Clinical trial NCT02504892
Conditions: Renal Cancer Birt-Hogg-Dube Syndrome
Keywords: Overall Response Rate Hereditary Cancer Syndrome mTOR Therapy Naive
Sponsor: National Cancer Institute (NCI)
Start date: 2015-07-21; Completion date: 2018-04-17
Enrollment: 3 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

\- Research has shown that the drug everolimus can stop cancer cells from growing. It is approved for people with advanced kidney cancer. Researchers want to see if it also helps people with two other types of kidney cancer.

Objective:

\- To see if everolimus is safe and effective in people with Birt-Hogg-Dube Syndrome (BHD)-associated kidney cancer or sporadic (nonfamilial) chromophobe renal cancer.

Eligibility:

\- People ages 18 and over with BHD-associated kidney cancer or advanced sporadic chromophobe renal cancer.

Design:

* Participants will be screened with:
* Medical history, physical exam, and blood and urine tests.
* Computed tomography (CT) scan or magnetic resonance imaging (MRI) scan. They will lie in a machine that takes pictures of their chest/abdomen/pelvis.
* They may also be screened with:
* Another scan, of the brain or neck.
* Bone scan.
* Positron emission tomography scan with fludeoxyglucose (FDG-PET).
* Heart and lung tests.
* Tests for hepatitis.
* Participants will take a tablet once a day by mouth for up to a year. They will keep a diary of when they take the tablet and any symptoms.
* During the study, participants will have physical exams and urine and blood tests. They will have scans of the chest/abdomen/pelvis. They may have FDG-PET and bone scans.
* Participants will have tests for hepatitis and may have a tumor sample taken.
* Participants will have a follow-up visit 4-5 weeks finishing taking the drug. They will have a physical exam and blood tests. They may have scans and/or hepatitis tests.
* Participants will be called about every 3-6 months after the study ends to see how they are doing

Detailed description:
Background:

* Birt-Hogg-Dube (BHD) is a hereditary cancer syndrome with clinical manifestations including cutaneous fibrofolliculomas, lung cysts/pneumothorax, and renal cell carcinoma (RCC). RCC occurs in approximately 30% of patients with BHD. It presents at an early age of onset and is commonly bilateral and multifocal.
* Tumors associated with BHD can have variable histology, however approximately 85% of these tumors have a chromophobe component (either alone or part of a hybrid tumor mixed with elements of oncocytoma).
* The current management includes surgical resection with partial nephrectomy when tumors reach 3 cm. While significant morbidity can be associated with repeat, partial nephrectomy with this approach, most patients can maintain renal function and do not develop systemic disease. There are no proven systemic therapy options for BHD to date.
* Germline mutations in the gene Folliculin (FLCN) are the genetic hallmark of BHD and can be found in greater than 90% of patients. FLCN is believed to function like a classic tumor suppressor gene with a second hit in the wild type allele (somatic mutation or loss of heterozygosity) occurring in the majority of renal tumors.
* BHD is in the family of hamartomatous disorders similar to Tuberous Sclerosis Complex (TSC) and Cowden Syndrome, and studies have found activation of the phosphoinositide 3-kinase (PI3K)/mTOR pathway in BHD renal tumors. FLCN is believed be part of a complex that interacts with 5' AMP-activated protein kinase (AMPK) and is involved with regulation of mTOR activity. In vitro and in vivo models of FLCN loss demonstrate activation of both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
* Preclinical data from conditional FLCN knockout mice demonstrate that treatment with sirolimus can reverse renal manifestations.
* We hypothesize that mTOR inhibition with everolimus treatment will be clinically active in BHD associated RCC.

Objectives:

-To determine the overall response rate with everolimus treatment in subjects with BHD-associated renal tumors.

Eligibility:

-Patients with renal cell carcinoma (RCC) associated with Birt-Hogg-Dube Syndrome (BHD).

Design:

* This is an open label, phase II study to evaluate the efficacy and safety of everolimus therapy in patients with BHD associated renal tumors. Up to 16 evaluable patients will be enrolled.
* Tumor response rate will be measured by Response Evaluation Criteria in Solid Tumors (RECIST) and efficacy analysis will be done.
* Secondary endpoints will evaluate growth rates (cm/year) while on therapy.
* Additionally, reduction in the size of lung cysts and cutaneous fibrofolliculomas will be evaluated.

Arms: arm 1: Birt-Hogg-Dube Syndrome (BHD)-associated renal tumors arm 2: Sporadic chromophobe renal tumors
Interventions: intervention 1: Everolimus
Intervention descriptions: intervention 1: Everolimus is a commercial agent and is supplied by Novartis.

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
Confidential Information 
Abbreviated Title: Phase II everolimus for BHD 
NCI Protocol #: 15-C-0166 B 
Version Date: March 7, 2017 
 
Title: Phase 2 Study of Everolimus Therapy in Patients with Birt-Hogg-Dubé Syndrome (BHD)-
Associated Kidney Cancer 
 
NCI Principal Investigator: 
Ramaprasad Srinivasan, M.D., Ph.D. A, B, C, D, E, F 
Urologic Oncology Branch, CCR, NCI 
 
 
10 Center Drive, Room 2W-5940 
 
 
 
 
Bethesda, MD 20892  
Phone: 240-760-6251 
 
 
 
 
Email: ramasrin@mail.nih.gov  
 
NIH Associate Investigators: W. Marston Linehan, M.D., UOB, CCR, NCI A, B, C, D, E, F 
 
 
 
 
Shawna Boyle, M.D., UOB, CCR, NCI A, B, C, D, E, F 
 
 
 
 
Adam Metwalli, M.D., UOB, CCR, NCI A, B, C, D, E, F 
 
 
 
 
Cathy Vocke, Ph.D., UOB, CCR, NCI E, F 
Donald P. Bottaro, Ph.D., UOB, CCR, NCI E, F 
Laura S. Schmidt, Ph.D., UOB, CCR, NCI E, F 
Peter Choyke, M.D., MIP, CCR, NCI B, E, F 
Ashkan Malayeri, M.D., Radiology & Imaging Sciences, CC B, E, F 
Maria Merino, M.D., LP, CCR, NCI B, E, F 
 
 
 
 
Martha Ninos, R.N., OCD, CCR, NCI A, B, E, F 
 
 
 
 
Joanna Shih, Ph.D. (Statistician), DCTD, NCI E, F 
Julia Friend, PA-C, UOB, CCR, NCI A, B, C, D, E, F 
 
Kai Hammerich, M.D., UOB, CCR, NCI A, B, C, D, E, F 
Louis Spencer Krane, M.D., UOB, CCR, NCI A, B, C, D, E, F 
Abhinav Sidana, M.D.; UOB, CCR, NCI A, B, C, D, E, F 
Mark Ball, M.D., UOB, CCR, NCI A, B, C, D, E, F 
Thomas Sanford, M.D., UOB, CCR, NCI A, B, C, D, E, F 
Vladimir Valera Romero, M.D., UOB, CCR, NCI A, B, C, D, E, F 
Cheryl Royce, NP, OCD CCR, NCI A, B, D 
 
 
 
 
 
Referral Contact/ 
 
Martha Ninos, R.N., OCD, CCR, NCI 
Study Coordinator:  
10 Center Drive, Room 2-5750 
 
 
 
 
Bethesda, MD 20892 
Phone: 240-760-6248 
Email: mninos@mail.nih.gov  
 


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Abbreviated Title: Phase II everolimus for BHD 
Version Date: March 7, 2017 
Confidential Information 
 
A. Obtain information by intervening or interacting with living individuals for research 
purposes 
B. Obtaining identifiable private information about living individuals 
C. Obtaining the voluntary informed consent of individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable private information or data/specimens for 
research purposes 
F. Studying, interpreting, or analyzing de-identified data or specimens for research purposes 
G. Some/all research activities performed outside NIH 
 
 
 
 
 
 
 
Commercial Agent:     
Everolimus/RAD001/Affinitor (supplied by Novartis) 
 


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Abbreviated Title: Phase II everolimus for BHD 
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Confidential Information 
PRÉCIS  
Background: 
• Birt-Hogg-Dubé (BHD) is a hereditary cancer syndrome with clinical manifestations 
including cutaneous fibrofolliculomas, lung cysts/pneumothorax, and renal cell 
carcinoma (RCC). RCC occurs in approximately 30% of patients with BHD. It presents 
at an early age of onset and is commonly bilateral and multifocal. 
• Tumors associated with BHD can have variable histology, however approximately 85% 
of these tumors have a chromophobe component (either alone or part of a hybrid tumor 
mixed with elements of oncocytoma).  
• The current management includes surgical resection with partial nephrectomy when 
tumors reach 3 cm. While significant morbidity can be associated with repeat, partial 
nephrectomy with this approach, most patients can maintain renal function and do not 
develop systemic disease. There are no proven systemic therapy options for BHD to date. 
• Germline mutations in the gene Folliculin (FLCN) are the genetic hallmark of BHD and 
can be found in greater than 90% of patients. FLCN is believed to function like a classic 
tumor suppressor gene with a second hit in the wild type allele (somatic mutation or loss 
of heterozygosity) occurring in the majority of renal tumors.  
• BHD is in the family of harmatomaous disorders similar to TSC and Cowden Syndrome, 
and studies have found activation of the PI3K/mTOR pathway in BHD renal tumors. 
FLCN is believed be part of a complex that interacts with AMPK and is involved with 
regulation of mTOR activity. In vitro and in vivo models of FLCN loss demonstrate 
activation of both mTORC1 and mTORC2.  
• Preclinical data from conditional FLCN knockout mice demonstrate that treatment with 
sirolimus can reverse renal manifestations.  
• We hypothesize that mTOR inhibition with everolimus treatment will be clinically active 
in BHD associated RCC. 
Objectives: 
• To determine the overall response rate with everolimus treatment in subjects with BHD-
associated renal tumors. 
Eligibility: 
• Patients with renal cell carcinoma (RCC) associated with Birt-Hogg-Dubé Syndrome 
(BHD). 
Design: 
• This is an open label, phase II study to evaluate the efficacy and safety of everolimus 
therapy in patients with BHD associated renal tumors. Up to 16 evaluable patients will be 
enrolled. 
• Tumor response rate will be measured by RECIST and efficacy analysis will be done.   
• Secondary endpoints will evaluate growth rates (cm/year) while on therapy.   
• Additionally, reduction in the size of lung cysts and cutaneous fibrofolliculomas will be 
evaluated. 


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Abbreviated Title: Phase II everolimus for BHD 
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TABLE OF CONTENTS  
Précis ............................................................................................................................................... 3 
Table of Contents ............................................................................................................................ 4 
1. 
INTRODUCTION .................................................................................................................. 7 
1.1 
Study Objectives ........................................................................................................... 7 
1.1.1 
Primary Objective ..................................................................................................... 7 
1.1.2 
Secondary Objectives................................................................................................ 7 
1.2 
Background and Rationale ............................................................................................ 7 
1.2.1 
Overview of Birt-Hogg-Dubé (BHD) Syndrome ..................................................... 7 
1.2.2 
Introduction to investigational treatment using everolimus...................................... 9 
1.2.3 
Overview of everolimus ............................................................................................ 9 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 13 
2.1 
Eligibility Criteria ....................................................................................................... 13 
2.1.1 
Inclusion Criteria .................................................................................................... 13 
2.1.2 
Exclusion Criteria ................................................................................................... 14 
2.2 
Screening Evaluation .................................................................................................. 16 
2.3 
Registration Procedures .............................................................................................. 17 
2.4 
Baseline Evaluation .................................................................................................... 17 
3 
STUDY IMPLEMENTATION ............................................................................................ 17 
3.1 
Study Design............................................................................................................... 17 
3.2 
Drug Administration ................................................................................................... 18 
3.3 
Dose Modifications..................................................................................................... 18 
3.3.1 
Dose modification and dose delay .......................................................................... 18 
3.3.2 
Management of specific toxicities .......................................................................... 21 
3.4 
Study Calendar ........................................................................................................... 27 
3.5 
Follow up Evaluations ................................................................................................ 31 
3.6 
Criteria for Removal from Protocol Therapy and Off Study Criteria ........................ 31 
3.6.1 
Criteria for removal from protocol therapy ............................................................ 31 
3.6.2 
Off-Study Criteria ................................................................................................... 31 
3.6.3 
Off-Study Procedure ............................................................................................... 32 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 32 
4.1 
Permitted concomitant therapy ................................................................................... 32 


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4.1.1 
Cytochrome P450 and P-glycoprotein inhibitors/inducers/substrates .................... 32 
4.1.2 
Everolimus and drugs influencing CYP3A4 enzyme ............................................. 32 
4.1.3 
Vaccinations ............................................................................................................ 34 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 34 
5.1 
Correlative Studies for Research ................................................................................ 34 
5.1.1 
Tumor Biopsy ......................................................................................................... 34 
5.1.2 
Collection, Storage, Use and Disposition of Human Specimens ............................ 35 
5.1.3 
Storage and Research Use of Human Specimens ................................................... 35 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 36 
6.1 
Data Collection ........................................................................................................... 36 
6.2 
Response Criteria ........................................................................................................ 36 
6.2.1 
Definitions............................................................................................................... 37 
6.2.2 
Disease Parameters ................................................................................................. 37 
6.2.3 
Methods for Evaluation of Measurable Disease ..................................................... 38 
6.2.4 
Response Criteria .................................................................................................... 40 
6.2.5 
Duration of Response .............................................................................................. 42 
6.3 
Toxicity Criteria ......................................................................................................... 42 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .. 43 
7.1 
Definitions .................................................................................................................. 43 
7.1.1 
Adverse Event ......................................................................................................... 43 
7.1.2 
Suspected adverse reaction ..................................................................................... 43 
7.1.3 
Unexpected adverse reaction .................................................................................. 43 
7.1.4 
Serious..................................................................................................................... 44 
7.1.5 
Serious Adverse Event ............................................................................................ 44 
7.1.6 
Disability ................................................................................................................. 44 
7.1.7 
Life-threatening adverse drug experience ............................................................... 44 
7.1.8 
Protocol Deviation (NIH Definition) ...................................................................... 44 
7.1.9 
Non-compliance (NIH Definition) .......................................................................... 44 
7.1.10 Unanticipated Problem............................................................................................ 44 
7.2 
Investigator Reporting: Novartis instructions for rapid notification of serious adverse events 45 
7.2.1 
Pregnancies ............................................................................................................. 45 
7.3 
NCI-IRB And NCI Clinical Director (CD) Reporting ............................................... 46 


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7.3.1 
NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths . 46 
7.3.2 
NCI-IRB Requirements for PI Reporting at Continuing Review ........................... 46 
7.3.3 
NCI-IRB Reporting of IND Safety Reports............................................................ 46 
7.4 
Data and Safety Monitoring Plan ............................................................................... 46 
7.4.1 
Principal Investigator/Research Team .................................................................... 46 
8 
STATISTICAL CONSIDERATIONS.................................................................................. 47 
9 
COLLABORATIVE AGREEMENTS ................................................................................. 47 
9.1 
Agreement Type ......................................................................................................... 47 
10 HUMAN SUBJECTS PROTECTIONS ............................................................................... 47 
10.1 
Rationale For Subject Selection ................................................................................. 47 
10.2 
Participation of Children ............................................................................................ 47 
10.3 
Participation of Subjects Unable to Give Consent ..................................................... 47 
10.4 
Evaluation of Benefits and Risks/Discomforts ........................................................... 48 
10.4.1 Benefits ................................................................................................................... 48 
10.4.2 Risks ........................................................................................................................ 48 
10.5 
Risks/Benefits Analysis .............................................................................................. 48 
10.6 
Consent and Assent Process and Documentation ....................................................... 49 
10.6.1 Telephone Re-Consent Procedure........................................................................... 49 
10.6.2 Informed Consent of Non-English Speaking Subjects ........................................... 50 
11 PHARMACEUTICAL INFORMATION ............................................................................. 50 
11.1 
Everolimus .................................................................................................................. 50 
11.1.1 Source ..................................................................................................................... 50 
11.1.2 Toxicity ................................................................................................................... 50 
11.1.3 Formulation and preparation ................................................................................... 50 
11.1.4 Stability and Storage ............................................................................................... 51 
11.1.5 Administration procedures ...................................................................................... 51 
11.1.6 Incompatibilities ..................................................................................................... 51 
12 REFERENCES ..................................................................................................................... 52 
13 APPENDICES ...................................................................................................................... 55 
13.1 
Appendix A: Performance Status Criteria .................................................................. 55 
13.2 
Appendix B:  Everolimus Pill and Side Effects Diary ............................................... 56 
13.3 
Appendix C: Patient Instructions for Everolimus Therapy ........................................ 57 


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Abbreviated Title: Phase II everolimus for BHD 
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1. INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
To determine the overall response rate with everolimus treatment in subjects with BHD-
associated renal tumors. 
 
1.1.2 Secondary Objectives 
1.1.2.1 To study the safety and tolerability of everolimus in patients with BHD-associated 
localized renal tumors. 
1.1.2.2 To assess changes in tumor growth rates and ability to delay surgical management in 
BHD patients. 
1.1.2.3 To assess progression-free survival (PFS) and overall survival (OS). 
1.1.2.4 To evaluate the effect of everolimus on mTOR activity in renal tumors (using pre- and 
on-treatment biopsies when available). 
1.1.2.5 To assess the effect of therapy on BHD associated lung cysts and cutaneous 
fibrofolliculomas. 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Overview of Birt-Hogg-Dubé (BHD) Syndrome 
Birt-Hogg-Dubé (BHD) is a hereditary cancer syndrome characterized by a propensity to 
develop cutaneous fibrofolliculomas/trichodiscomas, lung cysts/pneumothorax, and renal cell 
carcinoma (RCC).1 While fibrofilliculomas and lung cysts appear to be highly penetrant 
(affecting 70% or more patients), RCC occurs in approximately 12-34% of patients with BHD. It 
presents at an early age of onset (median age of onset around 50 years) and is commonly 
bilateral and multifocal.2-4 Renal tumors associated with BHD can have variable histology; 
however approximately 85% of these tumors have a chromophobe component (either alone or 
part of a hybrid tumor mixed with elements of oncocytoma).5 Clear cell RCC, papillary RCC and 
oncocytomas constitute the remainder of tumors. There is considerable variability in presentation 
and different members of a given family may present with dissimilar renal findings; furthermore, 
in any given individual, multiple histological variants of RCC can coexist. Microscopic foci of 
dysplastic cells defined as renal ‘oncocytosis’ have been observed in adjacent ‘normal’ kidney 
parenchyma in the majority of BHD patients who present with renal tumors independent of 
histology, thus suggesting that these oncocytic cells may be precursor lesions to hybrid oncocytic 
tumors as well as chromophobe and clear cell renal carcinomas.  
The current management of BHD patients with renal tumors includes surveillance of small 
tumors with nephron-sparing surgical resection when tumors reach 3 cm.6 While significant 
morbidity can be associated with repeat, partial nephrectomy, with this approach, most patients 
can maintain renal function and do not develop systemic disease. Once individual tumors reach a 
size of 3 cm or more, there is an incremental increased risk of metastatic disease. Although 
metastatic disease is rarely encountered in clinical practice in appropriately managed patients, 


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the disease is usually fatal once metastatic and there are no proven systemic therapy options for 
BHD to date. 6,7  
Germline mutations in the Folliculin (FLCN) gene are the genetic hallmark of BHD and 
mutations or deletions of this gene can be found in greater than 90% of patients.8,9 The gene for 
BHD was localized to the short arm of chromosome 17 (17p) by genetic linkage analysis and 
was further identified by positional cloning.3,10,11 The gene consists of 11 coding exons, and 
mutations have been identified in all 11 exons. The majority of germline folliculin mutations are 
insertions/deletions, nonsense mutations or splice-site alterations that result in a truncated protein 
with loss of function.1 More recently, partial deletions involving FLCN have been identified in 
the germline of BHD patients.  
FLCN is believed to function like a classic tumor suppressor gene with a second hit in the wild 
type allele occurring in the majority of renal tumors. In a study of 77 BHD-associated renal 
tumors, sequence alteration were identified in over half the tumors, while in 17% of samples the 
second allele was lost as a result of LOH on chromosome 17.12  
The exact function of folliculin and the mechanisms by which loss of function of this protein 
leads to renal tumors remain to be fully elucidated. However, recent studies have begun to 
provide some insight into the biochemical pathways involving folliculin. Co-
immunoprecipitation experiments in cells overexpressing FLCN identified a novel FLCN 
interacting protein, FNIP1, that associates with FLCN through its C-terminus and interacts with 
5’-AMP-activated protein kinase (AMPK), a kinase-competent complex that functions to 
monitor and maintain energy homeostasis in cells by negatively regulating mammalian target of 
rapamycin (mTOR), the master controller of protein synthesis and cell growth.13,14  Baba et al. 
showed that FLCN exists in multiple phosphorylated forms, which are dephosphorylated by 
different mechanisms (inhibition of mTOR signaling and inhibition of AMPK activity), 
suggesting the existence of phosphorylated FLCN residues that function to either inhibit or 
activate FLCN function, respectively.13 FLCN phosphorylation sites at serine 62 and serine 302 
were identified, which appear to be differently regulated by the mTORC1-dependent pathway. 
FNIP1 expression enhances FLCN phosphorylation and both proteins can serve as direct or 
indirect substrates of AMPK.13,15 A second folliculin interacting protein, FNIP2, was 
subsequently identified. FNIP2 shares significant homology with FNIP1 and was shown to be a 
heterodimeric partner for both FNIP1 and FLCN.16,17 
Several lines of evidence from Flcn-deficient mouse models suggest that Flcn may modulate the 
AKT-mTOR pathway. Conditional inactivation of Flcn specifically in mouse kidneys resulted in 
the development of enlarged multicystic kidneys with hyperplastic cells protruding into the 
cystic lumen and cystic renal cell carcinomas that resulted in morbidity by 21 days of age due to 
renal failure.18,19 Flcn-deficient kidneys showed significant upregulation of mTOR activity as 
evidenced by activation of downstream effectors. Rapamycin treatment extended the lifespan and 
ameliorated the cystic kidney phenotype confirming that the AKT-mTOR pathway was activated 
in the Flcn knockout kidneys. In support of these data, Flcn heterozygous knockout mice 
developed solid renal tumors at median age of 23 months that displayed loss of the remaining 
Flcn allele and histologies similar to human BHD tumors. These tumors demonstrated activated 
phospho-AKT, phospho-mTORC1 and phospho-mTORC2.20 Human BHD tumors also showed 
activated AKT-mTORC1 and AKT-mTORC2 pathways, supporting a role for FLCN in 
regulating AKT-mTORC1-mTORC2 signaling in human kidney.  


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Abbreviated Title: Phase II everolimus for BHD 
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Based on these data, we hypothesize that mTOR inhibition with everolimus treatment will be 
clinically active in BHD associated RCC. 
1.2.2 Introduction to investigational treatment using everolimus 
Everolimus is a novel derivative of rapamycin. It has been in clinical development since 1996 as 
an immunosuppressant in solid organ transplantation. Everolimus is approved in Europe and 
other global markets (trade name: Certican®) for cardiac and renal transplantation, and in the 
United States (trade name: Zortress®) for the prevention of organ rejection of kidney 
transplantation. 
Afinitor® and was approved for adults with advanced renal cell carcinoma (RCC) after failure of 
treatment with sunitinib or sorafinib in 2009. In 2010, Afinitor® received United States (US) 
approval for patients with subependymal giant cell astrocytoma (SEGA) associated with 
tuberous sclerosis complex (TSC). Everolimus is also available as Votubia® in the European 
Union (EU) for patients with SEGA associated with TSC who require therapeutic intervention 
but are not candidates for curative surgical resection. Afinitor® was approved for “progressive 
pancreatic neuroendocrine tumor (PNET) in patients with unresectable, locally advanced, or 
metastatic disease” in 2011 in various countries, including the US and Europe. In 2012 Afinitor® 
received approval for the treatment of postmenopausal women with advanced hormone receptor-
positive, HER2- negative breast cancer (advanced HR+ BC) in combination with exemestane, 
after failure of treatment with letrozole or anastrozole. Furthermore, in 2012, Afinitor® received 
approval for the treatment of patients with TSC who have renal angiomyolipoma not requiring 
immediate surgery. 
Approximately 30,582 cancer patients have been treated with everolimus as of 30-Sep-2013: 
• 16,671 patients in Novartis-sponsored clinical trials 
• 1,911 patients in the individual patient supply program 
• More than 12,000 patients in investigator-sponsored studies. 
• In addition, healthy volunteer subjects and non-oncology hepatically impaired subjects 
have participated in the clinical pharmacology studies. 
The following is a brief summary of the main characteristics of everolimus. More complete 
information can be obtained from the everolimus Investigator’s Brochure (IB).  
1.2.3 Overview of everolimus  
Everolimus is a derivative of rapamycin which acts as a signal transduction inhibitor (Table 1-1, 
Figure 1-1).  Everolimus selectively inhibits mTOR (mammalian target of rapamycin), 
specifically targeting the mTOR-raptor signal transduction complex.  mTOR is a key serine-
threonine kinase in the PI3K/AKT signaling cascade, which is known to be dysregulated in a 
wide spectrum of human cancers.23 
Everolimus is believed to act 
• directly on the tumor cells by inhibiting tumor cell growth and proliferation; 


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Abbreviated Title: Phase II everolimus for BHD 
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Confidential Information 
• indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent 
inhibition of tumor cell VEGF (vascular endothelial growth factor) production and 
VEGF-induced proliferation of endothelial cells). 
Table 1-1: Everolimus - Drug substance 
Chemical name 
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-
dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-
methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-
hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-
tetraene-2,3,10,14,20-pentaone 
International non-
proprietary name 
Everolimus 


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Abbreviated Title: Phase II everolimus for BHD 
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Figure 1-1: Chemical structure of Everolimus 
N
O
OH
C
H3
O
O
CH3
CH3
OH
C
H3
O
O
O
O
H
C
H3
O
CH3
O
C
H3
O
O
CH3
CH3
O
C
H3
 
1.2.3.1 mTOR pathway and cancer 
At the cellular and molecular level, everolimus acts as a signal transduction inhibitor. It 
selectively inhibits mTOR (mammalian target of rapamycin), a key protein kinase which 
regulates cell growth, proliferation and survival. The mTOR kinase is mainly activated via the 
phosphatidylinositol 3-kinase (PI3-Kinase) pathway through AKT/PKB and the tuberous 
sclerosis complex (TSC1/2). Mutations in these components or in PTEN, a negative regulator of 
PI3-kinase, may result in their dysregulation. Abnormal functioning of various components of 
the signaling pathways contributes to the pathophysiology of numerous human cancers. Various 
preclinical models have confirmed the role of this pathway in tumor development.24 
The main known functions of mTOR include the following 25: 
• 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 cancers26,27; 
• The loss of PTEN protein, either through gene deletion or functional silencing (promoter 
hypermethylation), is reported in approximately 60% of primary human colorectal 
cancers28; 
• 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. 


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1.2.3.2 Non-clinical experience 
Everolimus inhibits the proliferation of a range of human tumor cell lines in vitro including lines 
originating from lung, breast, prostate, colon, melanoma and glioblastoma. IC50s range from 
sub/low nM to µM. Everolimus also inhibits the proliferation of human umbilical vein 
endothelial cells (HUVECS) in vitro, with particular potency against VEGF-induced 
proliferation suggesting that everolimus may also act as an anti-angiogenic agent. The anti-
angiogenic activity of everolimus was confirmed in vivo. Everolimus selectively inhibited 
VEGF-dependent angiogenic response at well tolerated doses. Mice with primary and metastatic 
tumors treated with everolimus showed a significant reduction in blood vessel density when 
compared to controls. 
The potential of everolimus as an anti-cancer agent was shown in rodent models. Everolimus is 
orally bioavailable, residing longer in tumor tissue than in plasma in a subcutaneous mouse 
xenograft model, and demonstrating high tumor penetration in a rat pancreatic tumor model. The 
pharmacokinetic profile of everolimus indicates sufficient tumor penetration, above that needed 
to inhibit the proliferation of endothelial cells and tumor cell lines deemed sensitive to 
everolimus in vitro. 
Everolimus administered orally daily was a potent inhibitor of tumor growth, at well tolerated 
doses, in 11 different mouse xenograft models (including pancreatic, colon, epidermoid, lung and 
melanoma) and two syngeneic models (rat pancreatic, mouse orthotopic melanoma). These 
models included tumor lines considered sensitive and “relatively resistant” in vitro. In general, 
everolimus was better tolerated in mouse xenograft models than standard cytotoxic agents (i.e., 
doxorubicin and 5-fluorouracil), while possessing similar anti-tumor activity. Additionally, 
activity in a VEGF-impregnated subcutaneous implant model of angiogenesis and reduced 
vascularity (vessel density) of everolimus-treated tumors (murine melanoma) provided evidence 
of in vivo effects of angiogenesis. 
It is not clear which molecular determinants predict responsiveness of tumor cells to everolimus. 
Molecular analysis has revealed that relative sensitivity to everolimus in vitro correlates with the 
degree of phosphorylation (activation) of the AKT/PKB protein kinase and the S6 ribosomal 
protein; in some cases (i.e., glioblastoma) there is also a correlation with PTEN status. 
In vivo studies investigating the anti-tumor activity of everolimus in experimental animal tumor 
models showed that everolimus monotherapy typically reduced tumor cell growth rates rather 
than produced regressions. These effects occurred within the dose range of 2.5 mg to 10 mg/kg, 
orally once a day. 
In preclinical models, the administration of everolimus is associated with reduction of protein 
phosphorylation in target proteins downstream of mTOR, notably phosphorylated S6 (p-S6) and 
p-4E-BP1, and occasionally with an increase in phosphorylated AKT, a protein upstream of 
mTOR signaling pathway. 
All significant adverse events observed in toxicology studies with everolimus in mice, rats, 
monkeys and mini-pigs were consistent with its anticipated pharmacological action as an anti-
proliferative and immunosuppressant and at least in part reversible after a 2 or 4-week recovery 
period with the exception of the changes in male reproductive organs, most notably testes. 


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In vitro genotoxicity studies covering relevant genotoxicity end-points showed no evidence of 
clastogenic or mutagenic activity. 
In male fertility studies in rats, testicular morphology was affected at 0.5 mg/kg and above, and 
sperm motility, sperm head count and plasma testosterone levels were diminished at 5 mg/kg 
which corresponded to 0.7 times the estimated clinical exposure at 10 mg/day, and caused a 
decrease in male fertility. There was evidence of reversibility. Female fertility was not affected, 
but everolimus caused an increase of pre-implantation loss in female rats at doses > 0.1 mg/kg, 
suggesting it could also potentially impact fertility in females.  Everolimus crossed the placenta 
and was toxic to the conceptus. In rats, everolimus caused embryo/fetotoxicity at systemic 
exposure below the planned therapeutic level comprising mortality and reduced fetal weight. The 
incidence of skeletal variations and malformations at 0.3 and 0.9 mg/kg (e.g. sternal cleft) was 
increased. In rabbits, embryo toxicity was evident by an increase in late resorptions. Effects of 
everolimus on the pre- and postnatal development of rats were limited to slightly affected body 
weight and survival in the F1-generation at ≥0.1 mg/kg, and did not indicate a specific toxic 
potential.  
The potential reproductive risk for humans is unknown. However, due to the observed 
malformations in rats, everolimus should be considered potentially teratogenic. Everolimus 
should not be given to pregnant women unless the potential benefit outweighs the potential risk 
for the fetus. Women of childbearing potential should be advised to use highly effective 
contraception methods while they are receiving everolimus and up to 8 weeks after treatment has 
been stopped. It is not known whether everolimus is excreted in human milk. In animal studies, 
everolimus and/or its metabolites were readily transferred into the milk of lactating rats. 
Therefore, women who are taking everolimus should not breastfeed. 
Additional information about everolimus can be found in the Affinitor package insert. 
 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Patients must have a clinical diagnosis of Birt-Hogg-Dubé Syndrome (clinical features 
consistent with BHD and /or a germline FLCN mutation) and the presence of localized, 
locally advanced or advanced, renal tumor(s). 
2.1.1.2 Patients must have measurable disease, as defined by RECIST 1.1 
2.1.1.3 Age >18 years.   
2.1.1.4 ECOG performance status <1 (Karnofsky >70%, see Appendix A, Section 13.1). 
2.1.1.5 Patients must have normal organ and marrow function as defined below:  
− leukocytes  
 
 
 
 
>3,000/mcL 
− absolute neutrophil count  
>1,500/mcL 
− platelets  
 
 
 
 
 
>100,000/mcL 
− total bilirubin 
 
 
 
 
≤ 2mg/dL  
− AST(SGOT)/ALT(SGPT)  
<2.5 X institutional upper limit of       


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normal (≤5x ULN in patients with 
liver metastases) 
− creatinine 
 
 
 
 
 
≤ 2.0 X ULN  
OR 
− creatinine clearance  
 
 >30 mL/min/1.73 m2  
− fasting serum cholesterol  
 
≤300 mg/dL OR ≤7.75 mmol/L  
      AND 
− fasting triglycerides   
 
 
≤2.5x ULN 
 
NOTE: In case one or both of these thresholds (for fasting serum 
cholesterol or triglyceride) are exceeded, the patient can only be 
included after initiation of appropriate lipid lowering medication. 
 
2.1.1.6 No history of major bleeding, recent or active myocardial ischemia, GI perforation, 
cerebrovascular accidents or other significant illness. 
2.1.1.7 Recovery from acute toxicity of prior treatment for RCC (to ≤ grade 1 the active version 
of CTCAE or to a level permitted under other sections of Inclusion/ Exclusion criteria).  
Additionally, in patients who have received standard or experimental treatments for 
their RCC at least approximately 5 half-lives should have elapsed from the last dose at 
the time of study entry.  
2.1.1.8 No prior therapy with an mTOR-pathway inhibitor.  
2.1.1.9 Ability of subject to understand and the willingness to sign a written informed consent 
document. 
 
2.1.2 Exclusion Criteria 
2.1.2.1 Patients currently receiving anticancer therapies (including chemotherapy, radiation 
therapy, antibody based therapy, etc.). 
2.1.2.2 Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. 
sirolimus, temsirolimus). 
2.1.2.3 Patients with known brain metastases unless treated with an appropriate modality with no 
evidence of progression/recurrence for >3months 
2.1.2.4 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
requiring IV antibiotics, invasive fungal infection, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
2.1.2.5 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with everolimus.  Known impairment of 
gastrointestinal (GI) function or GI disease that may significantly alter the absorption of 
oral everolimus. 
2.1.2.6 Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. 
Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) 


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may be included, however blood glucose and antidiabetic treatment must be monitored 
closely throughout the trial and adjusted as necessary. 
2.1.2.7 Patients who have any severe and/or uncontrolled medical conditions such as: 
a. unstable angina pectoris, symptomatic congestive heart failure, myocardial 
infarction ≤6 months prior to start of everolimus, serious uncontrolled cardiac 
arrhythmia, or any other clinically significant cardiac disease. 
b. Symptomatic congestive heart failure of New York heart Association Class III or 
IV. 
c. known severely impaired lung function (spirometry and DLCO 50% or less of 
normal and O2 saturation 88% or less at rest on room air). 
d. active, bleeding diathesis. 
2.1.2.8 Chronic (treatment > 1 month) or ongoing treatment with corticosteroids or other 
immunosuppressive agents. Topical or inhaled corticosteroids are allowed. 
2.1.2.9 Patients who have received live attenuated vaccines within 1 week of start of everolimus  
Examples of live attenuated vaccines include intranasal influenza, measles, mumps, 
rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines. 
2.1.2.10 Patients, who in the opinion of the investigator, are unlikely to comply with follow-up 
visits or other study requirements. Patients who are currently part of or have 
participated in any clinical investigation with an investigational drug within 1 month 
prior to dosing. 
2.1.2.11 Pregnant or nursing (lactating) women. 
2.1.2.12 Women of child-bearing potential (WOCBP), defined as all women physiologically 
capable of becoming pregnant, who do not agree to use highly effective methods of 
contraception during the study and 8 weeks after.  
Highly effective contraception  methods include combination of any two of the 
following: 
a. Use of oral, injected or implanted hormonal methods of contraception or; 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
c. Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal 
suppository; 
d. Total abstinence or; 
e. Male/female sterilization. 
 
Women are considered post-menopausal and not of child-bearing potential 
if they have had 12 months of natural (spontaneous) amenorrhea with an 
appropriate clinical profile (e.g. age appropriate, history of vasomotor 
symptoms) or have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks prior to randomization. In the 
case of oophorectomy alone, only when the reproductive status of the woman 


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has been confirmed by follow up hormone level assessment is she considered 
not of child-bearing potential. 
2.1.2.13 Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate 
contraception, during the study and for 8 weeks after the end of treatment. 
2.1.2.14 Prior invasive malignancy of other histology currently requiring treatment. 
2.1.2.15 Patients with active Hepatitis B (detectable HBV-DNA or HBsAg +) or Hepatitis C 
infection (detectable HCV RNA by PCR) 
2.1.2.16 Patients who are currently on or have used potent  or moderate inhibitors or strong 
inducers CYP3A4 or PgP inhibitors in the past 2 weeks 
2.2 
SCREENING EVALUATION 
Screening evaluations must be performed within the timeframes indicated below.  Screening 
procedures may be performed on an NIH screening protocol or the UOB 02-C-0159. Imaging 
studies may also be performed at an outside institution for expedience.  If procedures are 
performed on this treatment protocol, the screening examination must start with the Informed 
Consent procedure. The investigator is obliged to give the patient thorough information about the 
study and the study related assessments, and the patient should be given ample time to consider 
his or her participation. The investigator must not start any study related procedure before ICF is 
signed and dated by both patient (and impartial witness, if applicable) and investigator. 
 To be performed within 2 weeks prior to subject receiving study drug 
o History and physical evaluation 
o Vital signs 
o Performance status 
o EKG 
o Hematology: CBC with differential 
o Biochemistry: BUN or uric acid, creatinine, LDH, total protein, sodium, potassium, 
calcium, total bilirubin, GGT, albumin, alkaline phosphatase, AST, fasting glucose 
o Fasting serum lipid profile 
o Urinalysis 
o CT chest/abdomen/pelvis and/or CT chest plus MRI abdomen/pelvis, bone scans in 
patients with known or suspected bone metastases 
o CT Neck in patients with known or suspected metastatic disease in the neck 
o Brain MRI or Brain CT (studies are to be performed with contrast unless renal 
impairment or allergy prohibits the use of contrast) 
o FDG-PET in patients with known or suspected metastatic disease 
o Serum β HCG (in female patients of childbearing potential) 
o HbA1c, pulmonary function tests (if clinically indicated), pulse oximetry 
o HBV-DNA, HBsAg, HBs Ab, HBc Ab, HCV-RNA-PCR  


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The management guidelines, in Section 3.3.2, are provided according to the results of the 
baseline assessment of viral load and serological markers for hepatitis B. 
The management guidelines, in Section 3.3.2, are provided according to the results of the 
baseline assessment of hepatitis C viral load. 
For baseline evaluations, please see Section 2.4.  
2.3 
REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office (HOIS) ncicentralregistration-
l@mail.nih.gov.  After confirmation of eligibility at Central Registration Office, CRO staff will 
call pharmacy to advise them of the acceptance of the patient on the protocol prior to the release 
of any investigational agents.  Verification of Registration will be forwarded electronically via e-
mail to the research team. A recorder is available during non-working hours.  
2.4 
BASELINE EVALUATION 
Baseline procedures need not be repeated if they have been performed within the appropriate 
screening timeframe (See Section 2.2). 
• Height 
• Weight 
• Thyroid function tests 
• Prothrombin time/partial thromboplastin time (PT/PTT) 
• Serum β hCG (in female patients of childbearing potential) within 2 weeks. 
• CBC with differential. 
• Total and direct bilirubin, AST/SGOT, ALT/SGPT, acute care panel, albumin, 
calcium, magnesium, LDH, amylase, lipase, lipid panel, T3, free thyroxine, TSH 
• PFT 
• Biopsies (optional) for correlative studies (see Section 5.1) 
• Obtain archival tumor tissue when available (tissue block and/or up to 30 unstained 
slides)  
• Photographic evaluation of skin lesions (only in patients with BHD- associated 
cutaneous) 
 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is an open label, phase II study to evaluate the efficacy and safety of everolimus therapy in 
patients with BHD. Up to 16 evaluable patients will be enrolled. 


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Patients with BHD typically have bilateral, multifocal tumors localized to the kidneys. In 
general, the growth rates of these tumors is relatively slow and they are not expected to pose a 
risk of metastatic spread when the size of the tumors is <3cm. Most of these patients have a 
surgical option (partial nephrectomy) and are less willing to accept side effects than are patients 
with metastatic disease. Therefore, everolimus will be administered at a starting dose of 5mg PO 
QD. If the following criteria are met at the time of the first restaging evaluation, the dose will be 
escalated to 10mg PO QD.  
A) The patient has not had a complete or partial response, and 
B) The patient has not experienced grade 2 or greater toxicity attributable to everolimus 
Restaging will be performed approximately every 12 weeks. Treatment can continue for up to 52 
weeks in the absence of unacceptable toxicity or disease progression, except in patients with 
metastatic RCC associated with BHD in whom everolimus will be continued until disease 
progression or unacceptable toxicity. 
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded. 
3.2 
DRUG ADMINISTRATION 
The investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient should be instructed to contact the investigator if he/she is 
unable for any reason to take the study drug as prescribed. 
Everolimus should be administered orally once daily at approximately the same time every day, 
either consistently with or consistently without food.   
The tablets should be swallowed whole with a glass of water and should not be chewed or 
crushed. For patients unable to swallow tablets, the tablet(s) should be dispersed completely in a 
glass of water (containing approximately 30 mL) by gently stirring until the tablet(s) is fully 
disintegrated (approximately 7 minutes), immediately prior to drinking. The glass should be 
rinsed with the same volume of water and the rinse completely swallowed to ensure the entire 
dose is administered.  
If vomiting occurs, no attempt should be made to replace the vomited dose. Patients should be 
instructed that if they miss a dose on one day, they must not take any extra dose the next day, but 
instead contact the study center as soon as possible to ask for advice.  
Patients should be instructed to take the study drug as per protocol and instructed to complete the 
medication diary found in Appendix B, Section 13.2.  All dosages prescribed and dispensed to 
the patient and any dose change or interruption must be recorded appropriately. 
3.3 
DOSE MODIFICATIONS 
3.3.1 Dose modification and dose delay 
3.3.1.1 Dosing 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.  


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All dose modifications should be based on the worst preceding toxicity. Dose modifications will 
be made only for those AEs thought to be related to everolimus.  
For each patient, once a dose reduction has occurred, the dose level may not be re-escalated 
during subsequent treatment cycles with everolimus.  Dose modifications will follow the scheme 
outlined in Table 3-1.  No more than 2 dose reductions will be allowed per patient. 
Table 3-1: Study treatment schedule adjustments and dose levels  
Dose level 
Dose and schedule* 
1 
10 mg PO QD 
0 (starting dose) 
5mg PO QD 
-1 
2.5mg PO QD 
* Once patients have had a dose escalation to the 10mg p.o. QD dose, dose reductions for AEs 
will be to move to the next lower dose level. 
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. 
Table 3-2 and Table 3-3 list the dosing guidelines for everolimus-related non-hematologic and 
hematologic toxicities.  
 


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Table 3-2: Dosing guidelines for everolimus-related non-hematologic toxicities 
Toxicity 
Action 
Non-Infectious Pneumonitis 
Please refer to Table 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 (> 5.0 - 20.0 ULN)* 
Interrupt everolimus administration until resolution to ≤ grade 1 (or ≤ 
grade 2 if baseline values were within the range of grade 2). If 
resolution occurs ≤ 7 days, everolimus should be re-started at the dose 
level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, hold 
everolimus until recovery to ≤ grade 1 or baseline grade / value and 
reintroduce everolimus at one dose level lower, if available. 
AST or ALT elevation 
Grade 4 (> 20 x ULN)* 
 
 
 
 
Discontinue everolimus. 
Intolerable grade 2 mucositis, or grade 
3 AE, except hyperglycemia or 
hypertriglyceridemia or 
hypercholesterolemia (see Section 
3.3.2.6) 
Interrupt everolimus administration until resolution to ≤ grade 1 or 
baseline grade / value. 
If resolution occurs within ≤ 7 days, everolimus should be re-started at 
the dose level prior to interruption. 
If resolution takes > 7 days, or if event recurs within 28 days, hold 
everolimus until recovery to ≤ grade 1 or baseline grade / value and 
reintroduce everolimus at one dose level lower, if available. 
Patients will be withdrawn from the study if they fail to recover to ≤ 
grade 1 or baseline grade / value within 28 days. 
Any other grade 4 
Discontinue everolimus. 
Grade 3 or 4 clinical liver failure 
(asterixis or encephalopathy/coma) 
Discontinue everolimus 
Recurrence of intolerable grade 2 
mucositis or grade 3 event after dose 
reduction 
Reduce dose to the next lower dose level, if available. The lowest 
possible dose level of everolimus is 2.5 mg daily. Below this level, 
everolimus must be discontinued. If toxicity recurs at Grade 3, consider 
discontinuation 
 
 
Any non-hematologic toxicity 
requiring Everolimus interruption for 
> 28 days 
Discontinue everolimus 
 


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Table 3-3 Dosing guidelines for everolimus-related 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 everolimus 
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 everolimus 
Febrile neutropenia 
Interrupt everolimus until resolution to grade ≤ 1 (or baseline value) 
and no fever. Reintroduce everolimus at one dose level lower, if 
available.* 
Recurrence of grade 3 toxicity after dose 
reduction 
Reduce dose to the next lower dose level, if available. The lowest 
possible dose level of everolimus is 5 mg every other day (2.5 mg 
daily). Below this level, everolimus must be discontinued. 
*Any hematologic toxicity requiring 
everolimus interruption for > 28 days 
Discontinue everolimus 
3.3.2 Management of specific toxicities 
Overall, safety data available from completed, controlled and uncontrolled studies indicate that 
everolimus is generally well tolerated at weekly or daily dose schedules. The safety profile is 
characterized by manageable adverse events (AEs). These AEs are generally reversible and non-
cumulative. 
Adverse events most frequently observed with everolimus are stomatitis, rash, diarrhea, fatigue, 
infections, asthenia, nausea, peripheral edema, decreased appetite, headache, dysgeusia, 
epistaxis, mucosal inflammation, pneumonitis, weight decreased, vomiting, pruritus, cough, 
dyspnea, dry skin, nail disorder, and pyrexia. Overall, the most frequently observed laboratory 
abnormalities include decreased hematology parameters including hemoglobin, lymphocytes, 
platelets, and neutrophils (or collectively as pancytopenia); increased clinical chemistry 
parameters including cholesterol, triglycerides, glucose, aspartate transaminases, creatinine, 
alanine transaminases, and bilirubin; and decreased clinical chemistry parameters including 
phosphate and potassium. The majority of these AEs have been of mild to moderate severity 
(NCI CTC grade 1-2).  
3.3.2.1 Management of infections 
Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, 
viral or protozoal infections, including infections with opportunistic pathogens. Localized and 
systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, 


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such as aspergillosis or candidiasis and viral infections including reactivation of hepatitis B 
virus, have been described in patients taking everolimus Some of these infections have been 
severe (e.g. leading to sepsis, respiratory or hepatic failure) and occasionally have had a fatal 
outcome. 
Physicians and patients should be aware of the increased risk of infection with everolimus Treat 
pre-existing infections prior to starting treatment with everolimus. While taking everolimus, be 
vigilant for symptoms and signs of infection; if a diagnosis of infection is made, institute 
appropriate treatment promptly and consider interruption or discontinuation of everolimus. 
If a diagnosis of invasive systemic fungal infection is made, discontinue everolimus and treat 
with appropriate antifungal therapy. 
3.3.2.2 Management of skin toxicity 
For patients with grade 1 toxicity, no specific supportive care is usually needed or indicated. 
Rash must be reported as an AE. Patients with grade 2 or higher toxicity may be treated with the 
following suggested supportive measures at the discretion of the investigator: oral minocycline, 
topical tetracycline, topical clindamycin, topical silver sulfadiazine, diphenhydramine, oral 
prednisolone (short course), topical corticosteroids, or pimecrolimus. 
3.3.2.3 Renal Failure Events 
Cases of renal failure (including acute renal failure), some with fatal outcome, occurred in 
patients treated with everolimus. Renal function of patients should be monitored particularly 
where patients have additional risk factors that may further impair renal function. 
Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients 
taking everolimus. Monitoring of renal function, including measurement of blood urea nitrogen 
(BUN), urinary protein, or serum creatinine, is recommended prior to the start of everolimus 
therapy and periodically thereafter. 


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3.3.2.4 Management of stomatitis / oral mucositis / mouth ulcers 
Adverse Drug Reaction 
Severity 
Everolimus Dose Adjustment and Management 
Recommendations 
Stomatitis 
Grade 1 
(Minimal 
symptoms, 
normal diet) 
No dose adjustment required.  
Manage with non-alcoholic or salt water (0.9%) mouth 
wash several times a day. 
 
Grade 2 
(Symptomatic 
but can eat and 
swallow 
modified diet) 
Temporary dose interruption until recovery to grade ≤1.  
Re-initiate everolimus at the same dose. 
If stomatitis recurs at grade 2, interrupt dose until recovery 
to grade ≤1. Re-initiate everolimus at a lower dose. 
Manage with topical analgesic mouth treatments (e.g. 
benzocaine, butyl aminobenzoate, tetracaine 
hydrocholoride, menthol or phenol) with or without topical 
corticosteroids (i.e. triamcinolone oral paste)*. 
 
Grade 3 
(Symptomatic 
and unable to 
adequately eat 
or hydrate 
orally) 
Temporary dose interruption until recovery to grade ≤1.  
Re-initiate everolimus at lower dose. 
Manage with topical analgesic mouth treatments (i.e. 
benzocaine, butyl aminobenzoate, tetracaine 
hydrocholoride, menthol or phenol) with or without topical 
corticosteroids (i.e. triamcinolone oral paste)* 
 
Grade 4 
(Symptoms 
associated with 
life-threatening 
consequences) 
Discontinue everolimus and treat with appropriate medical 
therapy. 
* using agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis as 
they may worsen mouth ulcers. 
 
3.3.2.5 Management of diarrhea 
Appearance of grade 1-2 diarrhea attributed to study drug toxicity may be treated with supportive 
care such as loperamide, initiated at the earliest onset (for example 4 mg orally followed by 2 mg 
orally every 2 hours until resolution of diarrhea). 


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3.3.2.6 Management of hyperlipidemia and hyperglycemia 
Adverse Drug Reaction 
Severity 
Everolimus Dose Adjustment and Management 
Recommendations 
Metabolic events 
(e.g. 
hyperglycemia, 
dyslipidemia) 
Grade 1 
No dose adjustment required. 
Initiate appropriate medical therapy and monitor. 
 
Grade 2 
No dose adjustment required. 
Manage with appropriate medical therapy and monitor. 
 
Grade 3 
Temporary dose interruption. 
Re-initiate everolimus at lower dose. 
Manage with appropriate medical therapy and monitor. 
 
Grade 4 
Discontinue everolimus and treat with appropriate 
medical therapy. 
3.3.2.7 Management of non-infectious pneumonitis 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious 
pneumonitis (including interstitial lung disease) have also been described in patients taking 
everolimus. Some of these have been severe and on rare occasions, a fatal outcome was 
observed. 
• A diagnosis of non-infectious pneumonitis should be considered in patients presenting 
with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, 
cough or dyspnea, and in whom infectious, neoplastic and other non-medicinal causes 
have been excluded by means of appropriate investigations. Patients should be advised to 
report promptly any new or worsening respiratory symptoms. 
If non-infectious pneumonitis develops, the guidelines in Table 3-4 should be followed. 
Consultation with a pulmonologist is recommended for any case of pneumonitis that develops 
during the study. 


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Table 3-4: Management of non-infectious pneumonitis 
Worst grade 
pneumonitis 
Suggested investigations 
Management of 
pneumonitis 
Everolimus dose adjustment 
Grade 1 
(Asymptomati
c, radiographic 
findings only) 
CT scans with lung windows. 
No specific 
therapy is required 
No dose adjustment required.  
Initiate appropriate monitoring. 
Grade 2 
(Symptomatic, 
not interfering 
with Activities 
of Daily 
Living) 
CT scan with lung windows. 
Consider pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 saturation 
at rest. Consider a bronchoscopy 
with biopsy and/or BAL. 
Monitoring at each visit until return 
to ≤ grade 1. Return to initial 
monitoring frequency if no 
recurrence. 
Symptomatic 
only. Consider 
corticosteroids 
and/or other 
supportive therapy 
if symptoms are 
troublesome. 
Rule out infection and consider 
interruption of everolimus until 
symptoms improve to Grade ≤ 1. 
Re-initiate everolimus at one dose 
level lower.  
Discontinue everolimus if failure 
to recover within ≤ 28 days. 
Grade 3 
(Symptomatic, 
Interfering 
with Activities 
of Daily 
Living. 
O2 indicated 
CT scan with lung windows and 
pulmonary function testing 
includes: spirometry, DLCO, and 
room air O2 saturation at rest. 
Monitoring at each visit until return 
to ≤ grade 1. Return to initial 
monitoring frequency if no 
recurrence. Bronchoscopy with 
biopsy and/or BAL is 
recommended. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically 
indicated. 
Rule out infection and interrupt 
everolimus until symptoms 
improve to Grade ≤ 1. 
Consider re-initiating everolimus 
at one dose level lower 
(approximately 50% lower than 
the dose previously administered 
depending on individual clinical 
circumstances) 
Discontinue everolimus if failure 
to recover within ≤ 28 days. If 
toxicity recurs at Grade 3, 
consider discontinuation 
Grade 4 (Life-
threatening, 
ventilatory 
support 
indicated) 
CT scan with lung windows and 
required pulmonary function 
testing, if possible, includes: 
spirometry, DLCO, and room air 
O2 saturation at rest. Monitoring at 
each visit until return to ≤ grade 1. 
Return to initial monitoring 
frequency if no recurrence. 
Bronchoscopy with biopsy and/or 
BAL is recommended if possible. 
Consider 
corticosteroids 
if 
infective origin is 
ruled out. Taper as 
medically 
indicated. 
Rule out infection and discontinue 
everolimus. 
 
3.3.2.8 Management of hepatitis reactivation / flare 
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving 
chemotherapy.29 Sporadic cases of Hepatitis B reactivation have also been seen in this setting 
with everolimus. Use of antivirals during anti-cancer therapy has been shown to reduce the risk 
of Hepatitis B virus reactivation and associated morbidity and mortality. 30 A detailed assessment 
of Hepatitis B/C medical history and risk factors must be done for all patients at screening, with 
testing performed prior to the first dose of everolimus.  


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Monitoring and prophylactic treatment for hepatitis B reactivation 
Table 3-5 provides details of monitoring and prophylactic therapy according to the screening 
results of viral load and serologic markers testing. 
Table 3-5: Action to be taken based on screening hepatitis B results 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBsAb 
+ or - 
+ or - 
+ 
and no prior HBV 
vaccination 
+ or - 
- 
or + with prior 
HBV vaccination 
HBcAb 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendation 
Pt will not be eligible for 
study 
 
 
No prophylaxis 
 
Monitor HBV-DNA 
approximately every 3-4 weeks  
No specific action 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of everolimus. 
For HBV reactivation definition and management guidelines, see Table 3-6. 
Table 3-6: Guidelines for the management of hepatitis B reactivation 
HBV reactivation (with or without clinical signs and symptoms)* 
For patients with baseline 
results: 
Negative HBV-DNA and 
HBsAg 
AND 
[Positive HBsAb (with no prior 
history of vaccination against 
HBV), OR positive HBcAb] 
------------------------------------- 
Reactivation is defined as: 
New appearance of measurable 
HBV-DNA 
Treat : Start first antiviral medication 
AND 
Interrupt everolimus administration until resolution: 
• 
≤ undetectable (negative) HBV-DNA levels 
If resolution occurs within ≤ 28 days, everolimus can be re-started at one 
dose lower, if available (see Table 3-1 for dose levels available). If the patient 
is already receiving the lowest dose of everolimus according to the protocol, 
the patient should restart at the same dose after resolution. Antiviral therapy 
should continue at least 4 weeks after last dose of everolimus. 
If resolution occurs > 28 days Patients should discontinue everolimus but 
continue antiviral therapy at least 4 weeks after last dose of everolimus. 
* All reactivations of HBV are to be recorded as grade 3 (e.g. CTCAE Version 3.0 - Investigations/Other: Viral 
Reactivation), unless considered life threatening by the investigator, in which case they should be recorded as 
grade 4. Date of viral reactivation is the date on which the rise or reappearance of HBV-DNA was recorded. 
 


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Monitoring for hepatitis C flare 
The following two categories of patients should be monitored every 4–8 weeks for HCV flare: 
• Patients known to have a history of HCV infection, despite a negative viral load test at 
screening (including those that were treated and are considered ‘cured’) 
For definitions of HCV flare and actions to be taken in the event of a flare, please refer to Table 
3-7. 
Table 3-7: Guidelines for the management of hepatitis C flare 
Baseline results 
HCV flare definition* 
HCV flare management 
Knowledge of past hepatitis C 
infection with no detectable 
HCV-RNA 
New appearance of detectable HCV-RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher. 
Discontinue everolimus 
* All flares of HCV are to be recorded as grade 3 (e.g. CTCAE Version 4.0 - Investigations - Other: Viral Flare), 
unless considered life threatening by the investigator; in which case they should be recorded as grade 4. Date of 
viral flare is the date on which both the clinical criteria described above were met. (e.g., for a patient whose 
HCV-RNA increased by 2 logs on 01 JAN 2011 and whose ALT reached > 5 x ULN on 22 JAN 2011, the date 
of viral flare is 22 JAN 2011). 
 
 
3.4 
STUDY CALENDAR 
1 cycle = 28 days 
Evaluations below may be performed within ± 3days of indicated time in order to accommodate 
patient schedules, holidays and weather emergencies. Imaging studies and optional tumor 
biopsies may be performed within ± 7days of indicated time. 
Baseline and Restaging evaluation will be performed at the NIH CC. However, mandated 
laboratory studies and other evaluations may be performed at local laboratory or by local health 
care providers. 
Restaging will be performed approximately every 12 weeks. Treatment can continue for 52 
weeks in the absence of unacceptable toxicity or disease progression. 
Patients with BHD associated tumors localized to the kidneys will be treated for one year in the 
absence of unacceptable toxicity or disease progression. Patients with locally advanced or 
metastatic disease will be treated until disease progression in the absence of unacceptable 
toxicity. 


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Screening / 
Baseline 
Day 1 
Cycle 1 
Day 14 
Cycle 2 
Day 1 
Cycle 2 
Day 14 
Cycle 3 
Day 1 
Cycle 3 
Day 14 
Cycle 4 
Day 1 
Start of 
Every 
Cycle 
EOT 
Follow 
up11 
Survival12 
Visit no. 
1 
2 
3 
4 
5 
6 
7 
8 
9, 10 
etc… 
 
EOT + 
28 
days 
 
Treatment days 
-14 to -1 
 
 
 
 
 
 
 
 
 
 
 
Demography/informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical history/current medical 
conditions  
X 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and extent of cancer  
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
X 
X* 
 
X 
 
X 
 
X 
X 
X 
 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
Weight  
X 
X* 
 
X 
 
X 
 
X 
X 
X 
X 
 
Physical examination  
X8 
 
 
 
 
 
 
 
 
 
 
 
ECOG/Karnofsky performance status  
X 
X* 
 
 
 
 
 
 
 
 
 
 
EKG1  
X 
 
 
 
 
 
 
 
 
 
 
 
Thyroid function tests 
X 
 
Every 12 weeks 
 
 
 
 
CBC with differential 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Serum Chemistries2 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Fasting serum Lipid Profile3  
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
Urinalysis4  
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Serum β hCG (in female patients of 
childbearing potential) 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
HbA1c, pulse oximetry 
X 
 
 
 
 
 
 
 
 
 
 
 
PT/PTT 
X 
 
 
 
 
 
 
 
 
 
 
 


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Screening / 
Baseline 
Day 1 
Cycle 1 
Day 14 
Cycle 2 
Day 1 
Cycle 2 
Day 14 
Cycle 3 
Day 1 
Cycle 3 
Day 14 
Cycle 4 
Day 1 
Start of 
Every 
Cycle 
EOT 
Follow 
up11 
Survival12 
Visit no. 
1 
2 
3 
4 
5 
6 
7 
8 
9, 10 
etc… 
 
EOT + 
28 
days 
 
Treatment days 
-14 to -1 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
Continuous during the study, up to 28 days after the last treatment 
 
Adverse events  
 
Continuous during the study, up to 28 days after the last treatment 
 
Tumor evaluation 
 
PFT 
X 
 
 
 
 
 
CT chest/abdomen/pelvis and/or, CT 
chest plus MRI abdomen/pelvis5 
X 
Every 12 weeks 
 
X 
 
 
CT Neck in patients with known or 
suspected metastatic disease in the neck6 
 
Every 12 weeks 
 
 
 
 
CT or MRI for Brain  
X 
 
 
 
 
 
 
 
 
 
 
 
Bone scans in patients with known or 
suspected bone metastases7 
X8 
 
 
 
 
 
 
 
 
 
 
 
FDG-PET in patients with known or 
suspected metastatic disease 
X8 
 
 
 
 
 
 
 
 
 
 
 
Optional biopsy (At baseline, archival 
tumor samples may be used) 
X 
 
 
 
 
X 
 
 
 
 
 
 
Everolimus Dosing  
 
Daily 
 
 
 
Follow up survival contact  
 
 
 
 
 
 
 
 
 
 
 
X 
HBV-DNA, HBsAg, HBs Ab, HBc Ab, 
HCV-RNA-PCR, ANTI- HCV 9 
X 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA10 
 
 
 
Every 3 - 4 weeks 
 
X 
X 
 


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Screening / 
Baseline 
Day 1 
Cycle 1 
Day 14 
Cycle 2 
Day 1 
Cycle 2 
Day 14 
Cycle 3 
Day 1 
Cycle 3 
Day 14 
Cycle 4 
Day 1 
Start of 
Every 
Cycle 
EOT 
Follow 
up11 
Survival12 
Visit no. 
1 
2 
3 
4 
5 
6 
7 
8 
9, 10 
etc… 
 
EOT + 
28 
days 
 
Treatment days 
-14 to -1 
 
 
 
 
 
 
 
 
 
 
 
HCV RNA-PCR10 
 
 
 
Every 4 – 8 weeks 
 
X 
X 
 
Photographic evaluation of skin lesions13 
X 
Every 12 weeks 
 
 
 
 
All attempts should be made to complete the visits within 72 hours of the day indicated on the evaluation schedule. Visit 2 must be conducted no more than 21 days 
after the screening visit and 28 days for patient positive for HepB and C. 
*If clinically indicated. 
1. Screening ECG is a standard 12 lead and must be performed within 14 days of first dose for patients enrolled and may be repeated at the investigator’s discretion if 
clinically indicated   
2. Serum Chemistry must include: Albumin, Alkaline phosphatase, ALT (alanine transaminase), AST (aspartate aminotransferase), BUN (blood urea nitrogen), 
Calcium, Serum chloride, CO2 (carbon dioxide), Creatinine, Direct bilirubin, Gamma-GT (gamma-glutamyl transpeptidase), Glucose test, LDH (lactate 
dehydrogenase), Phosphorus, Potassium test, Serum sodium, Total bilirubin, Total cholesterol, Total protein, Uric acid. 
3. Serum fasting lipid profile must include: total cholesterol and triglycerides. Patients should be in fasting state. 
4. Standard urinalysis dipstick assessment must include: protein, glucose, blood, ketones, and leukocytes. 
5. Chest, abdomen, pelvis scans need to be repeated at each tumor assessment visit (including if negative at baseline). Scans for complete and partial responses must 
be repeated at least at 4 weeks but no later than the next scheduled tumor assessment following the first documented response. Skin lesions should be photographed 
in addition to measuring. 
6. CT Neck in patients with known or suspected metastatic disease in the neck will be repeated at restaging if positive for metastasis.  
7. A bone scan or skeletal survey is to be performed at baseline and will be repeated at restaging if positive for metastasis.  
8. Repeat at restaging only if indicated 
9. All patients should be screened for hepatitis risk factors and any past illnesses of hepatitis B and hepatitis C as outlined in Sections 2.2. Patients with viral hepatitis 
B or C risk factors should be screened for Hep B and HCV RNA-PCR. 
10. Patients on antiviral prophylaxis treatment or positive HBV antibodies should be tested for HBV-DNA every 3 – 4 weeks. Patients with positive HCV-RNA PCR 
or a history of past infection, even if treated and considered ‘cured’ – should be followed by HCV-RNA PCR every 4 – 8 weeks. 
11. Follow up visits conducted at the EOT+28 days visit. 
12. After progression, an attempt will be made to follow patients to obtain information about survival every three to six months. 
Legend: wks stands for weeks, EOT for End of Treatment visit 
13. Photographic evaluation of skin lesions - only in patients with BHD- associated cutaneous manifestations. 


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3.5 
FOLLOW UP EVALUATIONS 
After subjects have stopped taking the study medication for any of the reasons listed in Section 
3.6.1, they will be seen at NIH, if feasible, for a safety visit within 4-5 weeks of drug 
discontinuation.  The safety assessments may be performed by a local physician and laboratory if 
patients unable to return to the NIH Clinical Center at this time.  
The following assessments may be completed at the end of treatment +28 days; every effort will 
be made to complete the following whenever feasible and the patient can comply: 
• History and Physical Examination 
• Serum Chemistries and CBC/Diff 
• HBV DNA, HCV RNA-PCR if indicated 
If there are unresolved grade 3 – 4 AEs, patients will be followed either at the NIH clinical 
center or by their local physician.  In the latter case, we will obtain the physician’s record of 
AEs. 
Any scans performed outside of the NIH will also be obtained when possible.   
 
3.6 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 28 days following the last dose of study therapy. 
3.6.1 Criteria for removal from protocol therapy 
• Completion of protocol therapy. 
• Progressive disease 
• Participant requests to be withdrawn from active therapy 
• Unacceptable Toxicity as defined in Section 6.2. 
• Investigator discretion 
• Positive pregnancy test 
3.6.2 Off-Study Criteria 
• Completed study follow-up period 
• Patient lost to follow-up 
• Investigator discretion 
• Participant requests to be withdrawn from study 
• Death 


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3.6.3 Off-Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off-
study. An off-study form from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
sent via encrypted email to:  NCI Central Registration Office (HOIS) ncicentralregistration-
l@mail.nih.gov. 
 
4 
CONCOMITANT MEDICATIONS/MEASURES 
Patients must be instructed not to take any medications (over-the-counter or other products) 
during the protocol treatment period without prior consultation with the investigator. The 
investigator should instruct the patient to notify the study site about any new medications he/she 
takes after the start of study drug. All medications (other than study drug) and significant non-
drug therapies (including physical therapy and blood transfusions) taken within 28 days of 
starting study treatment through the 30-day safety follow up visit should be reported on the CRF. 
 
Use of anti-neoplastic or anti-tumor agents not part of the study therapy, including 
chemotherapy, radiation therapy, immunotherapy, and hormonal anticancer therapy, is not 
permitted while participating in this study.  If indicated, a bisphosphonate or denosumab may be 
used. 
4.1 
PERMITTED CONCOMITANT THERAPY 
4.1.1 Cytochrome P450 and P-glycoprotein inhibitors/inducers/substrates 
Co-administration with strong or moderate inhibitors of CYP3A4 or PgP should be avoided as 
this may cause increased everolimus concentrations. For a current table of Substrates, Inhibitors 
and Inducers please access the following website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm  
Everolimus is metabolized by CYP3A4 in the liver and to some extent in the intestinal wall. 
Therefore, the following are recommended: 
• Co-administration with strong or moderate inhibitors of CYP3A4 (e.g., ketoconazole, 
itraconazole, ritonavir) or P-glycoprotein (PgP) inhibitor should be avoided. 
• Grapefruit, Seville oranges, and starfruit affect P450 and PgP activity. Concomitant use 
should be avoided. 
• Co-administration of a strong CYP3A4 inducer should be avoided. 
• Please refer to Table 4-1 listing relevant inducers and inhibitors of CYP3A and Table 4-2 
for a list of relevant substrates, inducers, and inhibitors of PgP. 
4.1.2 Everolimus and drugs influencing CYP3A4 enzyme 
Everolimus is a substrate of CYP3A4, and a substrate and moderate inhibitor of the multidrug 
efflux pump, PgP (PgP, MDR1, and ABCB1). Therefore, extent of absorption and subsequent 


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elimination of systemically absorbed everolimus may be influenced by products that are 
substrates, inhibitors, or inducers of CYP3A4 and/or PgP. Concurrent treatment with strong or 
moderate CYP3A4-inhibitors should be avoided.  Refer to Table 4-1 for a comprehensive list of 
inducers and inhibitors of CYP3A4 and Table 4-2 for a list of relevant substrates, inducers and 
inhibitors of PgP.  Inhibitors of PgP may decrease the efflux of everolimus from brain or tumor 
and therefore increase everolimus concentrations in these tissues. In vitro studies showed that 
everolimus is a competitive inhibitor of CYP3A4 and of CYP2D6, potentially increasing the 
concentrations of products eliminated by these enzymes. Thus, caution should be exercised when 
co-administering everolimus with CYP3A4 and CYP2D6 substrates with a narrow therapeutic 
index. Clinical studies have been conducted in healthy subjects to assess pharmacokinetic drug 
interactions between everolimus and potential CYP3A modifiers (ketoconazole, verapamil, 
erythromycin, rifampin, midazolam, and HMGCoA reductase inhibitors (statins). 
Table 4-1: Clinically relevant drug interactions: inducers, and inhibitors of isoenzyme CYP3A 
Inducers 
carbamazepine, glucocorticoids, modafinil, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, 
rifabutin, rifampin, St. John’s wort, troglitazone, efavirenz, nevirapine, topiramate, avasimibe, 
bosentan, etravirine, nafcillin, ritonavir, talviraline (not available in US market), tipranavir, 
amprenavir, aprepitant, armodafinil (R-modafinil), dexamethasone, nevirapine, prednisone, pleconaril 
(not available in US market), rufinamide 
Inhibitors 
Strong inhibitors: 
clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin, troleandamycin, voriconazole, tipranavir, elvitegravir, 
Posaconazole 31 
Moderate inhibitors: 
aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, darunavir, diltiazem, erythromycin, 
fluconazole, grapefruit juice (citrus parasidi fruit juice), imatinib, tofisopam, verapamil, amprenavir, 
fosamprenavir, dronedarone 
 
Table 4-2: Clinically relevant drug interactions: substrates, inducers, inhibitors of PgP and 
PgP/CYP3A dual inhibitors 


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Substrates 
digoxin, fexofenadine, indinavir, vincristine, colchicine, topotecan, paclitaxel 
Inducers 
rifampin, St John’s wort 
PgP Inhibitors and PgP/CYP3A Dual Inhibitors 
amiodarone, captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, elacridar, 
erythromycin, felodipine, fexofenadine, ginkgo (ginkgo biloba), indinavir, itraconazole, , lopinavir, 
mibefradil, milk thistle (silybum marianum), nifedipine, nitrendipine, quercetin, quinidine, ranolazine, 
ritonavir, saquinavir, Schisandra chinensis, St John’s wort (hypericum perforatum), talinolol, telmisartan, 
tipranavir, valspodar, verapamil 
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Oct. 2, 2011, 
which summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug 
Interaction Studies”, the University of Washington’s Drug Interaction Database, and Indiana University 
School of Medicine's Drug Interaction Table. 
 
4.1.3 Vaccinations 
Immunosuppressants may affect the response to vaccination and vaccination during treatment 
with everolimus may therefore be less effective. The use of live vaccines should be avoided 
during treatment with everolimus. Patient should also avoid close contact with others who have 
received live attenuated vaccines. Examples of live vaccines are: intranasal influenza, measles, 
mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. 
 
5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH 
5.1.1 Tumor Biopsy 
Tumor biopsies (renal primary or metastases or fibrofolliculomas) may be obtained from patients 
who have easily accessible lesions at baseline and at 8 weeks following initiation of therapy. The 
biopsies are optional and not required for trial participation. Core or excisional biopsy of an 
easily accessible sentinel lesion (such as cutaneous/subcutaneous lesions, percutaneously 
accessible hepatic lesions, lymph nodes etc.) may be performed. Biopsies that are to be used 
solely for research purposes will be obtained only if they can be performed with minimal risk of 
complications from the procedure and only after the procedure has been explained to the patient 
and informed consent obtained. Major surgical procedures such as laparotomy or laparoscopic 
procedures will not be performed solely to obtain biopsies for research purposes. The biopsies 
will be performed by members of the interventional radiology, dermatology or surgical staff. 
Ideally, 2-4 cores will be obtained as long as patient safety is not compromised. A portion of the 
biopsies will be frozen in liquid nitrogen immediately and transferred to the UOB laboratory 
(Contact for receiving and processing specimen: Robert Worell/ Cathy Vocke, Ph.D. - Tel: 301-
496-6353). Prior to freezing and depending on tissue availability, a small portion of the biopsy 
specimen may be transferred under sterile conditions to the UOB laboratory to be used to 
establish a tumor cell line. 


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In addition, attempts will be made to obtain any available archived tumor tissue on all patients to 
help evaluate FLCN and PTEN/mTOR status and/or components of relevant pathways. 
Samples will be processed for the following planned studies. In the event of limited sample 
availability, we plan to prioritize studies in the order listed below: 
• Analysis of somatic FLCN, PTEN, mTOR and other related mutations such as TSC1/2This 
will be accomplished by direct sequencing of these genes. 
• Analysis of mTOR activity at baseline and comparative analysis in paired pre- and on-
treatment tumors when available 
Correlative laboratory studies will be performed by investigators in the Urologic Oncology 
Branch (under the direction of Drs. Linehan, Srinivasan, Bottaro, Neckers) and/or Genitourinary 
Malignancies Branch (Jane Trepel’s laboratory) and may involve collaboration with other NIH 
intramural investigators. Studies listed will be performed wherever possible and as permitted or 
dictated by clinical outcome and/or sample and resource availability. 
 
5.1.2 Collection, Storage, Use and Disposition of Human Specimens 
5.1.2.1 Clinical Samples 
Blood and urine samples for clinically relevant, non-research hematology, serum chemistry, 
urinalysis, and skin biopsy tissue will be prepared using standard procedures.  Routine clinical 
analyses will be performed by the NIH Clinical Center central laboratories or NCI Pathology 
department.  Samples will be processed and disposed according to standard laboratory procedure. 
 
5.1.3 Storage and Research Use of Human Specimens 
5.1.3.1 Sample Collection and Planned Research Studies 
Research samples will be collected with a view to performing a variety of correlative/biomarker 
studies (as indicated in Section 5.1). 
5.1.3.2 Sample Processing and Storage 
Each patient research sample will be assigned a unique patient identifier and relevant sample 
characteristics (such as timing of sample collection, treatment cycle and day identifiers) will be 
recorded. The location of all samples will be carefully tracked in the secure UOB database.  All 
stored samples will be coded and no identifying patient information will be on placed on sample 
containers. Stored samples will be kept in freezers / refrigerators or secure containers located in 
the Urologic Oncology Branch research laboratories or in the laboratories of collaborators.   
Timeframe for research studies: Samples will be stored until requested by an authorized 
researcher(s).  All researchers are required to use the samples for research purposes associated 
with this trial (as per the NCI IRB approved protocol). Subjects will be given the option of 
consenting to future use of their research samples per the informed consent process with their 
option declared in the consent document.  Samples from those patients who consent to this will 
be stored permanently. However, these samples will be used only for research studies on active 
NCI IRB approved protocols covered by a valid informed consent document. Samples will be 


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Confidential Information 
destroyed at the completion of the study from those subjects who decline future use of their 
samples. Once primary research objectives for the protocol are achieved, intramural researchers 
can request access to remaining samples provided they have an IRB approved protocol and 
patient consent. Any unused samples must be returned to the UOB laboratories as appropriate. 
The PI will report destroyed samples to the IRB if samples become unsalvageable because of 
environmental factors (e.g. broken freezer or lack of dry ice in a shipping container) or if 
samples are destroyed because a patient withdraws consent. Samples will also be reported as lost 
if they are lost in transit between facilities or misplaced by a researcher.  Any freezer problems, 
lost samples or other problems associated with samples will be reported to the IRB, the NCI 
Clinical Director, and the office of the CCR, NCI. 
  
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
Data will be collected prospectively and entered into NCI CCR C3D database.  The PI will be 
responsible for overseeing entry of data into an in-house password protected electronic system 
and ensuring data accuracy, consistency and timeliness. The principal investigator, associate 
investigators/research nurses and/or a contracted data manager will assist with the data 
management efforts.  All data obtained during the conduct of the protocol will be kept in secure 
network drives or in approved alternative sites that comply with NIH security standards. Primary 
and final analyzed data will have identifiers so that research data can be attributed to an 
individual human subject participant. 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breech in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
Grade 1 AEs will be excluded. 
 
6.2 
RESPONSE CRITERIA 
Restaging will be performed approximately every 12 weeks. Treatment can continue for 52 
weeks in the absence of unacceptable toxicity or disease progression. 
In addition to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks 
following initial documentation of objective response. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).32  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 


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6.2.1 Definitions 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with everolimus. 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
6.2.2 Disease Parameters 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 


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lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
6.2.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 


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accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) 
and PSA response (in recurrent prostate cancer) have been published.33-35  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer.35 
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 


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in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
6.2.4 Response Criteria 
6.2.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
6.2.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
6.2.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 


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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as “symptomatic deterioration.”  Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
 
 
 
 
 
 
 
 


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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
6.2.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
6.3 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised 


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7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7.1 
DEFINITIONS 
7.1.1 Adverse Event 
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.  All AEs must be recorded on the AE case report form except for grade 1 AEs which can be 
excluded.  
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until return to baseline or stabilization of event. Serious adverse 
events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of at least possibly related to the agent/intervention 
should be recorded and reported as per sections 7.2 and 7.3. 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
7.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected” also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 


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pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
7.1.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
7.1.6 Disability 
 A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
7.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.   
7.1.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
7.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 


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(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.2 
INVESTIGATOR REPORTING:  NOVARTIS INSTRUCTIONS FOR RAPID NOTIFICATION OF 
SERIOUS ADVERSE EVENTS 
All serious adverse events must be reported to Novartis Pharmaceuticals Drug Safety and 
Epidemiology Department (DS&E) and reporting will be done via the Investigators or his/her 
designee.  
 
All events must be reported, by FAX (877-778-9739) to Novartis Pharmaceuticals DS&E 
Department within 24 hours of learning of its occurrence. This includes all serious, related, not 
related, labelled (expected) and unlabelled (unexpected) adverse experiences.  
 
All deaths during treatment or within 30 days following completion of active protocol therapy 
must be reported within 24 hours. 
 
Any serious adverse event occurring after the patient has provided informed consent and until 4 
weeks after the patient has stopped study participation must be reported. This includes the period 
in which the study protocol interferes with the standard medical treatment given to a patient (e.g. 
treatment withdrawal during washout period, change in treatment to a fixed dose of concomitant 
medication). 
 
Serious adverse events occurring more than 4 weeks after study discontinuation need only be 
reported if a relationship to the Novartis study drug (or therapy) is suspected.  
 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
7.2.1 
Pregnancies 
Any pregnancy that occurs during study participation should be reported by the site. To ensure 
patient safety each pregnancy must also be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including spontaneous 
or voluntary termination, details of birth, and the presence or absence of any birth defects, 
congenital abnormalities or maternal and newborn complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology (DS&E) department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment of 
the possible relationship to the Novartis study treatment of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 


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Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
7.3 
NCI-IRB AND NCI CLINICAL DIRECTOR (CD) REPORTING 
7.3.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI CD: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
7.3.2 NCI-IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.3.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 
 
7.4 
DATA AND SAFETY MONITORING PLAN 
7.4.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients.  


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All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
 
8 
STATISTICAL CONSIDERATIONS   
This trial will follow a two-stage minimax design, where 12 patients will be recruited at the first 
stage. The trial is designed to distinguish between a 5% vs. 25% response rate.   If none of the 
patients respond to therapy, treatment will be deemed ineffective and recruitment for additional 
patients will be terminated. Otherwise, an additional 4 patients will be recruited in the second 
stage, yielding a maximum of 16 patients. Treatment will be considered effective if at least 3 
patients respond. This will give an 80% power to declare everolimus effective if the response 
rate is 25% and a 10% type I error if the response rate is 5%.  Under this design, the probability 
of early termination is 54% and the expected sample size is 13.8 if the response rate is 5%. 
Up to 16 evaluable patients will be accrued. To allow for inevaluable patients, accrual ceiling 
will be set at 18. Anticipated duration of study is 2-3 years based on anticipated accrual of 0-1 
patient per month. 
 
9 
COLLABORATIVE AGREEMENTS  
9.1 
AGREEMENT TYPE 
This agent for this study, everolimus is being provided to the NIH under a cooperative research 
and development agreement (CRADA) with Novartis, the manufacturer of the agent. 
 
10 HUMAN SUBJECTS PROTECTIONS  
10.1 
RATIONALE FOR SUBJECT SELECTION 
Patients of all races, genders and ethnic origins will be eligible.  Eligibility assessment will be 
based solely on the patient’s medical status.  Recruitment of patients onto this study will be 
through standard CCR mechanisms.  No special recruitment efforts will be conducted. 
10.2 
PARTICIPATION OF CHILDREN 
This protocol will exclude children below 18 years of age since there are no safety data available 
in this group of patients. 
10.3 
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 


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decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 10.5), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 
10.4 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
10.4.1 Benefits 
The potential benefit to a patient who enters study is a reduction in the bulk of his/her tumor, 
which may or may not have a favorable impact on symptoms and/or outcome. 
10.4.2 Risks 
10.4.2.1 Study Agent 
The primary risks of participation in this study include the possible occurrence of any of a range 
of side effects from the study agent everolimus which are listed in the Section 11.1, the package 
insert and in the consent document.  Frequent monitoring for adverse effects and exclusion of 
subjects at risk for these adverse effects will help to minimize the risks associated with 
administration. 
10.4.2.2 Optional biopsies 
All care will be taken to minimize risks that may be incurred by tumor sampling. However, there 
are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained 
fully during informed consent. If patients suffer any physical injury as a result of the biopsies, 
immediate medical treatment is available at the NCI’s Clinical Center in Bethesda, MD.  
Although no compensation is available, any injury will be fully evaluated and treated in keeping 
with the benefits or care to which patients are entitled under applicable regulations. 
Some biopsies may be performed with CT guidance.  If that is the case, then this research study 
involves exposure to radiation from up to 2 CT scans with combined effective dose of 0.29 rem.  
This is below the guideline of 5.0 rem per year allowed for research subjects by the NIH 
Radiation Safety Committee. 
10.5 
RISKS/BENEFITS ANALYSIS 
Patients with BHD associated renal tumors typically undergo nephron sparing surgery when one 
of more tumors reach a size of approximately 3cm, to minimize the risk of metastatic spread. 
Once metastasis develops, there is no known curative therapy and no established systemic 
standard of care. Surgery, while safe in most patients, can be associated with morbidity. 
Furthermore, surgery is not curative and patients are at risk lifelong for the development of new 
renal tumors. Some patients require repeat surgery and most patients require lifelong 


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surveillance. Patients participating in this trial may derive a benefit from the treatment 
administered.  Although the possible toxicities from the proposed therapy may be potentially 
serious, given the nature of the underlying disease, they are acceptable. For these reasons, the 
risk/benefit ratio of this protocol is acceptable. This protocol involves greater than minimal risk 
to patients, but presents the potential for direct benefit to individual subjects. 
10.6 
CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
The investigator must explain to each subject the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved and any discomfort it 
may entail. Each subject must be informed that participation in the study is voluntary and that 
he/she may withdraw from the study at any time and that withdrawal of consent will not affect 
his/her subsequent medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject’s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning that the patient 
could not read or sign the documents. No patient can enter the study before his/her informed 
consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by the 
investigator with it for IRB approval.  
Fertile men and women of child bearing potential should be informed that taking the study 
medication may involve unknown risks to the fetus if pregnancy were to occur during the study 
and agree that in order to participate in the study they must adhere to the contraception 
requirement for the duration of the study. If there is any question that the patient will not reliably 
comply, they should not be entered in the study. 
For the optional research biopsy, the patient will consent at the time of the procedure.  If the 
patient refuses the optional biopsy at that time, the refusal will be documented in the medical 
record and in the research record.  
 
10.6.1 Telephone Re-Consent Procedure 
Re-consent on this study may be obtained via telephone according to the following procedure: 
The informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent.  The original informed consent document will be sent back to the 
consenting investigator who will sign and date the consent form with the date the consent was 
obtained via telephone.  A fully executed copy will be returned via mail for the subject’s records.  
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record. 
 


50 
Abbreviated Title: Phase II everolimus for BHD 
Version Date: March 7, 2017 
Confidential Information 
10.6.2 Informed Consent of Non-English Speaking Subjects 
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OSHRP SOP 12, and 45 CFR 46.117 (b) (2).  The summary that will be used is 
the English version of the extant IRB approved consent document.  Signed copies of both the 
English version of the consent and the translated short form will be given to the subject or their 
legally authorized representative and the signed original will be filed in the medical record. 
 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation (using either the long translated form or the short form). Preferably 
someone who is independent of the subject (i.e., not a family member) will assist in presenting 
information and obtaining consent. Whenever possible, interpreters will be provided copies of 
the relevant consent documents well before the consent conversation with the subject (24 to 48 
hours if possible).  
 
We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of the 
use of the Short Form. 
 
11 PHARMACEUTICAL INFORMATION   
11.1 
EVEROLIMUS  
(Please refer to the Package Insert for details) 
11.1.1 Source  
Everolimus is supplied by Novartis.  
11.1.2 Toxicity  
Everolimus has been evaluated as a single agent and in combination with other antitumor agents, 
including cytotoxic chemotherapeutic agents, targeted therapies, antibodies and hormonal agents. 
Approximately 25,645 patients (excluding those patients who received marketed 
Afinitor®/Votubia®) have been treated with everolimus as of 30-Sep-2012: of which 13,229 
patients in Novartis-sponsored clinical trials; 2,624 patients in the single patient use IND 
program; and 9,792 in investigator-sponsored studies. In addition, healthy volunteer subjects and 
hepatically impaired non-oncology subjects have participated in the clinical pharmacology 
studies described in the Investigator’s Brochure. 
11.1.3 Formulation and preparation  
Everolimus is formulated as tablets for oral administration of 2.5mg, 5mg, and 10mg strength. 
Tablets are blister-packed under aluminum foil, which should be opened only at the time of 
administration as drug is both hygroscopic and light-sensitive. Refer to label for expiration date 
and storage conditions. 


51 
Abbreviated Title: Phase II everolimus for BHD 
Version Date: March 7, 2017 
Confidential Information 
The extent of absorption of everolimus through topical exposure is not known.  Therefore, 
caregivers are advised to avoid contact with suspensions of Afinitor Tablets.  Wash hands 
thoroughly before and after preparation of either suspension. 
11.1.4 Stability and Storage  
The storage of all formulations is supported by ongoing stability studies. Refer to label for 
expiration date and storage conditions. 
11.1.5 Administration procedures 
Everolimus should be administered 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 until the tablet(s) is fully 
disintegrated (approximately 7 minutes), immediately prior to drinking. The glass should be 
rinsed with the same volume of water and the rinse completely swallowed to ensure the entire 
dose is administered.  
If vomiting occurs, no attempt should be made to replace the vomited dose. Patients should be 
instructed that if they miss a dose on one day, they must not take any extra dose the next day, but 
instead to immediately contact the study center as soon as possible to ask for advice. 
11.1.6 Incompatibilities   
Refer to the concomitant medications in Section 4 and the package insert for details. 
 


52 
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Version Date: March 7, 2017 
Confidential Information 
12 REFERENCES  
1. 
Schmidt LS. Birt-Hogg-Dube syndrome: from gene discovery to molecularly targeted 
therapies. Familial cancer 2013;12:357-64. 
2. 
Birt AR, Hogg GR, Dube WJ. Hereditary multiple fibrofolliculomas with trichodiscomas 
and acrochordons. Archives of dermatology 1977;113:1674-7. 
3. 
Schmidt LS, Warren MB, Nickerson ML, et al. Birt-Hogg-Dube syndrome, a 
genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to 
chromosome 17p11.2. American journal of human genetics 2001;69:876-82. 
4. 
Toro JR, Glenn G, Duray P, et al. Birt-Hogg-Dube syndrome: a novel marker of kidney 
neoplasia. Archives of dermatology 1999;135:1195-202. 
5. 
Pavlovich CP, Walther MM, Eyler RA, et al. Renal tumors in the Birt-Hogg-Dube 
syndrome. The American journal of surgical pathology 2002;26:1542-52. 
6. 
Stamatakis L, Metwalli AR, Middelton LA, Marston Linehan W. Diagnosis and 
management of BHD-associated kidney cancer. Familial cancer 2013;12:397-402. 
7. 
Pavlovich CP, Grubb RL, 3rd, Hurley K, et al. Evaluation and management of renal 
tumors in the Birt-Hogg-Dube syndrome. The Journal of urology 2005;173:1482-6. 
8. 
Benhammou JN, Vocke CD, Santani A, et al. Identification of intragenic deletions and 
duplication in the FLCN gene in Birt-Hogg-Dube syndrome. Genes, chromosomes & cancer 
2011;50:466-77. 
9. 
Toro JR, Wei MH, Glenn GM, et al. BHD mutations, clinical and molecular genetic 
investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of 
published reports. Journal of medical genetics 2008;45:321-31. 
10. 
Khoo SK, Bradley M, Wong FK, Hedblad MA, Nordenskjold M, Teh BT. Birt-Hogg-
Dube syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2. 
Oncogene 2001;20:5239-42. 
11. 
Nickerson ML, Warren MB, Toro JR, et al. Mutations in a novel gene lead to kidney 
tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-
Dube syndrome. Cancer cell 2002;2:157-64. 
12. 
Vocke CD, Yang Y, Pavlovich CP, et al. High frequency of somatic frameshift BHD 
gene mutations in Birt-Hogg-Dube-associated renal tumors. Journal of the National Cancer 
Institute 2005;97:931-5. 
13. 
Baba M, Hong SB, Sharma N, et al. Folliculin encoded by the BHD gene interacts with a 
binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. 
Proceedings of the National Academy of Sciences of the United States of America 
2006;103:15552-7. 
14. 
Shaw RJ. LKB1 and AMP-activated protein kinase control of mTOR signalling and 
growth. Acta physiologica 2009;196:65-80. 
15. 
Wang L, Kobayashi T, Piao X, et al. Serine 62 is a phosphorylation site in folliculin, the 
Birt-Hogg-Dube gene product. FEBS letters 2010;584:39-43. 


53 
Abbreviated Title: Phase II everolimus for BHD 
Version Date: March 7, 2017 
Confidential Information 
16. 
Takagi Y, Kobayashi T, Shiono M, et al. Interaction of folliculin (Birt-Hogg-Dube gene 
product) with a novel Fnip1-like (FnipL/Fnip2) protein. Oncogene 2008;27:5339-47. 
17. 
Hasumi H, Baba M, Hong SB, et al. Identification and characterization of a novel 
folliculin-interacting protein FNIP2. Gene 2008;415:60-7. 
18. 
Baba M, Furihata M, Hong SB, et al. Kidney-targeted Birt-Hogg-Dube gene inactivation 
in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic 
kidneys. Journal of the National Cancer Institute 2008;100:140-54. 
19. 
Chen J, Futami K, Petillo D, et al. Deficiency of FLCN in mouse kidney led to 
development of polycystic kidneys and renal neoplasia. PloS one 2008;3:e3581. 
20. 
Hasumi Y, Baba M, Ajima R, et al. Homozygous loss of BHD causes early embryonic 
lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proceedings 
of the National Academy of Sciences of the United States of America 2009;106:18722-7. 
21. 
Shuch B, Vourganti S, Friend JC, Zehngebot LM, Linehan WM, Srinivasan R. Targeting 
the mTOR pathway in Chromophobe Kidney Cancer. Journal of Cancer 2012;3:152-7. 
22. 
Davis CF, Ricketts CJ, Wang M, et al. The somatic genomic landscape of chromophobe 
renal cell carcinoma. Cancer cell 2014;26:319-30. 
23. 
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. 
24. 
Cohen HT, McGovern FJ. Renal-cell carcinoma. The New England journal of medicine 
2005;353:2477-90. 
25. 
Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nature 
reviews Cancer 2004;4:335-48. 
26. 
Frattini M, Signoroni S, Pilotti S, et al. Phosphatase protein homologue to tensin 
expression and phosphatidylinositol-3 phosphate kinase mutations in colorectal cancer. Cancer 
research 2005;65:11227. 
27. 
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. 
28. 
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. 
29. 
Yeo W, Lam KC, Zee B, et al. Hepatitis B reactivation in patients with hepatocellular 
carcinoma undergoing systemic chemotherapy. Annals of oncology : official journal of the 
European Society for Medical Oncology / ESMO 2004;15:1661-6. 
30. 
Loomba R, Rowley A, Wesley R, et al. Systematic review: the effect of preventive 
lamivudine on hepatitis B reactivation during chemotherapy. Annals of internal medicine 
2008;148:519-28. 


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Abbreviated Title: Phase II everolimus for BHD 
Version Date: March 7, 2017 
Confidential Information 
31. 
Krishna G, Moton A, Ma L, et al. Effects of oral posaconazole on the pharmacokinetic 
properties of oral and intravenous midazolam: a phase I, randomized, open-label, crossover study 
in healthy volunteers. Clinical therapeutics 2009;31:286-98. 
32. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). European journal of cancer 2009;45:228-47. 
33. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients 
with progressive prostate cancer and castrate levels of testosterone: recommendations of the 
Prostate Cancer Clinical Trials Working Group. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology 2008;26:1148-59. 
34. 
Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II 
clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-
Specific Antigen Working Group. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 1999;17:3461-7. 
35. 
Rustin GJ, Quinn M, Thigpen T, et al. Re: New guidelines to evaluate the response to 
treatment in solid tumors (ovarian cancer). Journal of the National Cancer Institute 2004;96:487-
8. 
 
 


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Abbreviated Title: Phase II everolimus for BHD 
Version Date: March 7, 2017 
Confidential Information 
13 APPENDICES 
13.1 
APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  Death 
not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


56 
Abbreviated Title: Phase II everolimus for BHD 
Version Date: March 7, 2017 
Confidential Information 
13.2 
APPENDIX B:  EVEROLIMUS PILL AND SIDE EFFECTS DIARY 
 
Today’s date ________________________________ Cycle__________ 
Week_________ Dose_________  
 
Patient Name_____________________________ 
  Patient Study ID ___________________________________ 
(initials acceptable) 
 
 
Date 
 
Day # 
Time 
Taken 
 
SIDE EFFECTS/COMMENTS 
 
Init 
 
#1   
 
 
 
 
#2   
 
 
 
 
# 3 
 
 
 
 
# 4  
 
 
 
 
# 5  
 
 
 
 
# 6  
 
 
 
 
# 7  
 
 
 
 
Physician’s Office will complete this section: 
1. 
Date patient started protocol treatment________________    
2. 
Patient’s planned daily dose________________________     
3. 
Total number of pills taken this week_____________________ 
Physician/Nurse/Data Manager’s Signature _______________________________________________________ 
 


57 
Abbreviated Title: Phase II everolimus for BHD 
Version Date: March 7, 2017 
Confidential Information 
13.3 
APPENDIX C: PATIENT INSTRUCTIONS FOR EVEROLIMUS THERAPY 
You are participating in a study of Everolimus and its effectiveness in the treatment of kidney cancer. It is 
important that you take your medication as instructed. If you are unable to take the medication as 
instructed, you should contact the Study Team as soon as possible. Please keep in mind the following: 
 
• 
You should take your medication once/ day, at approximately the same time every day. You should 
take the medication with a full glass of water. You may take the medication with or without food, 
whichever you choose, but should take it that way consistently. Record the date and time you have 
taken the medication on your diary. 
If you should vomit your medication after taking it, do not take the medication again.  
 
• 
Record any side effects you experience on your diary. Bring your Pill and Side Effect diaries, your 
remaining medication, and empty pill vials with you to each appointment. 
 
• 
You cannot eat grapefruit, Seville oranges, or star fruit, or drink their juices while on this study. 
 
• 
Your medication may decrease the effectiveness of your immune system. Wash your hands 
frequently, and avoid others with cold symptoms. If you develop a cough, fever, painful urination, 
sore throat, runny nose, or any symptom that does not feel right, call your study team. DO NOT 
RECEIVE VACCINES while on study until you check with your study team first! You cannot have 
close contact with individuals who have received live vaccines such a measles, mumps, rubella, 
varicella, typhoid, oral polio, BCG, or yellow fever for 4 weeks post vaccination. 
 
• 
Your medication may also affect your lungs. If you develop shortness of breath, at rest or on exertion, 
chest pain, or cough, call your study team as soon as possible. 
 
• 
A common side effect of your medication is sores in your mouth. Perform frequent oral hygiene, but 
avoid mouthwashes with alcohol. If you develop a mouth sore, rinse frequently with warm saline 
mouth rinses, or the mouth rinses provided by your study team. Eat soft, bland food. If you are having 
difficulty eating or drinking, call your study team immediately. 
 
• 
Avoid sun exposure, and always wear sunscreen when outdoors (> SPF 30). 
 
• 
Do not drink alcohol (including beer and wine) unless approved by the study team. 
 
• 
If you should need dental work or surgery, notify your team immediately. 
 
• 
You will be given medication at the beginning of the trial to be used only as needed. If you need any 
of these medications, follow the directions on the label, and record that you have taken the medication 
in your diary. If the symptoms persist even after taking the medication, call your study team. These 
medications are: 1.Ondansetron (Nausea); 2.Loperimide (Diarrhea); 3.Colace (Constipation); 4. 
Lidobenalox Oral Solution (Mouth Sores). 
 
Please call your study team with ANY questions or change in your condition. 
 
Martha Ninos RN (Study Coordinator)  
240-760-6248 (Mon-Fri: 8-4PM) *** 
 
Julia Friend PA-C  
 
 
 
301-240-271-8121 (Mon-Fri: 8-4PM) *** 
 
*** Evenings, weekends, and emergencies call Hospital paging @ 301-496-1211 and ask to speak to 
the Urology Fellow On Call 

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MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   15-C-0166 
CONTINUATION: page 2 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
The study drug, everolimus, supplied by Novartis Pharmaceuticals Corporation, works by 
inhibiting the activity of this protein.   
Experiments have shown that everolimus can prevent cancer cells from growing in number and 
clinical trials have shown that this drug is active in many human cancers. 
Everolimus has been FDA approved for adults with advanced kidney cancer (Renal Cell 
Carcinoma). Everolimus received approval for patients with subependymal giant cell 
astrocytoma (SEGA), a brain tumor seen with genetic conditions called tuberous sclerosis 
complex (TSC) who require therapy, but are not candidates for surgery.  Everolimus was 
approved for pancreatic neuroendocrine tumor (PNET) in patients with unresectable, locally 
advanced, or metastatic disease.  Everolimus received approval for the treatment of 
postmenopausal women with advanced hormone receptor-positive, HER2- negative breast cancer 
(advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or 
anastrozole.  Everolimus also received approval for the treatment of patients with TSC who have 
renal angiomyolipoma not requiring immediate surgery. 
Everolimus has been used to treat patients in clinical studies since 2002 and approximately 
30,582 patients (as of 30-Sep-2013) have been treated with everolimus.  
Everolimus has not been specifically approved for Birt-Hogg-Dubé Syndrome (BHD)-associated 
kidney cancer and the studies used to obtain FDA approval for this agent in Renal Cell 
Carcinoma were performed largely in patients with clear cell renal cell carcinoma, the most 
common variant of kidney cancer. 
Why are you being asked to take part in this study? 
You are being asked to take part in the study because you have been diagnosed with Birt-Hogg-
Dubé Syndrome (BHD)-associated kidney cancer.  
How many people will take part in this study?  
Approximately 18 people will be enrolled in this study. 
Description of Research Study 
Before you begin the study 
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  However, there are some extra exams, tests and procedures that you 
will need to have if you take part in this study. If you have had some of them recently, they may 
not need to be repeated.   
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   15-C-0166 
CONTINUATION: page 3 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
These tests include: 
• History and physical evaluation including vital signs 
• Routine blood and urine tests 
• Serum pregnancy test (if you are female and can have children) 
• CT scan of chest/abdomen/pelvis or MRI 
• Brain MRI or brain CT 
• CT scan of neck (if it is suspected that your tumor has spread to your neck) 
• Bone scan (if it is suspected that your tumor has spread to your bones) 
• FDG-PET (if your cancer is known or suspected to have spread outside the kidneys) 
• Tests to measure how well your lungs function 
• Electrocardiogram (EKG) 
• Tests for hepatitis if your doctor determines that you are at risk 
During the study 
If you join this study, you will be given tablets to be taken by mouth. It is very important for you 
to take the study drug just as the study doctor tells you. Do not skip any doses unless your study 
doctor tells you to skip doses.  If you throw up after taking the study drug, you should NOT take 
another tablet that day. Let your study doctor know that you got sick. If you do forget to take the 
study drug one day, do not take any extra doses the next day.  Call your study doctor and ask for 
advice.  
You will be asked to take one tablet once a day.  You will take everolimus for up to 52 weeks.  
You should take everolimus about the same time each day, either consistently with or without 
food. 
You should only take the study medicine as the doctor tells you to, and should not do anything 
else with it.  
During the study, you must talk to the study doctor before you take any drug other than the study 
drug. This includes homeopathic, alternative, or herbal medicines, and vitamins or other over-
the-counter medications. Please avoid eating grapefruit, star fruit, and Seville oranges or 
drinking their juices while in the study.  The juices in these fruits can change the way your body 
treats or breaks down everolimus. 
The amount of study drug you take and the time when you take it may be changed during the 
study. This may be because of test results or side effects that you experience. Your study doctor 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   15-C-0166 
CONTINUATION: page 4 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
may also ask you to stop taking your study drug for a brief time. If this happens, you will be told 
when it is safe to start taking the study drug again.  If study drug is stopped for a while, you may 
have to go to extra visits at the clinic for your safety. If you have any side effects that do not get 
better after stopping the study drug for a while, your study doctor may decide to discontinue the 
drug permanently. 
During the study, you may discuss with a doctor or health care professional, who is not directly 
involved in the study, health issues or medical problems related to the study treatment or disclose 
information related to the study treatment. In this case you should tell your doctor or health care 
professional that the Novartis drug which is part of the study treatment and information relating 
to it is Novartis’ property and is confidential. 
Your study doctor will tell you about any changes needed in the way you take the medicine. You 
must always remember not to throw away your empty study drug containers. Instead, keep them 
in a safe place and bring them back to the doctor’s office whenever your study doctor or nurse 
asks you to. At the end of the study, any study medicine or empty containers you still have 
should be given back to the study doctor.   
In order to monitor your progress during the study, we will divide the time you are on the study 
into cycles.  One cycle = 4 weeks or 28 days. 
You will need the following tests and procedures that are part of regular cancer care. 
• Physical evaluation and weight measurement will be done during week 1 of each cycle 
• Serum pregnancy test (if you are female and can have children) will be done during week 
1 of each cycle. 
• Urine tests will be done during week 1 of each cycle. 
• Vital signs will be taken every 2 weeks. 
• Blood tests will be performed at 2 weeks until the end of cycle 3 and then during week 1 
of each cycle. 
• CT scan of chest/abdomen/pelvis or MRI with or without a bone scan will be performed 
every 12 weeks. 
• FDG-PET (if your cancer is known or suspected to have spread outside the kidney) and 
bone scan (if it is suspected that your tumor has spread to your bones) at the start of the 
study. This may be repeated at one or more times while you are on the study if considered 
important to make clinical decisions about the management of your cancer. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   15-C-0166 
CONTINUATION: page 5 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• Tests for hepatitis if your doctor determines that you are at risk as needed for the duration 
of the study and during follow-up. 
You will need the following tests or procedures that are not usually part of regular cancer care to 
help us monitor your safety 
• Record when you take your medication and any symptoms that you experience in a diary 
provided by the study team 
You will also need the following tests for research to see how the drug is affecting your body and 
other research studies. 
• Tumor biopsy (optional) will be collected at the beginning of the study before you have 
taken any study drug and then at approximately 8 weeks (the end of cycle 2).  The tumor 
samples we obtain will be used to look for special markers that may be helpful in the 
study of kidney cancer and in understanding the effect of the study drugs on the tumor.  
Results of research done on your specimens and data will not be available to you or your 
doctor.  A separate consent form will be provided to you at the time of the biopsy for you 
to grant permission to that procedure if you agree to the biopsies. 
• At the beginning of the study, we would like to obtain your previously collected tumor 
tissue if it is available.  We would like to test your tissue for genes that may be linked to 
cancer. 
When you are finished taking the drugs (treatment) 
We would like to see you again within 4 to 5 weeks after you have finished taking the study drug 
in order to perform the following tests: 
• Physical evaluation and blood tests 
• CT or MRI for chest, abdomen, pelvis, bone scan if your doctor determines that you may 
need it. 
• Tests for hepatitis if your doctor determines that you are at risk. 
After you have completed this visit, we would also like to contact you by telephone 
approximately every 3-6 months to find out how you are doing. 
 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   15-C-0166 
CONTINUATION: page 6 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Birth Control 
Women who are pregnant or nursing a child cannot participate in this trial. You must confirm, to 
the best of your knowledge, that you are not now pregnant, and that you do not intend to become 
pregnant during the trial. 
The risks to an unborn human fetus or a nursing child from everolimus are not known.  Based on 
animal studies, everolimus exposure may result in birth defects or infant death, and may impact 
fertility in both male and female patients.   Women of childbearing potential must use a highly 
effective method of contraception while receiving everolimus, and for up to 8 weeks after ending 
treatment.  Highly effective contraceptive methods are also required for female partners of male 
patients who are sexually active and may become pregnant.   
Please discuss with your Study Doctor the most appropriate birth control method for you that 
also respect your cultural and religious situation.  
Examples of highly effective birth control methods are: 
• Total abstinence, when this is in line with your preferred and usual lifestyle. Periodic 
abstinence like calendar, ovulation, symptothermal, post-ovulation methods, and 
withdrawal are not acceptable methods of contraception. 
• Female sterilization, when you have been already surgically sterilized prior to the study 
by surgical bilateral removal of ovaries (woman's reproductive system that stores and 
releases eggs for fertilization and produces female sex hormones), or tubal ligation 
(getting your “tubes tied”) at least six weeks ago. 
• Your male partner has already been sterilized (with the appropriate documentation). The 
sterilized male partner should be your sole partner. 
Use of a combination of any two of the following (a+b or a+c or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception. Use of oral, 
injected or implanted hormonal methods of contraception or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example, hormone 
vaginal ring or transdermal hormone contraception (in case of oral contraception you 
should have been using the same pill on a stable dose before taking study treatment), 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS), 
c. Use of an occlusive cap (diaphragm or cervical/vault cap) by you, or a condom by your 
male partner combined with a spermicidal foam/gel/film/cream/vaginal suppository. 
If you become pregnant or suspect being pregnant during study treatment or within 8 weeks after 
completing study treatment, you must inform the Study Doctor immediately, and you have to 
stop ongoing study treatment immediately. You will not be allowed to continue study treatment 
if you are pregnant.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   15-C-0166 
CONTINUATION: page 7 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
As a male participant in the study you must agree to use a condom during intercourse and not 
father a child during the study and for the period of 8 weeks following stopping of study 
treatment. In addition, it is advised that your female partner uses a highly effective form of birth 
control method (contraception) if she is sexually active and may become pregnant.  
In case you father a child while in this study you will be asked to report the pregnancy to the 
Study Doctor.  
General Information on pregnancy and contraception 
85 out of 100 sexually active women who do not use birth control can expect to become pregnant 
in a year. No matter which birth control you are using from the list above, it is important to 
follow the manufacturer directions. If you don’t, you raise your chance of getting pregnant.  
Hormonal contraception is available in the form of pills which need to be taken every day, 
injections, which lasts approximately 3 months and as implanted devices. Hormonal methods are 
associated with some risks like changes in your cycle, nausea, headache, changes in mood, 
weight gain, breast tenderness, and blood clots.  
Implanted devices are inserted into the uterus and can stay there for several years. They can 
cause cramps, bleeding, and infertility. It is important to know that not all women experience all 
of the adverse effects listed above. 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
While on this study, you may feel side effects. These may be side effects of the study drug, or 
another medicine.  They could also be because of what happens during a study visit, including 
taking blood. You should discuss any symptoms with the study doctor or your regular doctor. 
Very common (>10%), common (1% to < 10%), and uncommon (<1%) side effects are listed in 
this document, but they will be different from person to person. Many side effects go away 
shortly after the study drug is stopped.  In some cases, the side effects may be serious, last a long 
time or be permanent, and may even cause death.   
Because certain drugs may increase or decrease the levels of the study drug in your blood, it is 
important that you follow your study team’s instructions about drugs you may or may not take 
while you are on this study. Please check with your study doctor before taking any medications, 
including over the counter drugs and herbal medications.  
Your study doctor will closely follow you during this study, and answer any questions you may 
have about risks, worries, and side effects. You should talk to your study doctor about any 
symptoms that you experience while in the study. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   15-C-0166 
CONTINUATION: page 8 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
This research study may involve unknown risks. Problems or side effects that are not now known 
could also occur. You will be given any available new information that may affect your desire to 
start or continue in the study.  Other side effects not mentioned below or observed in previous 
studies with the drug are also possible. 
All problems or side effects need to be reported to the study doctors or study nurses looking after 
you either by phone or at the next visit.  
For more information about risks and side effects, you should feel free to ask your study doctor.  
If you are concerned about your health between visits due to being in this study, please call the 
emergency telephone numbers provided at the end of this document. 
Adverse Drug Reactions 
One of the most common possible side effects of the study drug is mouth lining tenderness 
(called stomatitis) ranging from redness, irritation, and swelling, to mouth ulcers (sores in the 
mouth). This side effect is found in more than half of patients treated with everolimus.  
Additional very common side effects of everolimus occurring in more than 10% of patients 
include: fatigue, weakness (feeling weak or tired), chills, nausea and vomiting, loss of appetite, 
weight loss, skin problems such as rash or itching, diarrhea, pain or swelling of the arms or legs, 
bleeding of the nose, cough, shortness of breath, and headache. High levels of sugar in the blood, 
high levels of lipids (cholesterol) in the blood, abnormal or loss of taste, low levels of red blood 
cells, infections, and spontaneous bleeding or bruising could occur while taking everolimus.   
Everolimus may cause changes in the lungs. Very commonly, everolimus may be associated with 
inflammation in the lungs (pneumonitis). Generally mild, it has been severe in a few cases, 
although it resolves once the treatment is stopped. The consequences of these changes in patients 
with BHD associated lung cysts has not been previously studied and may be different from that 
in the general population. Rarely, everolimus is associated with a blood clot or blockage in your 
lungs or extremities. Tell your doctor right away if you experience new or worsening lung or 
breathing symptoms like cough or shortness of breath, even when symptoms are mild, as this 
might have life-threatening consequences. If you experience these symptoms, your study doctor 
may ask you to undergo chest CT scans and/or a pulmonary function test to evaluate the cause 
and seriousness of these symptoms. 
Common side effects (1% to <10%) of everolimus include: dry mouth, dehydration, skin 
changes (acne, rash, redness,  dryness or irritation, itching and skin inflammation), abdominal 
pain, stomach virus, passing gas, constipation, irritability, nail disorders, increased blood 
pressure, joint stiffness or pain, mouth pain, difficulty swallowing, (heartburn), fever, insomnia, 
inflammation of the lining of the digestive system and other mucous membranes such as the 
sinus, stomach pain, bleeding, and low white blood cells (leukopenia, lymphopenia and 
neutropenia).  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   15-C-0166 
CONTINUATION: page 9 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
As noted above, there could be a lowering of the number of your blood cells that help fight 
infection. This could lead to an infection (which could be potentially life-threatening). Examples 
of infections are common colds (sore throat, runny nose), throat infections, pneumonia, urinary 
tract infections, and ear infections. Therefore, it is important that your blood counts be regularly 
checked by your study doctor.  
In addition, there could be a lowering of the blood cells that help the blood to clot (which could 
cause you to bleed more easily), and a lowering of the protein in your blood (hemoglobin) that 
helps carry oxygen; this could lead to anemia. 
Drugs like everolimus can cause the patient’s immune system not to work as well as usual. A 
patient with hepatitis B or hepatitis C who takes everolimus could be susceptible to the virus 
becoming more active. If you have active hepatitis B or C, you will not be allowed into the 
study. 
Changes to the levels of blood sugar (glucose), which could lead to diabetes, could occur while 
taking everolimus, so your blood sugar levels will be checked often during the study. If you are 
taking another medicine which may increase blood sugar levels, more frequent monitoring may 
also be required. Another diabetes test (Hemoglobin A1c) will be checked at the beginning of the 
study.  
Everolimus may have an effect on the liver.  There could also be an increase in your blood of a 
waste product of your liver (bilirubin), which could mean that your liver is not working as well.  
These will be tested regularly during the study. The levels of cholesterol and triglycerides (fats in 
your blood) could increase.  Increased levels of cholesterol and triglycerides are an important 
factor of risk for heart disease, so your blood cholesterol and triglyceride levels will be regularly 
checked in this study.  Also, your doctor may prescribe medical treatment as appropriate. The 
levels of liver enzymes (transaminases), which are signs of liver function/damage, may also 
increase. Everolimus may cause toxicity to your kidneys and cause the levels of creatinine in 
your blood and protein in your urine to increase. These increases are an indication that the 
kidneys are not working as well as they did before.  This toxicity could lead to kidney failure. 
Therefore, your blood creatinine levels and urine protein levels (and other urine tests) will be 
regularly monitored in this study.  In addition, there could be a lowering of electrolytes 
(potassium, phosphate), which are also markers of kidney function, and will be monitored during 
the study. 
Everolimus may contribute to increased levels of an enzyme called blood lactate dehydrogenase 
which gives information about the health of certain organs. 
Other, uncommon side effects (<1%) include the following:  Severe decrease in red blood 
cells or all blood cells, loss of taste, rash of small blisters, bronchitis, coughing up of blood and 
congestive heart failure (fluid build-up and shortness of breath) as well as non-cardiac chest pain 
and impaired wound healing, increased daytime urination, inflammation of the gallbladder 
known as cholecystitis, and elevated number of white cells in the colon with inflammation 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   15-C-0166 
CONTINUATION: page 10 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
known as eosinophilic colitis.  An eye condition known as Anterior Uveitis (inflammation of the 
eye) has been observed in a very small number of patients. 
For women of child-bearing potential taking everolimus, changes to your menstrual period 
(menstruation) may occur. These changes may include: delayed or missing one or more 
menstrual period (secondary amenorrhea), increased or decreased blood flow during 
menstruation, or any other irregular change to your menstrual cycle. Also, a hormone called 
luteinizing hormone (LH) and follicle stimulating hormone (FSH) may be increased due to 
everolimus.  Fertility may be affected. 
If you experience any hypersensitivity or signs of serious allergic reaction such as rash, itching, 
hives, difficulty breathing or swallowing, dizziness, signs of serious allergic reaction, please 
contact your doctor. 
You should not receive live vaccines and have close contact with people who have received 
live vaccines within 7 days of starting everolimus and while on this study without 
consultation with your study doctor. Examples of live vaccines include intranasal influenza, 
measles, mumps, rubella, oral polio, BCG, yellow fever, varicella (Chicken Pox), and 
typhoid vaccines. 
Blood sampling risks 
Taking blood may cause some discomfort, bleeding or bruising where the needle enters the body, 
and in rare cases, it may result in fainting.  There is a small risk of infection.  Some people have 
not felt well when having their blood taken.  Some people have felt dizzy while having their 
blood drawn or after.  Let the nurse know if you would prefer to lie down while you have your 
blood drawn. 
Tumor Biopsy Risks 
The biopsy procedure usually causes only brief discomfort at the site from which the biopsy is 
taken.  Rarely, infection or bleeding may occur at the needle site. 
Research Radiation Risks   
The biopsy may be done under CT guidance.  If that is the case, then this research study involves 
exposure to radiation from up to 2 CT scans.  This radiation exposure is not required for your 
medical care and is for research purposes only. The amount of radiation you will receive in this 
study is 0.29 rem which is below the guideline of 5 rem (or 0.5 rem in children) per year allowed 
for research subjects by the NIH Radiation Safety Committee.  The average person in the United 
States receives a radiation exposure of 0.3 rem per year from natural sources, such as the sun, 
outer space, and the earth's air and soil.  If you would like more information about radiation, 
please ask the investigator for a copy of the pamphlet, An Introduction to Radiation for NIH 
Research Subjects. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   15-C-0166 
CONTINUATION: page 11 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
While there is no direct evidence that the amount of exposure received from participating in this 
study is harmful, there is indirect evidence it may not be completely safe.  There may be a very 
slight increase in the risk of cancer.  
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation. Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body.  
If you are pregnant you will not be permitted to participate in this research study.  It is best to 
avoid radiation exposure to unborn or nursing infants since they are more sensitive to radiation 
than adults.  
Side Effects Diary 
You will be asked to keep a diary of any side effects, when they occurred, how long they lasted, 
and what if anything helped to relieve the side effect. This diary will be reviewed by the study 
team during each visit. 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to see if this experimental treatment will cause your tumors to shrink.  
The benefits of everolimus are not established for people with your medical condition. We do not 
know if you will receive personal, medical benefit from taking part in this study.  These potential 
benefits could include shrinking of your tumor or lessening of your symptoms, such as pain, that 
are caused by the cancer.  Because there is not much information about the drug’s effect on your 
cancer, we do not know if you will benefit from taking part in this study, although the knowledge 
gained from this study may help others in the future who have cancer.   
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   15-C-0166 
CONTINUATION: page 12 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• Governmental agencies in other countries where the study drug may be considered for 
approval. 
• National Cancer Institute Institutional Review Board. 
• Qualified representatives from Novartis, the pharmaceutical company who produces 
everolimus. 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the 
Web site will include a summary of the results.  You can search this Web site at any time.  
 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   15-C-0166 
CONTINUATION: page 13 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Novartis or designated 
representatives. If you withdraw your consent and leave the trial, any samples of yours that have 
been obtained for the study and stored at the NCI can be destroyed upon request. However, any 
samples and data generated from the samples that have already been distributed to other 
researchers or placed in the research databases cannot be recalled and destroyed. 
Conflict of Interest  
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
 
The National Institutes of Health and the research team for this study are using a drug developed 
by Novartis through a joint study with your researchers and the company.   The company also 
provides financial support for this study.  
 
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   15-C-0166 
CONTINUATION: page 14 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
 
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
 
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:    15-C-0166 
CONTINUATION: page 15 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action.  
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Ram Srinivasan, M.D., Ph.D., Building 10, Room 2-5940, Telephone:  
240-760-6251. You may also call the Clinical Center Patient Representative at 301-496-2626. If 
you have any questions about the use of your specimens or data for future research studies, you 
may also contact the Office of the Clinical Director, Telephone:  240-760-6070.  
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:    15-C-0166 
CONTINUATION: page 16 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM MAY 08, 2017 THROUGH MAY 07, 2018.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name