Clinical trial NCT02539459
Conditions: Sporadic Angiomyolipomas (AMLs)
Sponsor: Fox Chase Cancer Center
Start date: 2015-09-23; Completion date: 2018-08-20
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this research study is to see if oral everolimus is tolerable and effective in the treatment of sporadic Angiomyolipomas (AMLs). AMLs are the most common non-cancerous tumor of the kidney. They are composed of blood vessels, muscle cells and fat cells.Everolimus is already an approved drug for several other diseases like kidney cancer, but is being studied now specifically to see if it is helpful for people with AML.

Detailed description:
Primary Objective

1\. To evaluate the efficacy and tolerability of everolimus in reducing tumor volume in sporadic AMLs as measured by dynamic contrast enhanced magnetic resonance imaging (DCE MRI), in patients who might otherwise be considered for active surgical or percutaneous intervention.

Secondary Objectives

1. To evaluate health-related quality of life (HRQoL) in subjects treated with everolimus for sporadic AMLs.
2. To assess the growth kinetics of sporadic AMLs in patients who have been treated with everolimus as part of the study and demonstrate an objective response as well as those who have been treated with everolimus during the study with a suboptimal or no response.
3. To measure the rate of surgical or percutaneous (embolization) intervention at 1 year from day 1 of study.
4. To assess the safety and tolerability of everolimus in patients with sporadic AML.

Arms: arm 1: Patients will take 10 mg (1 tablet) of everolimus each day for 4 months
Interventions: intervention 1: Everolimus
Intervention descriptions: intervention 1: 10 mg tablets

Protocol documents:
Prot_SAP_000.pdf: 
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A Phase II study of Sporadic Angiomyolipomas (AMLs) Growth Kinetics while on 
Everolimus Therapy (SAGE) 
 
Supported by: Novartis Pharmaceuticals 
 
Sponsor Investigator: 
Robert Uzzo, M.D. 
Fox Chase Cancer Center 
333 Cottman Avenue 
Department of Surgical Oncology 
Philadelphia PA 19111 
Phone: 215-728-3096 
Email: robert.uzzo@fccc.edu  
 
Co-Investigators: 
Daniel M. Geynisman, M.D. 
Fox Chase Cancer Center  
333 Cottman Avenue 
Department of Medical Oncology 
Philadelphia, PA 19111 
Phone 215-728-3889 
Email: daniel.geynisman@fccc.edu 
 
Barton Milestone, M.D. 
Fox Chase Cancer Center  
333 Cottman Avenue 
Department of Medical Oncology 
Philadelphia, PA 19111 
Phone 215-728-3024 
Email: Barton.Milestone@fccc.edu  
 
 
 
 
 
 
 
 
 
 
 


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Radiologists: 
Rosaleen Parsons, M.D. 
Fox Chase Cancer Center  
333 Cottman Avenue 
Department of Medical Oncology 
Philadelphia, PA 19111 
Phone 215-728-3024 
Email: rosaleen.parsons@fccc.edu   
 
Barton Milestone, M.D. 
Fox Chase Cancer Center  
333 Cottman Avenue 
Department of Medical Oncology 
Philadelphia, PA 19111 
Phone 215-728-3024 
Email: Barton.Milestone@fccc.edu  
 
Statistician: 
Eric Ross, PhD 
Fox Chase Cancer Center 
333 Cottman Avenue 
Biostatistics/Bioinformatics and Population Studies Facilities 
Philadelphia PA 19111 
Phone: 215-728-2891 
Email: eric.ross@fccc.edu   
 
Version Date:   4/24/2015 
Amendment 1: 7/30/2015 
Amendment 2: 03/28/2017 
 


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Table of Contents 
Table of Contents ............................................................................................................................ 3 
Study Schema.................................................................................................................................. 6 
1.0 Introduction ............................................................................................................................... 7 
 
Background ...................................................................................................................... 7 
 
Agent under Investigation ................................................................................................ 7 
 
mTOR pathway and cancer .............................................................................................. 8 
 
Non-clinical experience.................................................................................................... 8 
 
Study Rationale .............................................................................................................. 10 
2.0 Objectives ................................................................................................................................ 11 
 
Primary Objective .......................................................................................................... 11 
 
Secondary Objectives ..................................................................................................... 11 
 
Exploratory Objectives ................................................................................................... 11 
3.0 Study Plan ............................................................................................................................... 12 
4.0 Patient Selection ...................................................................................................................... 12 
 
Inclusion Criteria ............................................................................................................ 12 
 
Exclusion Criteria ........................................................................................................... 13 
 
Inclusion of Women and Minorities............................................................................... 16 
 
Participant Registration .................................................................................................. 16 
5.0 Treatment Plan ........................................................................................................................ 17 
 
Treatment Administration Tables................................................................................... 17 
 
Duration of Therapy ....................................................................................................... 17 
 
Duration of Follow up .................................................................................................... 17 
 
Criteria for Discontinuation ........................................................................................... 17 
 
Optional Tissue and Blood Collection for Exploratory Objectives ............................... 18 
6.0 Dosing, Toxicity and Specific Adverse Events ...................................................................... 18 
 
Dosing regimen .............................................................................................................. 18 
 
Description of selected adverse drug reactions .............................................................. 19 
 
Dose modifications ......................................................................................................... 19 
6.3.1. 
Dose adjustments and dose levels: .......................................................................... 19 
6.3.2. 
Non-hematologic toxicities ..................................................................................... 20 
6.3.3. 
Hematologic toxicities ............................................................................................ 21 
6.3.4. 
Non-infectious Pneumonitis.................................................................................... 22 
 
Management of specific toxicities.................................................................................. 23 


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6.4.1. 
Hepatitis B Reactivation ......................................................................................... 23 
6.4.2. 
Infections................................................................................................................. 23 
6.4.3. 
Skin Toxicity ........................................................................................................... 23 
6.4.4. 
Stomatitis / Oral Mucositis / Mouth Ulcers ............................................................ 23 
6.4.5. 
Diarrhea................................................................................................................... 24 
6.4.6. 
Hyperlipidemia, Hypertriglyceridemia and Hyperglycemia ................................... 24 
6.4.7. 
Non-infectious Pneumonitis.................................................................................... 25 
 
Fertility ........................................................................................................................... 25 
7.0 Study Agent Information ........................................................................................................ 26 
 
Everolimus Formulation, Product identification, Package and Labeling....................... 26 
 
Availability ..................................................................................................................... 27 
 
Drug Ordering, Storage and Handling ........................................................................... 27 
 
Destruction of Drug ........................................................................................................ 27 
 
Records to be kept at Site; Dispensing and Accountability ........................................... 27 
8.0 Study Calendar ........................................................................................................................ 28 
9.0 Adverse Events ....................................................................................................................... 29 
 
Definitions ...................................................................................................................... 29 
9.1.1. 
Adverse event (AE)................................................................................................. 29 
9.1.2. 
Serious Adverse Event (SAE) ................................................................................. 29 
9.1.3. 
Severity Rating........................................................................................................ 29 
9.1.4. 
Attribution/Relationship to study drug ................................................................... 29 
9.1.5. 
Expectedness ........................................................................................................... 30 
10.0 Recording and Reporting Responsibilities ............................................................................ 30 
 Site Recording responsibilities: ...................................................................................... 30 
 Site Reporting responsibilities: ...................................................................................... 30 
 Sponsor Reporting Responsibilities: .............................................................................. 31 
 Pregnancy ....................................................................................................................... 32 
11.0 Measures of Effect ................................................................................................................ 33 
 Response Evaluation Utilizing DCE-MRI ..................................................................... 33 
 Methods for Evaluation of Disease ................................................................................ 33 
 Response Criteria ........................................................................................................... 33 
 Health Related Quality of Life ....................................................................................... 34 
 Serum Corrrelatives........................................................................................................ 34 
12.0 Statistical Considerations ...................................................................................................... 34 


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 Study Design/Endpoints ................................................................................................. 34 
 Sample Size/Accrual Rate .............................................................................................. 35 
13.0 Data and Safety Monitoring Plan .......................................................................................... 35 
 Monitoring Plan.............................................................................................................. 35 
 Data Safety Monitoring Committee ............................................................................... 36 
14.0 Administrative ....................................................................................................................... 36 
 Data Reporting ............................................................................................................... 36 
 Retention of Records ...................................................................................................... 36 
 Study Agents .................................................................................................................. 37 
 Informed Consent ........................................................................................................... 37 
Appendix I: NYHA Classification ................................................................................................ 38 
Appendix II: Child-Pugh Criteria ................................................................................................. 39 
Appendix III: FACT FKSI-19 Questionnaire ............................................................................... 40 
Appendix IV: Novartis SAE Fax Covers ...................................................................................... 41 
15.0 References ............................................................................................................................. 43 
 
 
 


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Study Schema 
 
 
 
43 eligible patients with > 3cm 
sporadic AML  
Everolimus 10 mg po QD for 4, 28 
day cycles with dose adjustments 
per protocol 
 
Assess tumor size and volume with 
DCE MRI  
<25% volume reduction 
> 25% volume reduction 
Discontinue everolimus 
Continue Everolimus 10mg po, or 
adjusted dose per protocol QD x2 
more cycles then discontinue 
Assess size, volume, vascularity 
with DCE MRI  
DCE MRI after 6 cycles and 12 months 
after day 1 of everolimus 


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1.0 Introduction 
 
Background 
Renal angiomyolipomas (AMLs) are the most common benign tumors of the kidney1.  
They are composed of varying proportions of aneurysmal vascular cells, immature 
smooth muscle cells and fat cells. Clinically, the most worrisome aspect of AMLs is 
their propensity to rupture or spontaneously and bleed causing pain and occasionally 
acute life-threatening hemorrhage with up to 20% of patients presenting to the 
emergency room already in shock due to retroperitoneal bleeding1.  The risk of this 
appears to be directly proportionate to the size of the lesion.  This has led to the current 
clinical standard of care of surgical or percutaneous intervention (embolization) for 
patients with asymptomatic sporadic AMLs > 3-4 cm1.  These interventions are not 
without risk and can lead to renal loss in the affected kidney with the long-term risk of 
chronic kidney disease/end-stage renal disease. 
 
While sporadic AMLs are common, particularly in middle aged women, bilateral 
multifocal AMLs are strongly associated with tuberous sclerosis and exhibit constitutive 
activation of mammalian target of rapamycin (mTOR)2.  
 
In this population, a recent double blinded, placebo controlled phase III trial (EXIST-2) 
was performed in patients aged 18 years or older with at least one AML 3 cm or larger 
in its longest diameter.  Patients were randomly assigned, in a 2:1 fashion to receive 
everolimus 10 mg per day or placebo. The primary efficacy endpoint was the proportion 
of patients with confirmed response of at least a 50% reduction in total volume of target 
angiomyolipomas relative to baseline.  In the most updated analysis presented by Bissler 
at the 2014 World TSC Conference (unpublished), the authors noted an AML response 
rate of 53.6% for everolimus and 0% for placebo with an acceptable safety profile 
demonstrating a non-surgical treatment for AMLs associated with tuberous sclerosis2.  
On the basis of this trial, mTOR inhibitors have been felt to be effective in reducing the 
size of AMLs in patients with tuberous sclerosis complex (TSC) leading to a recent FDA 
approval for everolimus for AMLs in this population. 
 
While there have been some case reports using mTOR inhibitors for advanced AMLs34, 
there have been no prospective trials assessing outcomes and growth inhibition in 
sporadic AMLs in non-tuberous sclerosis populations. Here we propose to investigate 
the use of everolimus in a population of patients with sporadic AMLs who would 
otherwise be advised to undergo surgical or percutaneous intervention.  
 
 
Agent under Investigation 
Everolimus is a derivative of rapamycin which acts as a signal transduction inhibitor.  
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 cancers5.  
 


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Everolimus is being investigated as an antitumoral agent based on its potential to act 
directly on the tumor cells by inhibiting tumor cell growth and proliferation and 
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). 
 
 
mTOR pathway and cancer 
At the cellular and molecular level, everolimus acts as a signal transduction inhibitor. It 
selectively inhibits mTOR, 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 tumors, including AMLs. Various preclinical models have confirmed 
the role of this pathway in tumor development. 
 
The main known functions of mTOR include the following6: 
 
 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 cancers7 
 The loss of PTEN protein, either through gene deletion or functional silencing 
(promoter hypermethylation), is reported in approximately 60% of primary 
human colorectal cancers8 
 The mTOR pathway is involved in the production of pro-angiogenic factors (i.e., 
VEGF) and inhibition of endothelial cell growth and proliferation 
 Through inactivating eukaryotic initiation factor 4E binding proteins and 
activating the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates protein 
translation, including the HIF-1 proteins. Inhibition of mTOR is expected to lead 
to decreased expression of HIF-1 
 
 
Non-clinical experience 
Everolimus inhibits the proliferation of a range of human tumor cell lines in vitro 
including cell lines originating from lung, breast, prostate, colon, melanoma, and 
glioblastoma. IC50s range from sub/low nM to µM. Everolimus also inhibits the 


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proliferation of human umbilical vein endothelial cells (HUVECS) in vitro, with 
particular potency against VEGF-induced proliferation suggesting that everolimus may 
also act as an anti-angiogenic agent. The anti-angiogenic activity of everolimus was 
confirmed in vivo. Everolimus selectively inhibited VEGF-dependent angiogenic 
response at well tolerated doses. Mice with primary and metastatic tumors treated with 
everolimus showed a significant reduction in blood vessel density when compared to 
controls. 
 
The potential of everolimus as an anti-cancer agent was shown in rodent models. 
Everolimus is orally bioavailable, residing longer in tumor tissue than in plasma in a 
subcutaneous mouse xenograft model, and demonstrating high tumor penetration in a rat 
pancreatic tumor model. The pharmacokinetic profile of everolimus indicates sufficient 
tumor penetration, above that needed to inhibit the proliferation of endothelial cells and 
tumor cell lines deemed sensitive to everolimus in vitro. 
 
Everolimus administered orally daily was a potent inhibitor of tumor growth, at well 
tolerated doses, in 11 different mouse xenograft models (including pancreatic, colon, 
epidermoid, lung and melanoma) and two syngeneic models (rat pancreatic, mouse 
orthotopic melanoma). These models included tumor lines considered sensitive and 
“relatively resistant” in vitro. In general, everolimus was better tolerated in mouse 
xenograft models than standard cytotoxic agents (i.e., doxorubicin and 5-fluorouracil), 
while possessing similar anti-tumor activity. Additionally, activity in a VEGF-
impregnated subcutaneous implant model of angiogenesis and reduced vascularity 
(vessel density) of everolimus-treated tumors (murine melanoma) provided evidence of 
in vivo effects of angiogenesis. 
 
It is not clear which molecular determinants predict responsiveness of tumor cells to 
everolimus. Molecular analysis has revealed that relative sensitivity to everolimus in 
vitro correlates with the degree of phosphorylation (activation) of the AKT/PKB protein 
kinase and the S6 ribosomal protein; in some cases (i.e., glioblastoma) there is also a 
correlation with PTEN status. 
 
In vivo studies investigating the anti-tumor activity of everolimus in experimental 
animal tumor models showed that everolimus monotherapy typically reduced tumor cell 
growth rates rather than produced regressions. These effects occurred within the dose 
range of 2.5 mg to 10 mg/kg, orally once a day. 
 
In preclinical models, the administration of everolimus is associated with reduction of 
protein phosphorylation in target proteins downstream of mTOR, notably 
phosphorylated S6 (p-S6) and p-4E-BP1, and occasionally with an increase in 
phosphorylated AKT, a protein upstream of mTOR signaling pathway.  
 
All significant adverse events observed in toxicology studies with everolimus in mice, 
rats, monkeys and mini-pigs were consistent with its anticipated pharmacological action 
as an anti-proliferative and immunosuppressant and at least in part reversible after a 2 or 


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4-week recovery period with the exception of the changes in male reproductive organs, 
most notably testes. 
 
 
Study Rationale  
In a randomized trial evaluating 118 patients from 24 centers with a known history of 
TSC or sporadic lymphangioleiomyomatosis (LAM) (EXIST-2), patients were 
randomized 2:1 to receive everolimus (n=79) or placebo (n=39).   The AML response 
rate was 42% for the everolimus group and 0% for placebo with response rate defined as 
a radiographically confirmed reduction of at least 50% target volume. Moreover, 
everolimus was well tolerated with only two patients discontinuing medication due to 
adverse events9,10.  Due to the clear superiority of everolimus, patients initially 
randomized to placebo were offered everolimus and in total 112 participants received 
everolimus.  At the most updated analysis presented in July 2014 by Bissler 
(unpublished), the renal AML response rate was 53.6% with progression free rate of 
89.4% at 36 months.  Nine patients (8%) discontinued the study due to adverse events. 
 
In regard to toxicity from everolimus, there is now a well-defined experience with this 
drug in multiple clinical settings, as reflected by the FDA drug label. More specifically, 
in those patients with TSC undergoing treatment with everolimus the most frequent 
adverse drug reactions have been stomatitis, amenorrhea, upper respiratory tract 
infections, hypercholesterolemia, nasopharyngitis, acne, menstruation irregular, 
sinusitis, and pneumonia.  The most frequent grade 3/4 adverse reactions were 
stomatitis, amenorrhea, pneumonia, neutropenia, pyrexia, and gastroenteritis viral.  In 
the updated EXIST-2 data, grade 3 AEs were noted in 3.6% for decreased blood 
phosphorus, 2.7% for amenorrhea; grade 4 AEs were noted in 1.8% for increased blood 
uric acid and 1% for convulsion, hydrocephalus, hypertensive crisis, neutropenia, 
pancreatic carcinoma and rhabbdomyolysis2. 
 
These data provoke inquiry into the far more common clinical scenario of patients with 
sporadic AMLs11121314.  Although comparatively robust literature does not exist for 
sporadic AMLs, preclinical data seems to indicate that aberrant mTOR signaling is 
equally prevalent in sporadic AMLs15.   Kenerson et al examined the activity of this 
pathway in sporadic AMLs and PEComas using immunohistochemical and biochemical 
analyses and report increased levels of phospho-p70S6K, a marker of mTOR activity, in 
15 of 15 sporadic AMLs 15. This finding was accompanied by reduced phospho-AKT 
expression suggesting disruption of TSC1/2 function.  In their study Western blot 
analysis confirmed mTOR activation concurrent with the loss of TSC2 and not TSC1 in 
sporadic AMLs.  Similarly, elevated phospho-p70S6K and reduced phospho-AKT 
expression was detected in 14 of 15 cases.  Taken together, these observations provide 
functional evidence that mTOR activation is common to sporadic, non-TSC-related 
AMLs and suggest the possibility that mTOR inhibitors such as everolimus may be 
therapeutic for non-hereditary AMLs. 
 
Here we hypothesize that inhibition of the mTOR pathway may be an effective 
therapeutic strategy in patients with sporadic AMLs.  While EXIST-2 data demonstrate 
mTOR inhibition is unlikely to induce a complete response with disappearance of the 


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lesions, they do suggest a role for mTOR inhibitors in “resetting the biological clock” by 
decreasing tumor volume and thereby decreasing or delaying the risks/need for 
intervention.  The strategy of resetting the “biological clock” has evolved from the 
collective experience with surgically managing renal tumors in patients with Von 
Hippel-Lindau (VHL) where this strategy is now considered the standard of care in the 
absence of curative interventions16.  In the context of AMLs, resetting the biological 
clock suggests the ability to reduce the size of the tumor to <3cm and potentially reset 
future growth rates to delay or avoid the need for intervention. 
 
Given the above considerations, herein we seek to study the role of everolimus in (1) 
reducing the size/volume of clinically significant sporadic AMLs (>3cm) (2) 
quantitating re-growth upon discontinuation of the agent and (3) minimizing symptoms 
and the need for intervention within 12 months following discontinuation. 
 
2.0 Objectives  
 
Primary Objective 
1) To evaluate the efficacy and tolerability of everolimus in reducing tumor volume in 
sporadic AMLs as measured by dynamic contrast enhanced MRI (DCE MRI), in 
patients who might otherwise be considered for active surgical or percutaneous 
intervention. 
 
 
Secondary Objectives  
1) To evaluate health-related quality of life (HRQoL) in subjects treated with 
everolimus for sporadic AMLs. 
2) To assess the growth kinetics of sporadic AMLs in patients who have been treated 
with everolimus. 
3) To measure the rate of surgical or percutaneous (embolization) intervention at 1 year 
from day 1 of study. 
4) To assess the safety of everolimus in patients with sporadic AML. 
 
 
Exploratory Objectives  
1) To determine whether volumetric response rates in sporadic AMLs to everolimus 
qualitatively correspond to perfusion/angiogenic content/vascularity of baseline 
tumor as measured by qualitative DCE MRI using the principles of Choi response 
criteria (AUC for first 30 seconds post injection). 
2) To investigate and explore potential molecular mechanism(s) of response and/or 
resistance of sporadic AMLs to everolimus treatment using a) initial diagnostic 
tumor tissue samples and if a biopsy or tumor resection is clinically indicated and 
pursued that tumor tissue sample and b) serum cfDNA. 
 


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3.0 Study Plan 
After confirming eligibility criteria, patients will be enrolled in this study.  Volumetric and 
perfusion/vascularity analyses will be done by DCE-MRI at baseline.  Patients will then 
receive everolimus 10 mg daily.  Treatment duration will be continuous for 4 cycles unless 
treatment is discontinued. 
 
After 4 cycles of treatment, repeat imaging with DCE-MRI will be performed to assess tumor 
size kinetics (sum of volumes of all target AMLs identified at baseline).  If the tumor has 
decreased in size by greater than or equal to 25% and no new AMLs greater than 1 cm in 
longest diameter have appeared, then the drug will be continued for another two cycles (6 
cycles total treatment).  If on the other hand the tumor has grown or decreased by less than 
25% or there are new AMLs (at least 1 cm in longest diameter), then the drug will be 
discontinued.   
 
At the end of cycle 6 and 12 months after start of therapy with everolimus, imaging via DCE 
MRI will be repeated to assess growth/regrowth kinetics/qualitative perfusion. 
 
If for any reason a patient terminates treatment with everolimus earlier than the end of cycle 4, 
all imaging will still be performed and used for the statistical analysis and primary endpoint 
calculations.  Given that therapy with everolimus has potential toxicity and that the disease in 
question (sporadic AML) is not a malignant condition, patients will not be replaced if they 
drop out, in a way signaling that the therapy may not be feasible.  If a patient receives at least 
one dose of everolimus they will be included in the analysis.  If a patient does not get imaged 
after 4 cycles of treatment, for the purposes of statistical considerations they will be considered 
a non-responder. 
 
Treatment related toxicities and QOL will be assessed at baseline, day 1 of each 28 day cycle, 
at drug discontinuation and at the last study visit 
 
Tissue for exploratory objectives will be collected at baseline only if available from archival 
tissue.  Additional tissue will also be collected if the patient undergoes a partial or complete 
nephrectomy or embolization during the study period for the AML. Serum at baseline will also 
be collected for cfDNA and other future potential correlative studies. 
 
 
 
4.0 Patient Selection 
 
Inclusion Criteria   
4.1.1 18 years of age or older  
4.1.2 A diagnosis of renal AML > 3 cm confirmed on pre-enrollment DCE MRI. A 
previous diagnosis or treatment of a different AML lesion is allowed. 
4.1.3 ECOG Performance Status 0 or 1 
4.1.4 Patients must have normal organ and marrow function as defined below: 
 Absolute neutrophil count > 1,500/mcL 


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 Hemoglobin ≥ 10 g/dL 
 Platelets > 100,000/mcL 
 AST/ALT (SGOT/SGPT) < 2.5 X ULN  
 Total bilirubin ≤ 2.0mg/dL 
 Renal Function eGFR > 30 mL/min via calculated creatinine clearance  
 Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L  
 Fasting triglycerides  ≤300 mg/dL or ≤1.71 mmol/L. 
4.1.5 Ability to understand and willingness to sign a written informed consent and 
HIPAA consent document 
 
 
Exclusion Criteria   
4.2.1 History of tuberous sclerosis, LAM or any active malignancy 
4.2.2 Active treatment with any other investigational agents 
4.2.3 Administration of any investigational drug within 30 days or 5 half-lives, 
whichever is longer, preceding the first dose of study treatment. 
4.2.4 Concurrent therapy given to treat cancer  
4.2.5 Patients must not have received any prior treatment for AML 
4.2.6 Diagnosis of any other malignancy within 3 years prior to registration, except 
for adequately treated basal cell or squamous cell skin cancer, or carcinoma in 
situ of the breast or of the cervix or melanoma in-situ or low grade (Gleason 6 
or below) prostate cancer on surveillance with no plans for treatment 
intervention (eg, surgery, radiation or castration). 
4.2.7 Clinically significant gastrointestinal abnormalities that may increase the risk 
for gastrointestinal bleeding including, but not limited to: 
 Active peptic ulcer disease 
 Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease), or 
other gastrointestinal conditions with increased risk of perforation. 
 History of abdominal fistula, gastrointestinal perforation, or intra-
abdominal abscess within 28 days prior to beginning study treatment 
4.2.8 Active diarrhea of any grade. 
4.2.9 Clinically significant gastrointestinal abnormalities that may affect absorption 
of investigational product including, but not limited to: 
 Malabsorption syndrome 
 Major resection of the stomach or small bowel resulting in dumping 
syndrome or clinical signs of malabsorption 


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4.2.10  Active or prior history of human immunodeficiency virus (HIV), hepatitis B, 
or hepatitis C (screening for all three is mandatory prior to study) 
4.2.11 Presence of any active or ongoing infection. 
4.2.12 Any known uncontrolled underlying pulmonary disease by history, physical 
exam or if applicable PFTs (e.g. FEV1 or DLCO 50% or less of predicted OR 
O2 saturation 88% or less at rest on room air). 
4.2.13 History of any one or more of the following cardiovascular conditions within 
the past 6 months: 
 Cardiac angioplasty or stenting 
 Myocardial infarction 
 Unstable angina 
 Coronary artery bypass graft surgery 
 Symptomatic peripheral arterial vascular disease 
4.2.14 History of Class III or IV congestive heart failure, as defined by the New York 
Heart Association Classification of Congestive Heart Failure.  See Appendix I 
for NYHA Classification Table. 
4.2.15 History of cerebrovascular accident including transient ischemic attack (TIA), 
pulmonary embolism or untreated deep venous thrombosis (DVT) within the 
past 6 months. 
Note: Patients with recent DVT who have been treated with therapeutic 
anticoagulation agents for at least 6 weeks are eligible as long as their INR is 
stable and within inclusion criteria per 4.1.4 
4.2.16 Corrected QT interval (QTc) > 480 milliseconds as corrected by the Fridericia 
formula 
4.2.17 Poorly controlled hypertension, defined as systolic blood pressure (SBP) of 
≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg.  
Note: Screening/Baseline blood pressure (BP) must be assessed with three 
measurements at approximately 2-minute intervals. The mean SBP / DBP 
values from the three readings must be <140/90 mmHg in order for a subject 
to be eligible for the study. If the subject’s initial screening SBP/DBP is ≥ 
140/90 mmHg, initiation or adjustment of antihypertensive medication(s) is 
permitted in an attempt to control the subject’s BP level to below 140/90 
mmHg. Optimal blood pressure control must be achieved before registration 
and monitored. 
4.2.18 Evidence of active bleeding or bleeding diathesis 
4.2.19 Patients must not have uncontrolled diabetes mellitus (defined by a Hgb A1c 
>8) obtained within 14 days prior to registration. Optimal glucose control (Hgb 
A1c ≤ 8) must be achieved before registration and monitored during protocol 
treatment 


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4.2.20 Unable or unwilling to discontinue use of prohibited medications within 14 
days prior to randomization and while on treatment:  
 No chronic treatment with systemic steroids or another 
immunosuppressive agent. Topical or inhaled corticosteroids are allowed. 
 Growth factors (e.g. G-CSF, G-GM-CSF, erythropoietin, platelets growth 
factors etc.) are not to be administered prophylactically but may be 
prescribed by the treating physician for rescue from severe hematologic 
events. 
 Live vaccines must not be administered to patient due to 
immunosuppressant potential of everolimus. 
 Drugs known to be strong inhibitors or inducers of CYP3A4 must not be 
administered. Drugs or substances known to be moderate inhibitors or 
inducers of CYP3A should be avoided if possible or used subject to 
caution as these can alter everolimus metabolism. Co-administration with 
strong or moderate inhibitors of P-glycoprotein (PgP) should be avoided if 
possible, or used subject to caution Seville orange, star fruit, grapefruit 
and their juices affect P450 and PgP activity. Concomitant use should be 
avoided. 
4.2.21 Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy 
to drugs chemically related to everolimus that in the opinion of the investigator 
contraindicates their participation. 
4.2.22 Prior or current use of systemic anti-VEGF inhibitors, cytokines or mTOR 
inhibitors (e.g. interferon, interleukin 2). 
4.2.23 Patients with Child-Pugh A-C liver disease (See Appendix II: Child-Pugh 
Criteria) 
4.2.24 Pregnant or nursing (lactating) women 
4.2.25 Women of child-bearing potential (WOCBP), defined as all women 
physiologically capable of becoming pregnant, must use highly effective 
methods of contraception during the study and 8 weeks after stopping 
treatment. Highly effective contraception  methods include total abstinence, 
male partner sterilization (with post-vasectomy documentation of the absence 
of sperm in the ejaculate), or a combination of any two of the following: 
 Use of oral, injected or implanted hormonal methods of contraception 
o In case of use of oral contraception, women should have been 
stable on the oral agent before taking study treatment. 
 Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
 Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal 
suppository 


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Women are considered to be physiologically capable of becoming pregnant 
unless: 
 They have had 12 months of natural (spontaneous) amenorrhea with an 
appropriate clinical profile (e.g. age appropriate, history of vasomotor 
symptoms);  
 They have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks prior to randomization.  
o In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone 
level assessment is she considered not of child-bearing 
potential. 
4.2.26 Male patients whose sexual partner(s) are WOCBP must agree to use adequate 
contraception as defined above during the study and for 8 weeks after the end 
of treatment.  Condom use is required by all male patients in order to prevent 
delivery of the drug via seminal fluid. 
4.2.27 Any serious and/or unstable pre-existing medical, psychiatric, or other 
condition that could interfere with subject’s safety, provision of informed 
consent, or compliance to study procedures. Patients with low risk prostate and 
bladder cancer will be excluded (use AUA guidelines for bladder patients). 
 
 
Inclusion of Women and Minorities 
Men and women, regardless of race, ethnic group or sexual orientation are eligible for 
this study.   
 
 
Participant Registration 
Participants may be registered from 8:00 am to 4:00 pm EST excluding holidays by 
emailing the Investigator-Sponsored Research Unit (ISRU) at: 
FCCC.MONITOR@fccc.edu. Eligible participants will be entered on study centrally 
once the following items have been received by email: 
 
 Completed registration form  
 Consent and HIPAA signature pages  
 Eligibility checklist 
 
Following registration, participants must begin protocol treatment within 14 calendar 
days of registration.  Issues that would cause treatment delays must be discussed with the 
Sponsor-Investigator.  If a registered participant does not receive protocol therapy 
following registration, the participant will be recorded as withdrawn from study.  The 
Study Monitor must be notified as soon as possible if a participant does not begin 
protocol treatment as scheduled. For additional registration questions, please email 
FCCC.MONITOR@fccc.edu or call (215) 728-5544. 
 


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The FCCC ISRU will notify the site by email once registration is confirmed and the 
sequence number has been assigned.  Participants must be registered and have received a 
sequence number prior to the initiation of treatment.   
 
Exceptions to the current registration policies will not be permitted.  
 
5.0 Treatment Plan  
Patients will be treated with Everolimus for 4, 28 day cycles. At the end of the fourth cycle, 
patients who have experienced a partial response (PR) defined as a reduction of 25% or more 
will continue therapy for an additional 2 cycles.  
 
Patients with be treated continuously barring toxicity related delays. Missed days will not be 
made up.  Patients will document adherence in a pill diary and should be directed to contact 
their treating physician with the onset of any side effects for further direction.  
 
 
Treatment Administration Tables 
Treatment Administration 
Agent 
Dose 
Route 
Schedule 
Length 
Everolimus 
10 mg 
Oral 
Daily 
4 Cycles 
 
If  ≥ 25% volume reduction and no new AMLs are seen after 4 
Cycles, continue as follows: 
Everolimus 
10 mg 
Oral 
Daily 
2 Cycles 
 
 
Duration of Therapy 
Patients will receive no more than 6 cycles of therapy in total.  
 
 
Duration of Follow up 
Patients will be followed for 1 year from the initiation of treatment for radiographic 
evaluation of their AML(s).  Thus, maximum time on trial is 12 months. Patients who 
stop receiving Everolimus due to unacceptable adverse events will still be followed until 
the end of the study. 
 
 
Criteria for Discontinuation 
Patients will be removed from treatment if one of the following criteria applies: 
 Disease progression including: 
o Bleeding or pain 
o Requirement for surgical or percutaneous intervention 
o Greater than a 25% increase in tumor volume of AML 
 Intercurrent illness that prevents further administration of treatment 


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 Unacceptable adverse events 
 Treatment is temporarily held for > 21 days  
 Patient becomes pregnant  
 Patient decides to withdraw from the study  
 General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgment of the investigator. 
The reason for discontinuation and the date the patient was removed must be documented 
in the medical record and case report form. 
 
 
Optional Tissue and Blood Collection for Exploratory Objectives 
At time of trial initiation, patients will be consented to allow the use of their tissue and 
blood for future research, specifically including, but not limited to, the analysis of mTOR 
alterations, VEFG pathways and tumor genome sequencing (e.g. mutations (AKT/PI3K, 
PTEN), amplifications, deletions in TSC1 and TSC2). 
 
At screening, if archival biopsy tissue of the AML is available, unstained slides will be 
requested. If a patient undergoes a clinical procedure where tissue will be obtained during 
the study, that tissue will also be collected for exploratory objectives.  Biopsy, resection, 
and/or percutaneous intervention will be performed entirely at the discretion of the 
treating clinician based on individual clinical scenarios and needs.   
 
An EDTA and red top tube will be collected to provide plasma, serum and peripheral 
blood mononuclear cells (PBMCs).  All biological samples will be stored at Fox Chase 
Cancer Center for possible future research.   
 
6.0 Dosing, Toxicity and Specific Adverse Events  
 
Dosing regimen 
Everolimus should be taken orally once daily at 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. For patients unable to swallow tablets, the tablet(s) should be dispersed 
completely in a glass of water (containing approximately 30 mL) by gently stirring, 
immediately prior to drinking. The glass should be rinsed with the same volume of water 
and the rinse completely swallowed to ensure the entire dose is administered.  
If vomiting occurs, no attempt should be made to replace the vomited dose. Patients 
should be instructed that if they miss a dose on one day, they must not take any extra 
dose the next day, but instead to immediately contact the study center as soon as possible 
to ask for advice.  
 


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Description of selected adverse drug reactions 
In clinical trials and post-marketing spontaneous reports, everolimus has been associated 
with serious cases of the following: 
 Hepatitis B reactivation, including fatal outcome.  
 Reactivation of infections is an expected event during periods of 
immunosuppression.  
 Renal failure events (including fatal ones) and proteinuria. Monitoring of renal 
function is recommended. 
 Amenorrhea (including secondary amenorrhea). 
 Pneumocystis jirovecii pneumonia (PJP) some with a fatal outcome. 
 Angioedema has been reported with and without concomitant use of everolimus 
and ACE inhibitors 
 
 
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.  If multiple 
toxicities are experienced, dose modifications will be based on the toxicity requiring the 
largest dose reduction.  Once dose is reduced, patients will continue at new dose. No dose 
re-escalations are allowed.  Details of study treatment schedule adjustments for 
Everolimus-related toxicities and dose levels are provided in the below tables. 
 
6.3.1. Dose adjustments and dose levels:  
Dose level 
Dose and schedule 
0 (starting dose) 
10mg 
1 
5mg  
2 
5mg every other day 
 
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. 
 
 
 


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6.3.2. Non-hematologic toxicities 
Toxicity 
Action 
Non-Infectious Pneumonitis 
Please refer to 6.3.4. 
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 or higher (> 5.0 ULN)* 
 Discontinue study drug permanently 
Intolerable grade 2 mucositis,  
 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 21 days. 
Recurrence of intolerable grade 2 
mucositis 
 Reduce dose to the next lower dose level, if 
available.  
Grade 2 hyperlipidemia or 
hypertriglyceridemia 
 Reduce dose to the next lower dose level, if 
available. 
 If a patient is at the lowest dose of study drug, the 
drug may be held for ≤21 days to allow treatment 
and if the level returns to a grade 1 or lower, 
treatment can be resumed with a reevaluation 
monthly 
 See management of hyperlipidemia and 
hypertriglyceridemia and hyperglycemia below 
Grade 2 hyperglycemia 
 Adjust medications as medically appropriate and re-
evaluate at next visit 
 If after medical adjustment grade 2 dysfunction 
persists, reduce dose to the next lower dose level, if 
available. 
 If a patient is at the lowest dose of study drug, the 
drug may be held for ≤21 days to allow treatment 
and if the level returns to a grade 1 or lower, 
treatment can be resumed with a reevaluation 
monthly 
 See management of hyperglycemia below 


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Toxicity 
Action 
Grade 3 or higher hyperglycemia or 
hypertriglyceridemia or 
hyperlipidemia   
 Discontinue study drug permanently 
Grade 3 or higher clinical liver 
failure (asterixis or 
encephalopathy/coma) 
 Discontinue study drug permanently 
Grade 3 or higher skin toxicity 
 Discontinue study drug permanently 
Grade 3 or higher Diarrhea 
 Discontinue study drug permanently 
Any other grade 3 toxicity 
 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 21 days. 
Recurrence of a grade 3 toxicity 
after dose reduction 
 Reduce dose to the next lower dose level, if 
available.  
Any other grade 4 
 Discontinue study drug permanently 
 
 
6.3.3. Hematologic toxicities 
Toxicity 
Action 
Grade 2 thrombocytopenia 
(platelets <75, ≥ 50x109/L) 
 No action 
 
Grade 3 thrombocytopenia 
(platelets <50, ≥ 25 x109/L) 
 Interrupt everolimus until resolution to grade 1  
 If resolution occurs ≤ 7 days, reintroduce everolimus 
at the dose level prior to interruption. 
 If resolution occurs > 7 days, or event occurs within 
28 days, reintroduce everolimus at one dose level 
lower, if available. 
Grade 4 thrombocytopenia 
(platelets < 25 x109/L) 
 Discontinue study drug permanently 


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Grade 3 neutropenia or anemia 
(neutrophil <1, ≥0.5 x109/L) 
 Interrupt everolimus until resolution to grade ≤1 or 
baseline value 
 If AE resolution occurs ≤ 7 days, reintroduce 
everolimus at the same dose level. 
 If AE resolution occurs > 7 days, or event occurs 
within 28 days, reintroduce everolimus at one dose 
level lower, if available. 
Grade 4 neutropenia or anemia 
 Discontinue study drug permanently 
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. 
 
 
6.3.4. Non-infectious Pneumonitis 
Worst grade 
pneumonitis 
Required investigations 
Management 
of pneumonitis 
Everolimus 
dose adjustment 
Grade 1 
CT scans with lung windows. 
No specific 
therapy is 
required 
Stop study drug 
permanently. 
Grade 2 
CT scan with lung windows. Consider 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Consider a 
bronchoscopy with biopsy and/or BAL. 
Monitoring at each visit until return to ≤ 
grade 1. Return to initial monitoring 
frequency if no recurrence. 
Symptomatic 
only. Consider 
corticosteroids 
and/or other 
supportive 
therapy if 
symptoms are 
troublesome. 
Rule out 
infection and 
stop study drug 
permanently. 
Grade 3 
CT scan with lung windows and 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Monitoring at each visit 
until return to ≤ grade 1. Return to initial 
monitoring frequency if no recurrence. 
Bronchoscopy with biopsy and/or BAL is 
recommended. 
Consider  
corticosteroids 
if infective 
origin is ruled 
out. Taper as 
medically 
indicated. 
Rule out 
infection and 
stop study drug 
permanently. 
Grade 4 
CT scan with lung windows and required 
pulmonary function testing, if possible, 
includes: spirometry, DLCO, and room 
air O2 saturation at rest. Monitoring at 
each visit until return to ≤ grade 1. 
Return to initial monitoring frequency if 
no recurrence. Bronchoscopy with biopsy 
and/or BAL is recommended if possible. 
Consider 
corticosteroids 
if infective 
origin is ruled 
out. Taper as 
medically 
indicated. 
Rule out 
infection and 
stop study drug 
permanently.. 


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Management of specific toxicities 
Overall, safety data available from completed, controlled and uncontrolled studies 
indicate that everolimus is generally well tolerated at weekly or daily dose schedules. The 
safety profile is characterized by manageable adverse events (AEs). These AEs are 
generally reversible and non-cumulative17. 
 
Adverse events most frequently observed with everolimus are rash, stomatitis /oral 
mucositis, non-infectious pneumonitis, fatigue, headache, anorexia, nausea, vomiting, 
diarrhea, and infections. Overall, the most frequently observed laboratory abnormalities 
include neutropenia, thrombocytopenia, hypercholesterolemia, and/or 
hypertriglyceridemia. The majority of these AEs have been of mild to moderate severity 
(NCI CTC grade 1-2).  
 
6.4.1. Hepatitis B Reactivation  
In the case of reactivation of Hepatitis B even in the face of pre-study screening, 
the trial will be immediately terminated and appropriate Hepatitis B therapy 
initiated. 
 
6.4.2. 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 respiratory or hepatic failure) and occasionally have had a 
fatal outcome.  While taking Everolimus, be vigilant for symptoms and signs of 
infection; if a diagnosis of infection is made, institute appropriate treatment 
promptly and treatment will be permanently discontinued with everolimus.  
Referral for immediate and appropriate treatment will be made.  
 
6.4.3. Skin Toxicity 
For patients with grade 1 toxicity, no specific supportive care is usually needed or 
indicated. Rash must be reported as an AE. Patients with grade 2 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 prednisone (short course), topical 
corticosteroids, or pimecrolimus.   
 
6.4.4. Stomatitis / Oral Mucositis / Mouth Ulcers 
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with 
gastrointestinal morbidity associated with mouth/dental infections, irritation of 
esophageal mucosa e.g. gastroesophageal reflux disease (GERD) and pre-existing 


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stomatitis/mucositis must be monitored even more closely. Patients should be 
instructed to report the first onset of buccal mucosa irritation/reddening to their 
study physician immediately. 
 
Stomatitis/oral mucositis/mouth ulcers due to everolimus should be treated using 
local supportive care. Please note that investigators in earlier trials have described 
the oral toxicities associated with everolimus as mouth ulcers, rather than 
mucositis or stomatitis. If your examination reveals mouth ulcers rather than a 
more general inflammation of the mouth, please classify the adverse event as such. 
Please follow the paradigm below for treatment of stomatitis/oral mucositis/mouth 
ulcers: 
 All patients may elect to start an alcohol-free Dexamethasone oral solution 
5mg/5ml that is commercially available. They may take 10 mL up to 4 
times a day and swish in their mouth for 2 minutes after which they are to 
spit it out. This may be done as prophylaxis at the time of initiation of 
everolimus. 
 For mild toxicity (grade 1), use conservative measures such as non-
alcoholic mouth wash or salt water (0.9%) mouth wash several times a day 
until resolution. Patients may also use the above mentioned alcohol-free 
Dexamethasone oral solution 5mg/5mL that is commercially available. 
 For more severe toxicity (grade 2 in which case patients have pain but are 
able to maintain adequate oral alimentation, or grade 3 in which case 
patients cannot maintain adequate oral alimentation), the suggested 
treatments are topical analgesic mouth treatments (i.e., local anesthetics 
such as, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) with or without topical corticosteroids, such as 
triamcinolone oral paste 0.1% (Kenalog in Orabase®). 
 For Grade 3 (Symptomatic and Unable to adequately aliment or hydrate 
orally, temporary dose interruption until recovery to ≤ Grade 1. Agents 
containing alcohol, hydrogen peroxide, iodine, and thyme derivatives may 
tend to worsen mouth ulcers. It is preferable to avoid these agents. 
 Antifungal agents should not be used, other than topic creams and 
ointments, including vaginal preparations.  If a need arises for a systemic 
anti-fungal agent, the patient must come off study permanently.  
 
6.4.5. 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). . 
 
6.4.6. Hyperlipidemia, Hypertriglyceridemia and Hyperglycemia 
 


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Treatment of hyperlipidemia and hypertriglyceridemia should take into account the 
pre-treatment status and dietary habits of the patient. Grade 1 hypercholesterolemia 
or hypertriglyceridemia may be treated at the discretion of the provider with diet 
therapy or medications such as fibrates and an HMG-CoA reductase inhibitors.  
Grade 2 hypercholesterolemia or hypertriglyceridemia will further lead to a one 
level dose reduction as well as additional therapy with diet and medications as 
above.  
 
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 creatinine 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. 
 
Hyperglycemia has been reported in clinical trials. Hemoglobin A1C will be 
checked prior to study initiation and glucose will be monitored during the study.  
Hyperglycemia should be treated in standard clinical fashion.   
 
6.4.7. Non-infectious Pneumonitis 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of 
non-infectious pneumonitis (including interstitial lung disease) have also been 
described in patients taking everolimus. Some of these have been severe and on 
rare occasions, a fatal outcome was observed. A diagnosis of non-infectious 
pneumonitis should be considered in patients presenting with non-specific 
respiratory signs and symptoms such as hypoxia, pleural effusion, cough or 
dyspnea, and in whom infectious, neoplastic and other non-medicinal causes have 
been excluded by means of appropriate investigations. Patients should be advised 
to report promptly any new or worsening respiratory symptoms. Patients who 
develop radiological changes suggestive of non-infectious pneumonitis will have 
drug permanently discontinued.  
 
Individuals participating in this trial will need to be routinely questioned as to the 
presence of new or changed pulmonary symptoms consistent with lung toxicity.  In 
addition, pulmonary function tests (PFTs) and CT of the chest will be conducted, if 
clinically indicated, to monitor for pneumonitis. If any grade non-infectious 
pneumonitis develops, the patient will be taken off study.  
 
 
Fertility 
The potential for everolimus to cause infertility in male and female patients is unknown. 
However, menstrual irregularities, secondary amenorrhea and associated luteinizing 
hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed. 
Based on non-clinical findings, male and female fertility may be compromised by 
treatment with everolimus. 
 


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7.0 Study Agent Information 
 
Everolimus Formulation, Product identification, Package and Labeling 
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 
 
Everolimus (RAD001) is a selective mammalian target of rapamycin (mTOR) inhibitor, 
specifically targeting the mTOR-raptor signal transduction complex 1 (mTORC1). 
mTOR is a key serine-threonine kinase in the PI3K/AKT/mTOR signaling cascade, a 
pathway known to be dysregulated in the majority of human cancers and TSC. 
Everolimus exerts its activity through high affinity interaction with the intracellular 
receptor protein FKBP12. The FKBP12/everolimus complex binds to mTORC1, 
inhibiting its signaling capacity. mTORC1 signaling is affected through modulation of 
the phosphorylation of downstream effectors, the best characterized of  which are the  
translational regulators S6 ribosomal protein kinase (S6K1) and eukaryotic elongation 
factor 4E-binding protein (4E-BP). Disruption of S6K1 and 4E-BP1 function, as a 
consequence of mTORC1 inhibition, interferes with the translation of mRNAs encoding 
pivotal proteins involved in cell cycle regulation, glycolysis and adaptation to low 
oxygen conditions (hypoxia). This inhibits tumor growth and expression of hypoxia- 
inducible factors (e.g. HIF-1 transcription factors); the latter resulting in reduced 
expression of factors involved in the potentiation of tumor angiogenic processes (e.g. the 
vascular endothelial growth factor VEGF). Everolimus is a potent inhibitor of the growth 
and proliferation of tumor cells, endothelial cells, fibroblasts and blood vessel-associated 
smooth muscle cells. Consistent with the central regulatory role of mTORC1, everolimus 
has been shown to reduce tumor cell proliferation, glycolysis and angiogenesis in solid 
tumors in vivo, and thus provides two independent mechanisms for inhibiting tumor 
growth: direct antitumor cell activity and inhibition of the tumor stromal compartment. 
 


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Everolimus is formulated as tablets for oral administration of 5mg and 10mg strength.  
 
 
Availability  
Everolimus will be supplied for this protocol by Novartis. .  
 
 
Drug Ordering, Storage and Handling 
Following submission and approval of the required regulatory documents, participation in 
the study initiation meeting and receipt of the site activation letter from the CTO 
Regulatory Coordinator, the initial order may be placed.  Drugs will be ordered by 
contacting the study monitor as listed on the cover page of this protocol. 
 
Everolimus tablets are blister-packed under aluminum foil, which should be opened only 
at the time of administration as drug is both hygroscopic and light-sensitive. Refer to 
label for expiration date and storage conditions. 
 
It may be necessary to ensure that patients have enough medication for the built-in 
evaluation and visit windows throughout study treatment (+/- 5 days). 
 
The extent of absorption of everolimus through topical exposure is not known.  
Therefore, caregivers are advised to avoid contact with everolimus tablets.  Wash hands 
thoroughly before and after handling everolimus. 
 
 
Destruction of Drug   
At the time of study closure, the unused, used and expired study drug will be destroyed at 
the site per Institutional SOPs unless otherwise specified. 
 
 
Records to be kept at Site; Dispensing and Accountability 
It is the responsibility of the Investigator to ensure that a current record of investigational 
product disposition is maintained at each study site where investigational product is 
inventoried and disposed.  Records or logs must comply with applicable regulations and 
guidelines, and should include: 
 Amount received and placed in storage area. 
 Amount currently in storage area. 
 Label ID number or batch number. 
 Dates and initials of person responsible for each investigational product inventory 
entry/movement. 
 Amount dispensed to and returned by each patient, including unique patient 
identifiers. 
 Amount transferred to another area for dispensing or storage. 
 Non-study disposition (e.g., lost, wasted, broken). 


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8.0 Study Calendar 
 
Screening A 
Day 1 of 
Cycles  
1, 3, and 5 H 
Day 1 of 
Cycles  
2, 4, and 6 H 
Cycle 5 
Day 1 H 
Cycle 6 
Day 28 H 
Off 
Treatment 
12 Month 
Follow-up H 
Informed Consent 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Concurrent Medications 
X 
X 
X 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
 
X 
 
Physical exam 
X 
X 
X 
 
 
X 
 
Vital signs B 
X 
X 
X 
 
 
X 
  
ECOG Performance Status 
X 
X 
X 
 
 
X 
 
Serum chemistry C 
X 
X 
X 
  
  
X 
  
FKSI QOL Assesment 
X 
X 
X 
  
  
X 
X 
CBC w/diff, plts 
X 
X 
X 
  
  
X 
  
Fasting serum cholesterol 
& Triglycerides & Hgb A1c 
X 
X 
  
  
  
X 
  
EKG 
X 
  
  
  
  
  
  
Hepatitis B, Hepatitis C & 
HIV Screening D 
X 
  
  
  
  
  
  
Tumor Measurements 
X 
  
  
X 
X 
  
X 
Optional Correlative Tissue 
Collection 
 
X E  
X F 
Optional Correlative Serum 
Collection 
 
X E  
  
X 
X 
  
X 
Serum Pregnancy Test G 
X 
  
  
  
  
  
  
Urine or Serum Pregnancy 
Test G 
  
X 
X 
  
  
X 
  
Adverse Event 
Assessment 
  
X 
X 
  
  
  
  
A:    Screening H&P, EKG and all labs must be < 14 days prior to registration.   
Tumor measurements and radiologic evaluations must be < 30 days prior to registration.   
Pre-study assessments may be used for cycle 1 day 1 
B:    Screening blood pressure must be assessed with three measurements at approximately 2-minute intervals. 
C:    Serum chemistry includes Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, fasting 
glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, glucose. 
D:    Screening for Hepatitis B will include, HBsAg, HBsAb, and HBc Ab.  A positive HBsAb result in patients who have received prior HBV 
vaccination will not lead to exclusion from the study as long as HBsAg is negative. 
Screening for Hepatitis C will be via Hepatitis C antibody.  If positive confirmation with quantitative RNA PCR will be done.  
E:     If archival tissue is available from a previous renal lesion biopsy, unstained slides will be collected as detailed in 5.5. Correlative blood 
and tissue for this timepoint will be collected at Cycle 1 Day 1 only. 
 
F:     If a percutaneous intervention or surgical intervention is performed during the study, tissue will be collected for further analysis as 
detailed in 5.5 
G:     Women of Childbearing Potential Only.  Serum pregnancy test at time of screening must be completed <72 hours before registration 
H:     All study visits have a window of +/- 5 days.  Ensure that patients are given enough study drug to last until their next visit if scheduled 
more than 28 days from start of a cycle. 
 


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9.0 Adverse Events 
 
Definitions 
9.1.1. Adverse event (AE) 
An adverse event is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medicinal 
(investigational) product, treatment or procedure regardless of whether it is considered 
related to the medical treatment or procedure (NCI CTEP Guidelines March 28, 2011). 
 
9.1.2. Serious Adverse Event (SAE) 
A serious adverse event is an AE that is fatal or life threatening, requires inpatient 
hospitalization or prolongation of existing hospitalization (for > 24 hours), persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or is a congenital anomaly/ birth defect, or results in any important medical 
event that may not result in death, be life threatening, or require hospitalization may be 
considered an SAE when, based upon appropriate medical judgment, may jeopardize the 
subject and may require medical or surgical intervention to prevent any of the above 
outcomes.  A “life-threatening” adverse event places the patient at immediate risk of death 
in the judgment of the investigator or sponsor. 
 
9.1.3. Severity Rating  
The investigator will evaluate the severity of each adverse event.  NCI Common 
Terminology Criteria for Adverse Events (CTCAE v.4.0) or study specific toxicity tables 
provided in the protocol define severity.  If not included in CTCAE v.4.0, severity is 
expressed in numerical grade using the following definitions: 
 Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
 Grade 2: Moderate-minimal, local or noninvasive intervention indicated; limiting 
age appropriate instrumental ADL. 
 Grade 3: Severe-severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL. 
 Grade 4: Life-threatening consequences; urgent intervention indicated.  
 Grade 5: Death related to AE 
 
9.1.4. Attribution/Relationship to study drug  
 Definite – clearly related 
 Probable – likely related 
 Possible – may be related 
 Unlikely – doubtfully related 


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 Unrelated – clearly not related 
9.1.5. Expectedness 
An Expected Adverse Event is one where the specificity or severity is consistent with the 
current information available from the resources. 
 
An Unexpected Adverse Event is one where the nature, severity, or frequency of the event 
is related to participation in the research is not consistent with either: 
 The known or foreseeable risk of adverse events associated with the procedures 
involved in the research that are described in (a) the protocol-related documents, 
such as the IRB-approved research protocol, any applicable investigator brochure, 
and the current IRB-approved informed consent document, and (b) other relevant 
sources of information, such as product labeling and package inserts: or 
 The expected natural progression of any underlying disease, disorder, or condition 
of the subject (s) experiencing the adverse event and the subjects(s) predisposing 
risk factor profile for the adverse event. 
 
Information about common side effects already known about the investigational drug can 
be found in the Investigators’ Brochure. This information should be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
 
Adverse event monitoring should be continued for at least 30 days or five half-lives 
(whichever is longer) following the last dose of study treatment. 
 
10.0 Recording and Reporting Responsibilities 
 Site Recording responsibilities: 
Upon identification of an AE or SAE, the site investigator will utilize the above definitions to 
properly classify the event.  Each category listed above must be recorded for each event. 
All AEs and SAEs will be recorded in the “AE case report forms” (CRF) and in progress reports 
with details about the grade and attribution of each episode, action taken with respect to the 
study drug, and the patient’s outcome will be recorded in the CRF.  All events will be recorded 
on case report forms for the duration of the study until they resolve. 
 
All SAEs will be recorded on the FDA MedWatch form 3500a.    The principal investigator has 
the obligation to report all serious adverse events to the FDA (if applicable), IRB, and Novartis 
Pharmaceuticals Drug Safety and Epidemiology Department (DS&E). .  
 
 Site Reporting responsibilities: 
1) 
The investigator/ site is responsible to report all SAEs that occur on or after the first 
day of study treatment to the sponsor within 24 hours of becoming aware of the event.  
All subsequent SAEs must be reported for up to 30 days after the last treatment. 
Each investigator is responsible to report all AEs/SAEs to their local IRB following 
guidelines set by that IRB.  The FCCC OCR reserves the right to request an event be 


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reported to the IRB at their discretion.  Copies of events reviewed by the IRB must be 
sent by email to SAE.FCCC@fccc.edu. 
2) 
If the investigator or IRB feels the event warrants a revision to the informed consent 
that was not already initiated by the OCR, draft revisions will be made in track 
changes and submitted to the OCR for consideration.  Any consent revisions must 
receive OCR approval prior to submission to the IRB. 
3) 
Any investigator who is in doubt of whether a particular AE needs to be reported is 
directed to call the Study Monitor for confirmation with the Sponsor-Investigator. 
4) 
If the results of an investigator or OCR investigation show an adverse event not 
initially determined to be reportable is so reportable, the investigator will report the 
event following the above guidelines based on the date the determination is made. 
5) 
Copies of all related correspondence and reporting documents must be submitted to 
the ISRU and will be maintained in the trial master file. 
 
The participating site should report events to: 
 
Investigator-Sponsored Research Unit 
Office of Clinical Research 
Fox Chase Cancer Center 
SAE.FCCC@fccc.edu  
 
 Sponsor Reporting Responsibilities: 
1) Adverse events which meet all of the following criteria must be reported to all 
participating institutions for IRB submission within 2 weeks of notification of the event. 
 
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; 
 
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 
 
Serious (refer to above definition) or otherwise one that suggests that the research 
places subjects or others at a greater risk of physical or psychological harm than 
was previously known or recognized. 
2) If the adverse event requires modification of the study protocol and informed consent, 
these changes will be provided to all participating institutions in the form of an 
amendment from the ISRU for each site’s IRB of record along with the report of the 
adverse event.   
3) Copies of all related correspondence and reporting documents will be maintained in a 
centralized regulatory file for this study within the OCR. 


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4) SAEs that are related, unexpected, fatal, or life-threatening are reportable through the 
Food and Drug Administration (FDA) MedWatch program by telephone or fax no later 
than 7 calendar days after initial receipt of the information.  Further information on the 
timing of submissions is as directed by FDA guidelines 
(www.fda.gov/medwatch/index.html).  Serious, unexpected events that suggest 
significant clinical risk will be submitted to within 15 calendar days after initial receipt 
of this information. 
 
Food and Drug Administration: 
Telephone 1-800-332-1088 
Fax 1-800-332-0178 
http://www.fda.gov/medwatch/report.htm  
 
5) The investigator must assess and record the relationship of each SAE to each specific 
study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form along with the Novartis provided 
fax cover sheet to the Novartis Oncology Drug Safety and Epidemiology (DS&E) 
department by fax (fax: 877-778-9739) within 24 hours.. 
6) Any SAEs experienced after this 30 days period should only be reported to Novartis if 
the sponsor-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. 
 
 Pregnancy  
All WOCBP must be instructed to contact the Investigator immediately if they suspect they 
might be pregnant (e.g., missed or late menstrual period) at any time during study participation. 
 
In the event of a confirmed pregnancy in a patient participating in the study, the Site 
Investigator must immediately notify the Fox Chase Cancer Center Study Monitor, who will 
notify Dr. Robert Uzzo, MD; the study PI.  Novartis will also be notified by the FCCC CTO 
within 24 hours. 
 
The study drug will be immediately discontinued. 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. 
 


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11.0 Measures of Effect 
 Response Evaluation Utilizing DCE-MRI  
DCE-MRI assessments will be performed at baseline, on Cycle 5 Day 1, on Cycle 6 Day 28, 
and 12 months after the start of treatment. The Cycle 6 Day 28 MRI and the 12 month MRI will 
be done even if patient doesn’t continue onto cycles 5 and 6. 
 
Location and size of the IV, as well as type and amount of contrast and injection rate should be 
the same for all time points of each individual patient.  These can be different between patients. 
 
Protocol should contain at minimum breathhold axial T1W in and out of phase multiplanar 
gradient echo sequence. To evaluate volume of the index lesion perform axial and coronal 
breathhold T1W 3-d gradient echo sequences with and without fat saturation (VIBE, 
LAVA/FAME and THRIVE for Siemens, GE and Philips respectively).  Then, dynamic pre and 
post contrast enhanced nonbreathhold coronal T1W fast 3-d gradient echo sequences to run for 
two minutes.  Each individual volume acquisition time should be maximum 4-5 seconds. These 
should be lower resolution with 5 mm slice thickness and adjust slice number to cover the size 
of the index lesion usually 15-20 slices. Phase encoding of 128 or less to keep acquisition time 
of less than 5 seconds.   Patients should be instructed to perform shallow breathing.  Start 
injection of the contrast 15 seconds after the start of the acquisitions.  Acquisitions stop at 2 
minutes after the start and at 2.5 minutes repeat the coronal and axial breathhold T1W fast 3-d 
gradient echo sequences with fat sat in that order. 
 
Choose a central slice of the index lesion on the pre and post coronal breathhold images and 
trace the perimeter and get a signal intensity number for both.  If possible choose a slice with a 
large soft tissue component and trace that separately re and post.   Calculate a percent 
enhancement as follows:  (Post – Pre/Pre) x 100.  Dynamic data can be used to choose post time 
point with maximum enhancement.  If possible, calculate an AUC 45 (area under the curve for 
45 seconds) from the dynamic data. Volumes can be calculated on the breathhold 3-d sequences 
with or without fat sat.  If dynamic sequences are unusable secondary to artifacts, then percent 
enhancement can be calculated from the breathhold 3-d T1W sequences with or without fat sat.  
 
 Methods for Evaluation of Disease 
ROI’s should be drawn around the solid nonfat portions of the tumor. One should evaluate 
signal intensity on arterial and portal venous phase images using identical delay times after start 
of injection for each time.  For the exploratory objective 2.3.1, principles of Choi response 
criteria should be use (measure AUC for first 30 seconds post injection).   
 
 Response Criteria 
Patients who have ≥25% decrease in tumor volume after 4 cycles of everolimus therapy will 
continue study drug for 2 additional cycles. Those with < 25% reduction or a new lesion 
(defined at 1 cm in longest diameter or more) will be taken off treatment.  
 


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 Health Related Quality of Life 
Health-related quality of life will be assessed with the use of patient responses to the 19-item 
Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index (FKSI-19; on a 
scale from 0 to 76, with higher scores indicating fewer symptoms)18 (Appendix III).  The 
instruments will be administered at baseline, on day 1 of each 28 day cycle, at study drug 
discontinuation and at the final study visit. 
 
 Serum Corrrelatives 
PBMC, serum and plasma will be collected at baseline to look for evidence of mTOR inhibition 
– seeing an increase in pAKT and a decrease/inhibition of pS6—as well as future research like 
plasma RNA (nanostring panel) and cfDNA. For cfDNA blood will be collected at a single time 
point using either two 7ml STRECK tubes per patient (if cannot be frozen immediately) or 
frozen as per the lab manual. cfDNA will be extracted using QIAamp circulating nucleic acid kit 
and stored for future use.  
 
 
12.0 Statistical Considerations 
 Study Design/Endpoints 
 
The required sample size for this trial is 43 patients, using a Simon two-stage design.  The 
sample size justification and details are below. 
 
We will conduct a single arm Phase II study to assess the efficacy of everolimus in patients with 
≥3cm sporadic AMLs.  Response for a patient will be defined by a decrease in size of ≥25% 
after 4 cycles of treatment. 
 
We will implement an optimal two-stage Simon design for this trial.  The new treatment would 
be of interest if the proportion, p, of responding patients is at least 25%. A proportion of patients 
with a response rate of less than 10% will be of no interest. Forty three (43) patients will allow 
us to test the null hypothesis: p ≤10% against the alternative hypothesis: p ≥ 25% at the 5% 
level of significance (α) with 80% power for a one-sided test.  The early stopping point is 18 
patients for both efficacy and toxicity.  For efficacy, if 2 or fewer patients respond among the 
first 18 patients then the null hypothesis will not be rejected and the trial will be terminated. The 
probability of early stopping under the null is 73%.  If the trial progresses until 43 patients are 
evaluated and 8 or more patients respond, then the null hypothesis will be rejected.   
 
For toxicity, the trial will be paused and termination considered if out of the first 18 patients, 3 
or more come off trial due to any adverse events as defined in the protocol. If the study 
proceeds to stage II (total enrollment = 43 patients), the trial will be paused and termination 
considered if at any point 8 or more patients come off trial due to any adverse events as defined 
in the protocol. If the true rate of any adverse events necessitating a patient to come off trial is 
20%, the probability of early stopping is 73%; if the true rate of any adverse events 
necessitating a patient to come off trial is 5%, the probability of early stopping is 6%. Pause and 


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termination consideration for toxicity will occur, either early or finally, with probability 81% if 
true toxicity proportion is 20%; and 6% if it is 5%.   
 
To ensure oversight with respect to toxicity, an interim review will be conducted if the early 
stopping rule for toxicity is reached in the first 18 patients. For this interim review, all available 
data related to primary and secondary efficacy and toxicity endpoints will be collected, 
summarized and presented. The data will be reviewed at a meeting of the invested trial parties, 
including but not limited to investigators at all participating sites (PIs or representatives at 
outside centers may call in to the meeting), staff on the research team, members of the FCCC 
Investigator Sponsored Research Unit, and statistics team. A summary recommendation will 
emerge from the meeting as to whether the study should be terminated or modified to a new 
dosing schema. This recommendation will be forwarded to the FCCC DSMB for signoff. Study 
accrual will halt until the outcome of the interim review is accepted by the FCCC DSMB. If the 
DSMB does not concur with the findings of the Investigator Meeting, the local FCCC IRB will 
review the trial for final decision.  
 
In secondary analyses we will use graphs, standard descriptive statistics (mean, median, 
minimum, maximum, standard deviation, two-sided 95% confidence intervals) and Generalized 
Estimating Equation methods to characterize and model longitudinal health-related quality of 
life (HRQoL) measurements. Tumor regrowth kinetics will be characterized by the percent 
change in volume from the date of everolimus treatment termination. Values will be 
summarized using plots and standard descriptive statistics (mean, median, minimum, maximum, 
standard deviation, two-sided 95% confidence intervals) separately for each measurement 
following treatment discontinuation.  Safety and tolerability objective will be measured by the 
incidence of adverse events, serious adverse events, deaths and laboratory abnormalities. 
Spearman’s correlation coefficients will be computed to estimate the association between the 
largest percentage volumetric response from baseline with levels of perfusion/angiogenic 
content/vascularity of baseline tumor as measured by DCE MRI. 
 
We will tabulate the frequencies of all grade 2 or higher adverse events as defined by NCI 
CTCAE version 4 criteria.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
 
 
 Sample Size/Accrual Rate 
This study will require the enrollment of 43 evaluable participants over a 24 month period, or an 
approximate average of 2 participants per month for 2 years.  The study is planned to be 
amended in the future for additional 2-4 sites to help increase accrual.  
 
13.0 Data and Safety Monitoring Plan 
 Monitoring Plan  
FCCC ISRU will monitor the medical and study records of each participant accrued throughout 
the course of the study.  In addition, the ISRU will collect and report data to the Sponsor-
Investigator who will review these data on a regular basis at a rate dependent on subject accrual.  


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All serious adverse events (SAEs) will be reviewed on a real time basis first by the study site PI 
and subsequently by the ISRU and Sponsor-Investigator as applicable. 
 
 Data Safety Monitoring Board   
Interim analysis of toxicity, outcome and ongoing scientific investigations will be performed at 
least by the Fox Chase Cancer Center Data Safety Monitoring Board (FCCCDSMB).  In this 
capacity the FCCCDSMB will serve as an advisory committee to the Sponsor-Investigator.  The 
FCCCDSMB will review those aspects of this trial that are outlined in the responsibilities 
section of the Data and Safety Monitoring Plan (DSMP).  If the committee decides that changes 
should be made to this trial, it will make recommendations in writing to the Sponsor-
Investigator, the Associate Director of Clinical Research, and the Protocol Management 
Executive Committee, which, in turn, have the authority to approve or disapprove these 
recommendations.  These changes will be discussed with the Sponsor-Investigator before they 
are implemented.  These changes may include early termination of accrual.  Other changes 
might include altering the accrual goals or changing the eligibility criteria for the trial. 
 
14.0 Administrative   
This study will be conducted in accordance will local, state, and Federal regulations and according to 
accepted good clinical practice guidelines. 
 
 Data Reporting 
The FCCC Study Monitor will request case report form submission upon resolution of 
outstanding queries.  Participating sites are responsible to respond to queries prior to the next 
scheduled monitoring visit.  Participating sites are responsible for submitting case report forms 
to the Study Monitor within two weeks of request. 
 
The ISRU is responsible for compiling and submitting data to the Sponsor-Investigator and 
statistician on an ongoing basis for monitoring as described in the data safety monitoring plan 
and reporting to the Data and Safety Monitoring Board. 
 
All patient information will be stored in an EDC system accessible only to the study team 
members for the purpose of entering, reviewing and analyzing data.  Any paper records, such as 
case report files, produced will be stored in a secure location.  
 
The ISRU is responsible for distributing and tracking review of all IND Action Letters, Safety 
Reports, study specific Serious Adverse Events 
 
 Retention of Records   
Time points for the retention of records are described in detail in the contract between the 
grantor and the OCR and passed on to the participating site.  Please refer to the study specific 
terms for specific time points.  In all cases the Study Monitor must be notified of any plans to 
move records to an offsite location prior to doing so. 
 


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 Study Agents 
Any study agent supplied through the OCR from the manufacturer or a third party distributor 
may not be used for any purpose outside the scope of this protocol.  The agent may not be 
transferred to any party not participating in the clinical trial. 
 
 Informed Consent  
The IRB approved informed consent documents must be signed by the patient, or the patient’s 
legally authorized representative, before his or her participation in the study. 
 
The case history for each patient shall document that informed consent was obtained prior to 
participation in the study.  A copy of the informed consent documents must be provided to the 
patient or the patient’s legally authorized representative. If applicable, they will be provided in a 
certified translation of the local language. Original signed consent forms must be filed in each 
patient’s study file or medical record with a copy in the study file. 
 
 


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Appendix I: NYHA Classification 
 
 
 
 


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Appendix II: Child-Pugh Criteria 
 
 
 
 


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Appendix III: FACT FKSI-19 Questionnaire 
 


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Appendix IV: Novartis SAE Fax Covers  
 
 
Commented [CM1]: Please use updated SA# Suspected/Non 
Suspect Coverage, version 3, Mar 2017, on the attached email. 


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15.0 References 
1 Margulis V, Matin SF, Wood CG;  Chapter 51: Benign Renal Tumors. In: Campbell-Walsh Urology. Edition 10. (Wein AJ, 
et al, eds).  Elsevier, Philadelphia, PA, 2010. 
2 Sooriakumaran P, Anderson CJ. Everolimus for renal angiomyolipoma in tuberous sclerosis. Lancet 2013;381:783-5. 
3 Shitara K, Yatabe Y, Mizota A, Sano T, Nimura Y, Muro K. Dramatic tumor response to everolimus for malignant 
epithelioid angiomyolipoma. Jpn J Clin Oncol. 2011 Jun;41(6):814-6.  
4 Gennatas C1, Michalaki V, Kairi PV, Kondi-Paphiti A, Voros D. Successful treatment with the mTOR inhibitor everolimus 
in a patient with perivascular epithelioid cell tumor.World J Surg Oncol. 2012;10:181. 
5 Boulay A, Lane HA. The mammalian target of rapamycin kinase and tumor growth inhibition. Recent results in cancer 
research Fortschritte der Krebsforschung Progres dans les recherches sur le cancer 2007;172:99-124. 
6 Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nature reviews Cancer 2004;4:335-48. 
7 Velho S, Oliveira C, Ferreira A, et al. The prevalence of PIK3CA mutations in gastric and colon cancer. European journal 
of cancer 2005;41:1649-54. 
8 Goel A, Arnold CN, Niedzwiecki D, et al. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite 
instability-high sporadic colorectal cancers. Cancer research 2004;64:3014-21. 
9 Kingswood JC, Jozwiak S, Belousova ED, et al. The effect of everolimus on renal angiomyolipoma in patients with 
tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, 
placebo-controlled, Phase 3 trial EXIST-1. Nephrology, dialysis, transplantation : official publication of the European 
Dialysis and Transplant Association - European Renal Association 2014;29:1203-10. 
10 Bissler JJ, Kingswood JC, Radzikowska E, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis 
complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled 
trial. Lancet 2013;381:817-24. 
11 Budde K, Gaedeke J. Tuberous sclerosis complex-associated angiomyolipomas: focus on mTOR inhibition. American 
journal of kidney diseases : the official journal of the National Kidney Foundation 2012;59:276-83. 
12 Coombs EJ. Role of mTOR inhibition in the treatment of patients with renal angiomyolipomas. Journal of the American 
Association of Nurse Practitioners 2013;25:588-96. 
13 Faria E, Turturro F, Rao P, Matin SF. Malignant epithelioid angiomyolipoma: tumor and metabolic response to everolimus 
as evaluated with positron emission tomography. Clinical genitourinary cancer 2013;11:e1-5. 
14 Gennatas C, Michalaki V, Kairi PV, Kondi-Paphiti A, Voros D. Successful treatment with the mTOR inhibitor everolimus 
in a patient with perivascular epithelioid cell tumor. World journal of surgical oncology 2012;10:181. 
15 Kenerson H, Folpe AL, Takayama TK, Yeung RS. Activation of the mTOR pathway in sporadic angiomyolipomas and 
other perivascular epithelioid cell neoplasms. Human pathology 2007;38:1361-71. 
16 Grubb RL, Choyke PL, Pinto PA, Linehan WM, Walther MM. Management of von Hippel-Lindau-associated kidney 
cancer. Nat Clin Pract Urol. 2005 May;2(5):248-55. 
17 Curatolo P, Moavero R. mTOR Inhibitors in Tuberous Sclerosis Complex. Current neuropharmacology 2012;10:404-15. 
18 Rao D, Butt Z, Rosenbloom S, et al. A Comparison of the Renal Cell Carcinoma-Symptom Index (RCC-SI) and the 
Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI). Journal of pain and symptom management 
2009;38:291-8.