
 
Patients will be followed for 30 days after the last dose of everolimus or until death, 
whichever occurs first.  Patients removed from study for unacceptable adverse events will 
be followed until resolution or stabilization of the adverse event. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. Details of study treatment 
schedule adjustments and dose levels are provided below. 
 
Dose level 
Dose and schedule 
0 (starting dose) 
10 mg QD 
-1 
5 mg QD 
-2 
2.5 mg QD 
 
If a patient has already decreased 2 dose levels, no further dose reduction is permitted. Patients 
who need an additional dose reduction will be required to discontinue everolimus. 
 
Please refer to Section 5.3.1 for alternative dose modifications relating to concomitant 
medications. 
 
The tables below list the dosing guidelines for everolimus-related non-hematologic and 
hematologic toxicities.  
 
Management of severe or intolerable adverse drug reactions (ADRs) may require temporary dose 
interruption (with or without dose reduction) of everolimus therapy. If dose reduction is required, 
the suggested dose is approximately 50% lower than the daily dose previously administered. 
  
The proceeding sections summarize recommendations for dose interruption, reduction, or 
discontinuation of everolimus in the management of ADRs. General management 
recommendations are also provided as applicable. Clinical judgment of the treating physician 
should guide the management plan of each patient based on individual benefit/risk assessment. 


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Dosing guidelines for Everolimus-related non-hematologic toxicities 
Toxicity 
Action 
Non-Infectious Pneumonitis 
See Section 5.2.9 
Reactivation of HBV or HCV flare 
See Section 5.2.10 
AST or ALT elevation 
Grade 1 (> ULN - 3.0 x ULN) 
Grade 2 (> 3.0 - 5.0 x ULN) 
Maintain current dose level 
AST or ALT elevation 
Grade 3 (> 5.0 - 20.0 ULN)* 
Interrupt everolimus administration until resolution to ≤ grade 1 (or ≤ 
grade 2 if baseline values were within the range of grade 2). If 
resolution occurs ≤ 7 days, everolimus should be re-started at the dose 
level prior to interruption. 
 
If resolution takes > 7 days, or if event recurs within 28 days, hold 
everolimus until recovery to ≤ grade 1 or baseline grade / value and 
reintroduce everolimus at one dose level lower, if available. 
AST or ALT elevation 
Grade 4 (> 20 x ULN)* 
 
 
Interrupt everolimus administration until resolution to ≤ grade 1 (or ≤ 
grade 2 if baseline values were within the range of grade 2). If 
resolution occurs ≤ 7 days, everolimus should be re-started at one dose 
level lower. If resolution takes > 7 days, discontinue everolimus. 
Recurrence of grade 4 AST or ALT 
elevation after dose reduction or 
toxicity requiring everolimus 
interruption for > 28 days 
Discontinue everolimus. 
Intolerable grade 2 mucositis, or grade 
3 AE, except hyperglycemia or 
hypertriglyceridemia or 
hypercholesterolemia (see Section 
5.2.8) 
Interrupt everolimus administration until resolution to ≤ grade 1 or 
baseline grade / value. 
 
If resolution occurs within ≤ 7 days, everolimus should be re-started at 
the dose level prior to interruption. 
 
If resolution takes > 7 days, or if event recurs within 28 days, hold 
everolimus until recovery to ≤ grade 1 or baseline grade / value and 
reintroduce everolimus at one dose level lower, if available. 
 
Patients will be withdrawn from the study if they fail to recover to  
grade 1 or baseline grade / value within 28 days. 
Any other grade 4 
Hold everolimus until recovery to grade  1 or baseline value 
Reintroduce everolimus at one dose level lower, if available. 
Grade 3 or 4 clinical liver failure 
(asterixis or encephalopathy/coma) 
Discontinue everolimus 
Recurrence of intolerable grade 2 
mucositis or grade 3 event after dose 
reduction 
Reduce dose to the next lower dose level, if available. The lowest 
possible dose level of everolimus is 2.5 mg daily. Below this level, 
everolimus must be discontinued. If toxicity recurs at Grade 3, consider 
discontinuation 
Recurrence of grade 4 after dose 
reduction 
Discontinue everolimus 
Any non-hematologic toxicity 
requiring everolimus interruption for > 
28 days 
Discontinue everolimus 
* Should HCV flare be confirmed, the guidelines for flare must take precedence 


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Dosing guidelines for Everolimus-related hematologic toxicities 
Toxicity 
Action 
Grade 3 thrombocytopenia, neutropenia, 
or anemia 
Interrupt everolimus until resolution to grade 1  
 
If resolution occurs ≤ 7 days, reintroduce everolimus at the dose 
level prior to interruption. 
 
If resolution occurs > 7 days, or event occurs within 28 days, 
reintroduce everolimus at one dose level lower, if available. 
Grade 4 thrombocytopenia, neutropenia, 
or anemia 
Interrupt everolimus until recovery to grade  1. Then reintroduce 
everolimus at one dose level lower, if available. 
Febrile neutropenia 
Interrupt everolimus until resolution to grade  1 (or baseline value) 
and no fever. Reintroduce everolimus at one dose level lower, if 
available.* 
Recurrence of grade 3 toxicity after dose 
reduction 
Reduce dose to the next lower dose level, if available. The lowest 
possible dose level of everolimus is 5 mg every other day (2.5 mg 
daily). Below this level, everolimus must be discontinued. 
*Recurrence of grade 4 toxicity 
(including febrile neutropenia) after dose 
reduction 
Discontinue everolimus 
*Any hematologic toxicity requiring 
Everolimus interruption for > 28 days 
Discontinue everolimus 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined 
in Section 7.2. 
 
Novartis Pharmaceuticals requires that every SAE regardless of suspected causality that occurs 
after the patient has provided consent and after protocol-specified procedures have begun be 
reported as outlined in Section 7.4. 
 
7.1 
Definitions 
 
7.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
all toxicity reporting.  A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 


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terms listed that should be used are those provided by the Department of Health 
and Human Services’ Office for Human Research Protections (OHRP).  A copy of 
this 
guidance 
can 
be 
found 
on 
OHRP’s 
website:  
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
7.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above 
 
7.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
7.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 
7.1.5 Unanticipated Problems 
 
Definition: 
 
 unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) 
the characteristics of the subject population being studied; 
 related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and 
 suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 


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previously known or recognized. 
 
7.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
7.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
7.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event.   
 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
 Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
 Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
 Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 


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reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
7.4 
Reporting to Novartis 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
 after the patient has provided informed consent and until at least 30 days after the 
patient has stopped study treatment/participation 
 after protocol-specified procedures begin (e.g., placebo run-in, washout period, 
double-blind treatment, etc.) and 30 days after the patient has stopped study 
treatment 
 after the start of any period in which the study protocol interferes with the standard 
medical treatment given to a patient (e.g., treatment withdrawal during washout 
period, change in treatment to a fixed dose of concomitant medication) and until 30 
days after the patient has stopped study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence (fax: 
877-778-9739). This includes serious, related, not related, labeled (expected) and 
unlabeled (unexpected) adverse experiences. All deaths during treatment or within 
30 days following completion of active protocol therapy must be reported within 
24 hours. 
 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the 
original episode within 24 hours of the investigator receiving the follow-up information. A 
SAE occurring at a different time interval or otherwise considered completely unrelated to 
a previously reported one should be reported separately as a new event.  The end date of 
the first event must be provided. 
 
The original copy of the SAE Report and the fax confirmation sheet must be kept within 
the Trial Master File at the study site. 
 
Follow-up information is sent to the same fax number as the original SAE Report Form 
was sent, using a new fax cover sheet, stating that this is a follow-up to the previously 
reported SAE, and giving the date of the original report. Each re-occurrence, complication, 
or progression of 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 Everolimus Investigator Brochure or 
Package Insert (new occurrence) and is thought to be related to the Novartis study drug, a 
DS&E associate may urgently require further information from the investigator for Health 


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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. 
 
7.4.1 Pregnancy 
 
Preclinical data regarding reproductive toxicity is described in the most recent 
Investigator Brochure. The potential reproductive risk for humans is unknown.  
Women of childbearing potential should be advised to use highly effective 
contraception methods while they are receiving everolimus and up to 8 weeks after 
treatment has been stopped.   
 
To ensure patient safety, each pregnancy occurring while the patient is on study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications. 
The newborn will be followed for at least 12 months. 
 
7.5 
Timeframe for Reporting Required Events  
 
Adverse events will be tracked for 30 days following the last day of study treatment. 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Everolimus 
 
8.1.1 Everolimus Description 
 
Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and an 
antineoplastic agent. 
 
Chemical name: 
(1R,9S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-
12{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-
methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-
tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone. 
 
Molecular formula: C53H83NO14 
 
Molecular weight: 958.2 
 
8.1.2 Clinical Pharmacology 


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Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-
threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is 
dysregulated in several human cancers. Everolimus binds to an intracellular protein, 
FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 
(mTORC1) and thus inhibition of mTOR kinase activity. Everolimus reduced the 
activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 
4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein 
synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the activation 
domain 1 of the estrogen receptor which results in ligand-independent activation of 
the receptor. In addition, everolimus inhibited the expression of hypoxia-inducible 
factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth 
factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell 
proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies. 
 
Constitutive activation of the PI3K/Akt/mTOR pathway can contribute to 
endocrine resistance in breast cancer. In vitro studies show that estrogen-dependent 
and HER2+ breast cancer cells are sensitive to the inhibitory effects of everolimus, 
and that combination treatment with everolimus and Akt, HER2, or aromatase 
inhibitors enhances the anti-tumor activity of everolimus in a synergistic manner. 
 
Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-
sclerosis complexes 1 and 2 (TSC1, TSC2). Loss or inactivation of either TSC1 or 
TSC2 leads to activation of downstream signaling. In TSC, a genetic disorder, 
inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma 
formation throughout the body.  
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
After administration of everolimus tablets in patients with advanced solid tumors, 
peak everolimus concentrations are reached 1 to 2 hours after administration of oral 
doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-
proportional with daily dosing between 5 mg and 10 mg. With single doses of 20 
mg and higher, the increase in Cmax is less than dose-proportional, however AUC 
shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was 
achieved within 2 weeks following once-daily dosing. 
 
Dose Proportionality in Patients with SEGA and TSC: In patients with SEGA and 
TSC, everolimus Cmin was approximately dose-proportional within the dose range 
from 1.35 mg/m2 to 14.4 mg/m2. 
 
Food effect: In healthy subjects, high-fat meals reduced systemic exposure to 
everolimus 10 mg tablet (as measured by AUC) by 22% and the peak blood 
concentration Cmax by 54%. Light-fat meals reduced AUC by 32% and Cmax by 
42%. Food, however, had no apparent effect on the post absorption phase 
concentration-time profile.  


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The blood-to-plasma ratio of everolimus, which is concentration-dependent over 
the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined 
to the plasma is approximately 20% at blood concentrations observed in cancer 
patients given everolimus 10 mg/day. Plasma protein binding is approximately 74% 
both in healthy subjects and in patients with moderate hepatic impairment.  
 
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, 
everolimus is the main circulating component in human blood. Six main 
metabolites of everolimus have been detected in human blood, including three 
monohydroxylated metabolites, two hydrolytic ring-opened products, and a 
phosphatidylcholine conjugate of everolimus. These metabolites were also 
identified in animal species used in toxicity studies, and showed approximately 
100-times less activity than everolimus itself. 
 
In vitro, everolimus competitively inhibited the metabolism of CYP3A4 and was a 
mixed inhibitor of the CYP2D6 substrate dextromethorphan.  
 
No specific elimination studies have been undertaken in cancer patients. Following 
the administration of a 3 mg single dose of radiolabeled everolimus in patients who 
were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, 
while 5% was excreted in the urine. The parent substance was not detected in urine 
or feces. The mean elimination half-life of everolimus is approximately 30 hours.  
 
8.1.4 Supplier(s) 
 
Everolimus will be provided by Novartis Pharmaceuticals. 
 
8.1.5 Dosage Form and Preparation 
 
Everolimus is formulated as tablets for oral administration of 2.5 mg, 5 mg, and 10 
mg strength.  Tablets are blister-packed under aluminum foil, which should be 
opened only at the time of administration as the drug is both hygroscopic and light-
sensitive. 
 
8.1.6 Storage and Stability 
 
Store at 25°C (77°F); excursions permitted between 15°C-30°C (59°-85°F).  Store 
in the original container.  Protect from light and moisture. 
 
8.1.7 Administration 
 
Everolimus is an oral drug which will be administered on an outpatient basis at a 
dose of 10 mg daily.   
 
8.1.8 Special Handling Instructions 


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The extent of absorption of everolimus through topical exposure is not known.  
Therefore, caregivers are advised to avoid contact with suspensions of tablets.  
Wash hands thoroughly before and after preparation of either suspension. 
 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Archived Tumor Tissue 
 
If mutational testing has not already been performed, next generation sequencing and 
screening for mutations in TSC1, TSC2, NF1, NF2 and STK11 will be performed on 
archived formalin-fixed paraffin-embedded (FFPE) tumor tissue as part of the patient’s 
routine care at any qualifying CLIA-certified laboratory that reports clinical next-
generation sequencing of these genes.  If the archival tissue does not have adequate viable 
cells for next generation sequencing to be performed, a fresh biopsy may be done prior to 
initiation of treatment.  This is being done as part of routine care, and only patients who 
show a mutation in TSC1, TSC2, NF1, NF2 and STK11 may enroll to the study. 
 
9.2 
Fresh Tumor Biopsy 
 
9.2.1 Collection of Specimen(s) 
 
Accessible lesions that clearly show progression will be biopsied using standard of 
care parameters at the time of progression. 
 
9.2.2 Handling of Specimen(s) 
 
Collect and place in normal saline for delivery to the Siteman Cancer Center Tissue 
Procurement Core. 
 
 
 


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10.0 
STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy.  Scans 
and x-rays must be done no more than 28 days prior to the start of the protocol therapy.  All visits 
have a window of +/- 3 days. 
 
 
Screening 
Day 1 
of each 
cycle 
End of every 
even-numbered 
cycle 
End of 
treatment 
Follow-
up4 
Informed consent 
X 
 
 
 
 
H&P, ECOG PS, weight 
X 
 
 
X 
 
CBC 
X 
X6 
 
X 
 
CMP 
X 
X6 
 
X 
 
Hepatitis B and C testing 
X 
 
 
 
 
Lipid panel5 
X 
 
 
 
 
INR 
X 
 
 
 
 
HbA1c 
X 
 
 
 
 
Pregnancy test1 
X 
 
 
 
 
Standard of care imaging 
X 
 
X 
X 
 
Archival tissue for TSC1, 
TSC2, NF1, NF2 and STK11 
mutations7 
X 
 
 
 
 
Fresh tissue for research 
purposes 
 
 
 
X3 
 
Everolimus 
 
X ------------------ X2 
 
 
Adverse event assessment 
X ------------------------------------------------------------- X 
Concomitant medications 
X -------------------------------------------------- X 
 
1. Women of childbearing potential only 
2. To be taken PO QD 
3. At time of progression, biopsy of accessible lesions showing progression will be done 
4. 30 days post-EOT 
5. Should be performed periodically during treatment at the discretion of the treating physician 
6. If screening labs are performed within 3 days prior to C1D1, the labs do not need to be repeated 
7. Mutation testing can be done at any point prior to study enrollment 
 
 


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11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Tumor Biopsy Form 
Prior to starting treatment 
Treatment Form 
Every cycle 
Toxicity Form 
Concomitant Medications Form Continuous 
Treatment Summary Form 
Tumor Biopsy Form 
Completion of treatment 
Follow Up Form 
30 days after end of treatment 
Tumor Measurement Form 
Baseline, end of every even numbered 
cycles, and end of treatment 
Adverse Events Form 
See Section 7.0 for reporting requirements 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained 8 weeks (not less 
than 4) weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
12.2 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 


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Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
12.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 


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Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a PET-
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then 
the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 


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recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
 
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
 No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
 FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 


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12.4 
Response Criteria 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
12.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
12.4.3 Evaluation of Best Overall Response 
 


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The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
12.4.4 Duration of Response 
 


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Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or one 
year after accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least monthly and provide a semi-annual 
report to the Quality Assurance and Safety Monitoring Committee (QASMC).  This report will 
include: 
 HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
 Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
 History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
 Study-wide target accrual and study-wide actual accrual 
 Protocol activation date 
 Average rate of accrual observed in year 1, year 2, and subsequent years 
 Expected accrual end date  
 Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
 Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
 Summary of toxicities 
 Abstract submissions/publications 
 Summary of any recent literature that may affect the safety or ethics of the study  
 


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The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Study Design 
 
This is an open label, single-arm phase II trial focusing on the response rate of the 
therapeutic agent. Since this is a study in patients with specifically targeted mutations, a 
rather big treatment effect size is expected. Based on historical data, we assume a null 
hypothesis of an overall response rate of <1% in this setting.9 We hypothesize that an 
overall response rate of 30% or higher warrants further investigation.    A total of N=12 
patients will be enrolled for this study, based on the exact single-stage design with 85% 
power at a 1-sided 0.05 significance level (using ph2single function from library clinfun in 
the R package). If 2 or more responders are observed out of these 12 patients, we would 
conclude that preliminary evidence for efficacy exists and that further investigation of the 
treatment is warranted. 
 
14.2 
Data Analysis 
 
The primary endpoint will be to describe the response rate using RECIST 1.1. Response 
rate will be defined as complete response (disappearance of all target lesion) plus partial 
response (a least a 30% decrease in the sum of diameters of target lesions). Secondary 
endpoint will be to further evaluate molecular markers of response or resistance using 
exome sequencing and transcriptome sequencing when feasible. 
 
Demographic and clinical characteristics of the sample, as well as response, and toxicity 
by grade will be summarized using descriptive statistics. The overall response rate and its 
90% confidence interval will be estimated.  If possible, permutation tests will also be 
performed to compare the differences of secondary endpoints between responders and non-
responders. The distribution associated with no difference (the null distribution) can be 
identified using the data in hand. If there is no difference between the values seen in 
responders and those in non-responders, then, for this purpose, it does not matter whether 
a given patient is labeled as a responder or a nonresponder. So we can randomly shuffle 
the response labels and calculate the test statistic from the shuffled data. If this procedure 
is repeated 10,000 times, the resulting 10,000 test statistics provide an accurate 
representation of the null distribution. The observed test statistic, based on patients 
assigned to the correct response group, is then compared to the null distribution. If the 
observed test statistic is unusually large or small, so very few values from the null 
distribution are larger or smaller than the observed test statistic, then the observed 
difference between responders and non-responders is unlikely if the null hypothesis were 
correct. In that case, we can reject the null hypothesis of no difference and conclude that 
there is a true difference between responders and non-responders. Then the null distribution 


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of the test statistics will be generated by simulating 10,000 datasets where the status of 
response was randomly shuffled. In order to quantify the extent to which the observed test 
statistic is “unusual,” a permutation test generates a p-value, which is equal to the 
proportion of test statistics from the label-shuffled samples that exceed the observed test 
statistics. 
 
 
 
 
 


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15.0 
REFERENCES 
 
1. 
Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000;103:253-62. 
2. 
Wislez M, Spencer ML, Izzo JG, et al. Inhibition of mammalian target of rapamycin 
reverses alveolar epithelial neoplasia induced by oncogenic K-ras. Cancer Res 2005;65:3226-35. 
3. 
Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia-inducible factor 1alpha 
expression and function by the mammalian target of rapamycin. Mol Cell Biol 2002;22:7004-14. 
4. 
Ma BB, Lui VW, Hui EP, et al. The activity of mTOR inhibitor RAD001 (everolimus) in 
nasopharyngeal carcinoma and cisplatin-resistant cell lines. Invest New Drugs 2010;28:413-20. 
5. 
Huynh H, Chow KH, Soo KC, et al. RAD001 (everolimus) inhibits tumour growth in 
xenograft models of human hepatocellular carcinoma. J Cell Mol Med 2009;13:1371-80. 
6. 
Chu C, Noel-Hudson MS, Boige V, et al. Therapeutic efficiency of everolimus and 
lapatinib in xenograft model of human colorectal carcinoma with KRAS mutation. Fundam Clin 
Pharmacol 2013;27:434-42. 
7. 
Liakakos T, Roukos DH. Everolimus and sunitinib: from mouse models to treatment of 
pancreatic neuroendocrine tumors. Future Oncol 2011;7:1025-9. 
8. 
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. 
9. 
Iyer G, Hanrahan AJ, Milowsky MI, et al. Genome sequencing identifies a basis for 
everolimus sensitivity. Science 2012;338:221. 
10. 
 Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched 
evolution revealed by multiregion sequencing. The New England journal of medicine 
2012;366:883-92. 
11. 
 Ding L, Ley TJ, Larson DE, et al. Clonal evolution in relapsed acute myeloid leukaemia 
revealed by whole-genome sequencing. Nature 2012;481:506-10. 
12. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor 
receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. The New England 
journal of medicine 2004;350:2129-39. 
13. 
 Fong T, Morgensztern D, Govindan R. EGFR inhibitors as first-line therapy in advanced 
non-small cell lung cancer. Journal of thoracic oncology : official publication of the International 
Association for the Study of Lung Cancer 2008;3:303-10. 
14. 
 Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-
line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung 
cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. The lancet oncology 
2012;13:239-46. 
15. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of 
lung cancers acquiring resistance to EGFR inhibitors. Science translational medicine 
2011;3:75ra26. 
16. Piantadosi S. Translational clinical trials: an entropy-based approach to sample size. Clinical 
trials 2005;2:182-92. 
 
 
 


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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 


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APPENDIX B: PATIENT’S MEDICATION DIARY 
Today’s Date:    
 
 
 
 
 
 
Agent:  Everolimus 
 
Cycle:    
 
 
 
 
 
 
 
 
 
Patient Name:    
 
 
 
 
 
 
Study ID#:   
 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take ___ mg ( ___pills) of everolimus at approximately the same time 
every day, either consistently with or consistently without food.  Take it with a glass of water and drink the glass 
of water in as little time as possible.  Swallow the pills whole and do not chew them. 
2. Record the date, the number of pills taken, and when you took them. 
3. If you forgot to take your dose before 6:00PM, then do not take a dose that day.  Restart taking it the next day. 
4. If you have any questions or notice any side effects, please record them in the comments section.  Record the 
time if you should vomit. 
5. Please return the forms to your physician or your study coordinator when you go to your next appointment.  
Bring your unused pills and/or empty bottles with you to each clinic visit so that a pill count can be done. 
Day 
Date 
What time was 
dose taken? 
# of pills taken 
 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
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24 
 
 
 
 
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28