Conditions: Neuroendocrine Tumors Neuroendocrine Carcinoma Neuroendocrine Neoplasms Carcinoma, Neuroendocrine Neuroendocrine Tumors of the Gastrointestinal Tract and Pancreas
Keywords: MEN1 VHL Neoplasm NF1 mTOR
Allocation: NON_RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 16
Healthy volunteers: no

Brief summary:
Background:

\- Neuroendocrine tumors (NETs) come from cells of the hormonal and nervous systems. Some people have surgery to shrink the tumor. Sometimes the tumors come back. Researchers think that treatment with drugs based on knowing the defective gene might give better results.

Objective:

\- To see if drugs selected based on the defective gene result in better tumor response. The drugs are Sunitinib and Everolimus.

Eligibility:

\- People age 18 and older with an advanced low- or intermediate-grade gastrointestinal or pancreatic neuroendocrine tumor.

Design:

* Participants will be screened with:
* Medical history
* Physical exam
* Scans
* Blood, urine, and lab tests
* The study team will see if participants should have surgery.
* If yes, participants will:
* Sign a separate consent
* Have computed tomography (CT) scan before and after surgery
* Have as much of the tumor removed as possible. A small piece will be tested for mutation type.
* If no, participants will have a small piece of tumor removed for the testing.
* If the surgery might cure them, the participant will leave the study. The other participants will be assigned to take either Sunitinib or Everolimus.
* Participants will take their drug by mouth once a day. They will keep a medicine diary. Some will keep track of their blood pressure at least weekly.
* Screening tests may be repeated at study visits. Participants also may have their heart evaluated.
* About 30 days after the last day of their study drug, participants will have a follow-up visit that repeats the screening tests.
* Participants will be contacted every 3 months after this visit.

Detailed description:
Background:

* Neuroendocrine tumors (NETs) of the gastrointestinal tract and pancreas are a rare and heterogeneous group of neoplasms with unique tumor biology, natural history, and clinical management issues.
* Most NETs are sporadic, but they can be part of familial cancer syndromes such as multiple endocrine neoplasia type 1 (MEN1), neurofibromatosis type 1 (NF1) or Von Hippel-Lindau (VHL) syndrome.
* Well-differentiated, low or intermediate grade NETs have a heterogeneous natural history.
* Surgery is the only curative treatment option in patients with localized early stage NETs.
* The optimal management strategy for patients with advanced NETs is unknown.
* The majority of NETs have somatic mutations in MEN1 and cyclin dependent kinase inhibitor 1B (CDKN1B), and genes involved in the phosphatidylinositol-3-kinase (PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway, and/or overexpression of growth factors and their receptors such as vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor (PDGF), and platelet-derived growth factor receptors (PDGFR) that can be targeted for therapy.
* Survival in patients with NETs and somatic mutations is better than patients with wild type NETs.
* Sunitinib (multi-tyrosine kinase inhibitor) and Everolimus (mTOR signaling pathway inhibitor) are currently approved for the treatment of progressive, unresectable, locally advanced or metastatic pancreatic NETs.
* However, mutation targeted therapy with Sunitinib or Everolimus has not been studied in this patient population.
* The present proposal aims to determine if mutation targeting therapy for patients with advanced low- or intermediate grade NETs is more effective than historically expected results.

Objectives:

-To determine the progression-free survival in patients with NETs of the gastrointestinal tract and pancreas treated with Sunitinib or Everolimus based on tumor genotyping.

Eligibility:

-Patients with:

* progressive, histologically or cytologically diagnosed low or intermediate grade locally advanced or metastatic NETs.
* Age greater than or equal to 18 years

Design:

* Phase II open labeled clinical trial.
* Tumor biopsy for tumor genotyping will be performed if the patient does not have archival tissue available and does not have MEN1, VHL or NF1.
* Patients with somatic or germline mutations in MEN1/PDGFR/KIT/FMS-like tyrosine kinase-3 will be treated with Sunitinib. (Arm 1)
* Patients with somatic/germline mutations in NF1/PTEN/PI3K/AKT/mTOR/VHL will be treated with Everolimus. (Arm 2)
* Patients with wildtype tumor will be treated with Sunitinib. (Arm 1)
* Patients who have disease-progression on either Sunitinib or Everolimus will cross-over to the other drug.
* Treatment will continue until disease progression, unacceptable toxicity, or consent withdrawal.
* Up to 120 patients will be accrued to the study. It is anticipated that 20-30 patients per year may enroll into this trial; thus accrual may be completed in 4-5 years.

Arms:
arm 1: Sunitinib arm 2: Everolimus

Interventions: intervention 1: Sunitinib intervention 2: Everolimus
Intervention descriptions: intervention 1: 37.5 mg once daily will continue until progression or unacceptable treatment-related toxicity intervention 2: 10 mg daily will continue until progression or unacceptable treatment-related toxicity

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: Targeted Rx in Advanced NETs 
Version Date: 01/15/2019 
1 
Abbreviated Title: Targeted Rx in Advanced NETs 
CC Protocol: 15C0040 J 
Version Date: 01/15/2019 
NCT Number: NCT02315625 
Title: A Phase II Trial of Mutation-Targeted Therapy with Sunitinib or Everolimus in Patients 
with Advanced Low-or Intermediate Grade Neuroendocrine Tumors of the Gastrointestinal Tract 
and Pancreas 
 
 
NCI Principal Investigator:    Naris Nilubol, MD  
 
Surgical Oncology Program (SOP) 
 
Bldg. 10-CRC Room 4-5932  
 
10 Center Drive  
 
Bethesda, MD 20892  
 
Phone: 240-760-6154 
 
Email: naris.nilubol@nih.gov  
 
 
 
 
Investigational Agents: None 
 
Commercial Agents: Everolimus, Sunitinib 
 
 
 


Abbreviated Title: Targeted Rx in Advanced NETs 
Version Date: 01/15/2019 
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Précis  
Background: 
x Neuroendocrine tumors (NETs) of the gastrointestinal tract and pancreas are a rare and 
heterogeneous group of neoplasms with unique tumor biology, natural history, and 
clinical management issues. 
x Most NETs are sporadic, but they can be part of familial cancer syndromes such as 
multiple endocrine neoplasia type 1 (MEN1), neurofibromatosis type 1 (NF1) or Von 
Hippel-Lindau (VHL) syndrome. 
x Well-differentiated, low or intermediate grade NETs have a heterogeneous natural 
history. 
x Surgery is the only curative treatment option in patients with localized early stage NETs. 
x The optimal management strategy for patients with advanced NETs is unknown.  
x The majority of NETs have somatic mutations in MEN1 and CDKN1B, and genes 
involved in the PI3K/AKT/mTOR signaling pathway, and/or overexpression of growth 
factors and their receptors such as VEGF, VEGFR, PDGF, and PDGFR that can be 
targeted for therapy. 
x Survival in patients with NETs and somatic mutations is better than patients with 
wildtype NETs. 
x Sunitinib (multi-tyrosine kinase inhibitor) and everolimus (mTOR signaling pathway 
inhibitor) are currently approved for the treatment of progressive, unresectable, locally 
advanced or metastatic pancreatic NETs. 
x However, mutation targeted therapy with sunitinib or everolimus has not been studied in 
this patient population.  
x The present proposal aims to determine if mutation targeting therapy for patients with 
advanced low- or intermediate grade NETs is more effective than historically expected 
results. 
Objectives: 
x To determine the progression-free survival in patients with NETs of the gastrointestinal 
tract and pancreas treated with sunitinib or everolimus based on tumor genotyping.  
Eligibility: 
x Patients with: 
o progressive, histologically or cytologically diagnosed low or intermediate grade 
locally advanced or metastatic NETs. 
o Age t 18 years 
Design: 
x Phase II open labeled clinical trial. 
x Tumor biopsy for tumor genotyping will be performed if the patient does not have 
archival tissue available and does not have MEN1, VHL or NF1. 


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x Patients with somatic or germline mutations in MEN1/PDGFR/KIT/FMS-like tyrosine 
kinase-3 will be treated with sunitinib (Arm 1). 
x Patients with somatic/germline mutations in NF1/PTEN/PI3K/AKT/mTOR/VHL will be 
treated with everolimus (Arm 2). 
x Patients with wildtype tumor will be treated with sunitinib (Arm 1). 
x Patients who have disease-progression on either sunitinib or everolimus will cross-over to 
the other drug. 
x Treatment will continue until disease progression, unacceptable toxicity, or consent 
withdrawal. 
x Up to 120 patients will be accrued to the study. It is anticipated that 20-30 patients per 
year may enroll into this trial; thus, accrual may be completed in 4-5 years.  


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Version Date: 01/15/2019 
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TABLE OF CONTENTS 
PRÉCIS .......................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 4 
1 INTRODUCTION .................................................................................................................... 8 
1.1 
Study Objectives .............................................................................................................. 8 
1.1.1 
Primary Objective: .................................................................................................... 8 
1.1.2 
Secondary Objectives: .............................................................................................. 8 
1.2 
Background and Rationale ............................................................................................... 8 
1.2.1 
Neuroendocrine tumors ............................................................................................. 8 
1.2.2 
Everolimus .............................................................................................................. 13 
1.2.3 
Sunitinib .................................................................................................................. 16 
1.2.4 
Rationale ................................................................................................................. 20 
2 ELIGIBILITY ASSESSMENT AND ENROLLMENT ......................................................... 21 
2.1 
Eligibility criteria ........................................................................................................... 21 
2.1.1 
Inclusion Criteria .................................................................................................. 21 
2.1.2 
Exclusion Criteria ................................................................................................. 22 
2.2 
Screening Evaluation ..................................................................................................... 24 
2.3 
Registration Procedures ................................................................................................. 25 
2.3.1 
Treatment Assignment Procedures (For registration purposes only):................. 25 
2.4 
Baseline Evaluation ....................................................................................................... 25 
3 STUDY IMPLEMENTATION .............................................................................................. 26 
3.1 
Study Design .................................................................................................................. 26 
3.1.1 
Cross-over ............................................................................................................... 26 
3.1.2 
Long term follow up ............................................................................................... 27 
3.2 
Study Drug Administration ............................................................................................ 28 
3.2.1 
Sunitinib Treatment and dose ................................................................................. 28 
3.2.2 
Everolimus Treatment and dose .............................................................................. 29 
3.2.3 
CCR Self-Administered Study Drugs Policy .......................................................... 30 
3.3 
Dose Modifications/Dose Delay .................................................................................... 30 
3.3.1 
Sunitinib .................................................................................................................. 30 
3.3.2 
Everolimus .............................................................................................................. 35 
3.4 
Study Calendar ............................................................................................................... 39 
3.5 
Criteria for Removal from Protocol Therapy and Off Study Criteria............................ 42 
3.5.1 
Criteria for removal from protocol therapy ............................................................ 42 
3.5.2 
Off-Study Criteria ................................................................................................... 42 
3.5.3 
Off Protocol Therapy and Off Study Procedure ..................................................... 43 
4 CONCOMITANT MEDICATIONS/MEASURES ................................................................ 43 
4.1 
Supportive Care ............................................................................................................. 43 
4.1.1 
Management of Sunitinib-Induced Hypertension ................................................... 43 


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4.1.2 
Management of specific everolimus toxicities ....................................................... 45 
4.2 
Concurrent medications ................................................................................................. 53 
4.2.1 
General guidelines .................................................................................................. 53 
4.2.2 
Cytochrome P450 and P-glycoprotein inhibitors/inducers/substrates .................... 53 
4.2.3 
Vaccinations ............................................................................................................ 56 
5 BIOSPECIMEN COLLECTION ............................................................................................ 56 
5.1 
Sample collection for genotyping and research Studies ................................................ 56 
5.1.1 
Tumor Sample ......................................................................................................... 56 
5.1.2 
Saliva Collection and Peripheral Blood .................................................................. 57 
5.2 
Sample Storage, Tracking and Disposition.................................................................... 57 
5.2.1 
Procedures for Storage of Specimens in the Laboratory of Dr. Naris Nilubol ....... 57 
5.2.2 
Procedures for Storage of Tissue Specimens in the Laboratory of Pathology ....... 58 
5.3 
Samples for Genetic/Genomic Analysis ........................................................................ 59 
5.3.1 
Description of the scope of genetic/genomic analysis ............................................ 59 
5.3.2 
Privacy and Confidentiality of medical information/biological specimens ............ 59 
5.3.3 
A Certificate of Confidentiality will be obtained for the study as described in 
Section 10.3.1.5. ..................................................................................................... 59 
5.3.4 
Management of Results........................................................................................... 59 
6 DATA COLLECTION AND EVALUATION ....................................................................... 60 
6.1 
DATA COLLECTION .................................................................................................. 60 
6.1.1 
Source Documents .................................................................................................. 60 
6.1.2 
Case Report Forms .................................................................................................. 61 
6.1.3 
Data Quality Assurance .......................................................................................... 61 
6.2 
Data Sharing Plans ......................................................................................................... 61 
6.2.1 
Human Data Sharing Plan ....................................................................................... 61 
6.2.2 
Genomic Data Sharing Plan .................................................................................... 62 
6.3 
Response Criteria ........................................................................................................... 62 
6.3.1 
Definitions............................................................................................................... 62 
6.3.2 
Disease Parameters ................................................................................................. 62 
6.3.3 
Methods for Evaluation of Measurable Disease ..................................................... 63 
6.3.4 
Response Criteria .................................................................................................... 64 
6.3.5 
Duration of Response .............................................................................................. 66 
6.3.6 
Progression-Free Survival ....................................................................................... 66 
6.3.7 
Response Review .................................................................................................... 66 
6.4 
Toxicity Criteria ............................................................................................................. 66 
7 SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
................................................................................................................................................. 66 
7.1 
Definitions ..................................................................................................................... 66 
7.1.1 
Adverse Event ......................................................................................................... 66 
7.1.2 
Suspected adverse reaction ..................................................................................... 66 
7.1.3 
Unexpected adverse reaction .................................................................................. 67 
7.1.4 
Serious..................................................................................................................... 67 


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7.1.5 
Serious Adverse Event ............................................................................................ 67 
7.1.6 
Disability ................................................................................................................. 67 
7.1.7 
Life-threatening adverse drug experience ............................................................... 67 
7.1.8 
Protocol Deviation (NIH Definition) ...................................................................... 67 
7.1.9 
Non-compliance (NIH Definition) .......................................................................... 67 
7.1.10 Unanticipated Problem............................................................................................ 68 
7.2 
NIH Intramural IRB and Clinical Director Reporting ................................................... 68 
7.2.1 
NIH Intramural IRB and NCI CD Expedited Reporting of Unanticipated Problems 
and Deaths .............................................................................................................. 68 
7.2.2 
NIH Intramural IRB Requirements for PI Reporting at Continuing Review ......... 68 
7.2.3 
NIH Intramural IRB Reporting of IND Safety Reports .......................................... 68 
7.3 
Safety Reporting Criteria to the Pharmaceutical Collaborators..................................... 69 
7.3.1 
Novartis ................................................................................................................... 69 
7.3.2 
Pfizer ....................................................................................................................... 69 
7.4 
Data And Safety Monitoring Plan ................................................................................. 70 
7.4.1 
Principal Investigator/Research Team .................................................................... 70 
8 STATISTICAL CONSIDERATIONS.................................................................................... 70 
9 COLLABORATIVE AGREEMENTS ................................................................................... 71 
9.1 
Cooperative Research and Development Agreement (CRADA) .................................. 71 
9.2 
Clinical Trials Agreement (CTA) .................................................................................. 71 
10 HUMAN SUBJECTS PROTECTIONS ................................................................................. 71 
10.1 Rationale For Subject Selection ..................................................................................... 71 
10.2 Participation of Children ................................................................................................ 71 
10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT ......................... 72 
10.4 Evaluation of Benefits and Risks/Discomforts .............................................................. 72 
10.4.1 Risks/Benefits Analysis .......................................................................................... 72 
10.5 Consent Process and Documentation ............................................................................. 73 
10.5.1 Procedure for Consent via Telephone ..................................................................... 74 
11 PHARMACEUTICAL INFORMATION ............................................................................... 74 
11.1 Sunitinib ......................................................................................................................... 74 
11.1.1 Source ..................................................................................................................... 74 
11.1.2 Toxicity ................................................................................................................... 74 
11.1.3 Formulation and preparation ................................................................................... 75 
11.1.4 Stability and Storage ............................................................................................... 75 
11.1.5 Administration procedures ...................................................................................... 75 
11.1.6 Incompatibilities ..................................................................................................... 75 
11.2 Everolimus ..................................................................................................................... 75 
11.2.1 Drug substance ........................................................................................................ 75 
11.2.2 Chemical structure .................................................................................................. 76 
11.2.3 Source ..................................................................................................................... 76 
11.2.4 Toxicity ................................................................................................................... 76 


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11.2.5 Formulation and preparation ................................................................................... 76 
11.2.6 Stability and Storage ............................................................................................... 77 
11.2.7 Administration procedures ...................................................................................... 77 
11.2.8 Hazards and precautions ......................................................................................... 77 
11.2.9 Incompatibilities ..................................................................................................... 78 
12 REFERENCES ....................................................................................................................... 79 
13 APPENDICES ........................................................................................................................ 86 
13.1 Appendix A: Performance Status Criteria ..................................................................... 86 
13.2 Appendix B: Pregnancy and assessments of fertility..................................................... 87 
13.3 Appendix C: Panel of 197 genes tested for in Clinical Molecular Profiling Core (CLIA-
compliant). Genes implicated in NETs are in bold. ....................................................... 89 
13.4 Appendix D: Pathway analysis of 193 mapped genes using ingenuity pathway analysis*
 
91 
13.5 Appendix E: Collection/Recording of Blood Pressure Information .............................. 92 
13.6 Appendix F: Patient Drug Administration Diary ........................................................... 94 
13.6.1 Sunitinib .................................................................................................................. 94 
13.6.2 Everolimus .............................................................................................................. 96 
13.7 Appendix G: Child Pugh Score ..................................................................................... 97 
 


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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective: 
x To determine the progression-free survival (PFS) on first-line therapy in patients with 
NETs of the gastrointestinal tract and pancreas treated with sunitinib or everolimus 
based on tumor genotyping.  
1.1.2 Secondary Objectives: 
x To determine overall response rate (ORR; i.e., sum of complete response [CR], partial 
response [PR], and stable disease [SD]) and duration of response 
x To determine overall survival and median survival time (MST) 
x To evaluate any relationship between tumor genotype, treatment and PFS 
x Safety endpoints (i.e. AEs, clinical laboratory evaluations, ECGs, physical 
examination findings, and vital sign measurements). 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Neuroendocrine tumors 
Neuroendocrine tumors (NETs) of the gastrointestinal tract and pancreas are a rare and 
heterogeneous, but clinically important group of neoplasms with unique tumor biology, natural 
history, and clinical management issues[1-4]. NETs arise in the disseminated neuroendocrine 
cells of the gastrointestinal tract (GI) mucosa (also called “carcinoids”) and the pancreatic islet 
cells. Approximately 85% of NETs are sporadic and the remainder occur as part of familial 
cancer syndromes including multiple endocrine neoplasia-type 1 (MEN1), von Hippel–Lindau 
disease (VHL), von Recklinghausen’s disease (neurofibromatosis 1, NF-1), and tuberous 
sclerosis (TS)[5-9]. 
Neuroendocrine cells are one of the largest group of hormone-producing cells in the body. At 
least 13 distinct gut neuroendocrine cells exist, all of which may oversecrete various bioactive 
peptides or amines including serotonin, somatostatin, histamine, and gastrin, which can result in 
significant morbidity and mortality. Up to 20% of patients with NETs may develop carcinoid 
syndrome associated with flushing, abdominal pain, diarrhea, bronchoconstriction, and carcinoid 
heart disease[10]. 
A unique feature of most NETs is the expression of somatostatin receptors (SSTR) by the tumor 
cells. There are five different SSTR subtypes; more than 80% of NETs of both the GI tract and 
pancreas express multiple subtypes, with a predominance of receptor subtypes 2 and 5[11-14]. 
Somatostatin is an endogenous SSTR agonist which inhibits the secretion of a broad range of 
hormones from the endocrine system, including serotonin, insulin, glucagon, and gastrin[15]. 
Somatostatin analogs have limited clinical use due to its short half-life (<3 min); however, long-
acting somatostatin analogues play a central role in the treatment of hormonal symptoms 
produced by NETs but do not have significant antitumor activity[13, 16]. 


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Epidemiology 
The annual incidence of NETs has been increasing in the United States and worldwide[2, 7, 17-
20]. Whereas early studies have reported incidences of < 1 per 100,000 persons per year[21-23], 
recent age-adjusted epidemiologic studies have shown a significant, more than five-fold, increase 
in NETs incidence from 1973 to 2005[7, 18-20, 24]. Based on data from the National Cancer 
Institute’s Surveillance, Epidemiology and End Results (SEER) cancer registry, the annual 
incidence of NETs was estimated to be 7.8 per 100,000 persons in 2013[7]. The prevalence of 
NETs has been estimated as 35 per 100,000 and may be considerably higher if clinically “silent” 
tumors are included[25]. 
Classification 
NETs are generally classified into functioning (hormone hypersecreting) or nonfunctioning 
(clinically “silent”) tumors, based on their ability to produce hormone-associated symptoms. 
However, other classification systems with many common themes, such as the distinction of 
well-differentiated (low and intermediate-grade) from poorly differentiated (high-grade) NETs 
and the prognostic significance of proliferative rate index have been used over the past 5 decades 
(Table 1). In general, well-differentiated, low or intermediate grade NETs have a relatively 
indolent behavior with slow progression but poorly differentiated tumors may exhibit highly 
aggressive behavior with a rapid metastatic spread that is clinically indistinguishable from 
pancreatic adenocarcinoma or small-cell lung cancer[5, 7, 26]. Fortunately, poorly differentiated 
tumors account for only a small subset of all NETs. 
Recent large, epidemiologic studies have shown that majority of NETs (60-90%) are clinically 
non-functioning, well-differentiated, slow-growing neoplasms diagnosed, in most instances, 
incidentally during an unrelated procedure[2, 6, 10, 13, 27-29]. As a result of this insidious 
biological behavior, many patients with NETs have advanced disease at diagnosis, with regional 
or distant metastasis observed in more than 50% of patients[13, 20].  
Table 1:. Nomenclature and Classification of Neuroendocrine Tumors 
Differentiation & 
Grade 
Mitotic Count 
(/10 HPF)a 
Ki-
67Index 
(%)b 
Traditional 
Classification 
ENETS/WHO 
Classification 
Moran et al[30] 
Well 
differentiated 
 
 
Low grade (grade 
1) 
< 2 
≤ 2 
Carcinoid, 
islet 
cell, PNET 
Neuroendocrine 
tumor, grade 1 
Neuroendocrine 
carcinoma, grade 1 
Intermediate grade 
(grade 2) 
2-20 
3-20 
Carcinoid, 
atypical 
carcinoidc, 
islet
cell, PNET 
Neuroendocrine 
tumor, grade 2 
Neuroendocrine 
carcinoma, grade 2 
Poorly 
differentiated 
 
 
High grade (grade 
3) 
> 20 
> 20 
Small-cell 
carcinoma 
Neuroendocrine 
carcinoma, grade 3, 
small cell 
Neuroendocrine 
carcinoma, grade 3, 
small cell 
 
 
 
Large-cell 
neuroendocrine 
carcinoma 
Neuroendocrine 
carcinoma, grade 3, 
large cell 
Neuroendocrine 
carcinoma, grade 3, 
large cell 


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Abbreviations: HPF, high-power field; ENETS, European Neuroendocrine Tumor Society; PNET, pancreatic neuroendocrine 
tumor. 
a HPF = 2 mm2; at least 40 fields (at ×40 magnification) were evaluated in areas of highest mitotic density. Cutoff values were 
taken from American Joint Committee on Cancer staging system (seventh edition). 
b Ki67/MIB1 antibody; percentage of 2,000 tumor cells in areas of highest nuclear labeling. Cutoff values were taken from 
American Joint Committee on Cancer staging system (seventh edition). 
c The term atypical carcinoid only applies to intermediate-grade neuroendocrine tumor of the lung.  
 
Prognosis 
Even though there has been a significant improvement in the diagnosis and management of 
NETs, no significant change in survival has been observed over the last 30 years[6, 7]. Reported 
survival times for patients with advanced NETs in population-based and institutional series are 
highly variable likely due to variability in tumor biology, classification, treatment modalities, 
and patient selection. According to data from the SEER database, the median overall survival 
(OS) for patients with metastatic NETs was two years[20], whereas in a large institutional 
database, the median OS for a similar group of patients was 5.8 years[31]. According to the 
European Neuroendocrine Tumor Society (ENETS) consensus statement, the median OS of 
nonfunctional NETs was 38 months with a 5-year survival rate of 43%[32].  
Management of advanced NETs 
Advanced NETs are characterized by local invasion, and regional and distant metastases. While 
the treatment of localized NETs is surgical resection, a variety of therapeutic options are 
available for patients with advanced NETs. These include medical control of excess hormone 
levels and associated symptoms, cytoreductive surgery for patients with advanced disease, 
radioembolization, chemoembolization, systemic chemotherapy, interferon, long-acting 
somatostatin analogs, receptor-targeted radionuclide therapy, and or liver transplantation[33-36]. 
When to apply a given option, what combination therapeutic approach should be used, how long 
treatment should be continued, and in what subgroup of patients a particular treatment option 
should be used is unclear and controversial[37]. 
When feasible, aggressive surgical resection has been associated with the best symptom-free and 
long-term survival results in patients with advanced NETs[6, 38-46]. Despite the lack of 
randomized control data, a recent consensus statement from the ENETS emphasized that 
resection should be the first-line treatment option for patients with advanced NETs if up to 90% 
of the disease burden is resectable[47]. However, only 5% to 20% of patients with advanced 
NETs meet this “conventional” criterion[43, 48]. Furthermore, a significant number of patients 
undergoing debulking surgery will have residual disease and recurrence rates are high[49]. Thus, 
it is becoming increasingly clear that combination (surgical and medical) therapeutic strategies to 
improve the outcomes of patients with advanced NETs need to be explored. 
Mutation-targeted therapy 
Our understanding of the genetic changes associated with sporadic and familial NETs has 
improved considerably over the last 3 decades. Driver oncogene and tumor suppressor genes 
have been identified in most NETs[50-56]. Overall, the majority of NETs will have somatic 
mutations in MEN1, the phosphatidylinositol 3-kinase (PI3K)/AKT/ mammalian target of 
rapamycin (mTOR) signaling pathway[20, 57-61], and or overexpression of growth factors and 
their receptor such as vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), 
platelet-derived growth factor (PDGF), and PDGF receptor (PDGFR) (Figure 1)[62-65]. The 
most common mutations (somatic and germline for familial cancer syndromes) are in MEN1, 


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VHL, DAX, ATRX, TP53 and CDKN1B. These mutations are present in 87% of pancreatic 
neuroendocrine tumors and in 60% of gastrointestinal neuroendocrine tumors. 
 
Figure 1. Signaling pathways commonly activated in NETs.  
 
 
mTOR pathway in NETs 
Several studies, using whole exome-sequencing and expression profiling, have consistently 
identified somatic mutations implicating the mTOR pathway as a common event in NETs 
(Figure 1)[57-59, 61, 63]. The mTOR pathway has a central role in cancer cell growth, 
proliferation, differentiation, and apoptosis. Tuberous sclerosis 2 (TSC2), phosphatase and tensin 
homolog (PTEN), PIK3CA, and fibroblast growth factor 13 (FGF13) are among the key 
modulators of the mTOR pathway[52, 56]. Several studies of global gene expression profiling in 
a large panel of pancreatic NETs showed that TSC2 gene and PTEN gene were downregulated in 
most tumors, and their low expression was significantly associated with shorter disease-free and 
overall survival[59, 66]. In addition, expression of FGF13 was significantly associated with liver 
metastasis and shorter disease-free survival[59, 66]. A recent whole-exome sequencing study 
also revealed the presence of somatic mutations in MEN1, DAXX, ATRX, TSC2, PTEN, and 
PIK3CA genes in the majority of s of sporadic pancreatic NETs[58]. Moreover, the presence of 
these mutations was associated with better survival when compared to patients with NETs, which 
had wild type MEN1, and/or DAXX/ATRX[58]. 


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Activation of the mTOR pathway has also been implicated in several familial cancer syndromes 
(TS, NF-1, and VHL) associated with the development of NETs[20, 51, 59, 66-68]. Findings of 
these and other studies further support the critical role of the mTOR pathway in NETs and adds 
to the wealth of data that has spurred the clinical development of mTOR inhibitors as a treatment 
option for patients with advanced NETs (Table 2).  
Key drivers of angiogenesis: growth factors and their receptors in NETs 
The highly vascular nature of NETs led to initial interest in investigating neoangiogenesis in 
NETs. A number of studies have found elevated expression of several cellular growth factors and 
their receptors in NETs; VEGF, VEGF receptor (VEGFR), platelet-derived growth factor 
(PDGF), PDGF receptor (PDGFR), and stem cell factor receptor (c-KIT), and epidermal growth 
factor receptor (EGFR)[62-65, 69, 70]. Many of these receptors with their respective growth 
factor ligands function as tyrosine kinases (TKs) directly and indirectly regulating tumor growth, 
survival and angiogenesis. The hypothesis that inhibiting these targets in concert will result in 
broad antitumor efficacy in patients with NETs has been studied in several clinical trials (Table 
2). 
 
Table 2. Phase II and III Trials in advanced NETs 
Study tumor type 
and Regimen 
Total No. of Patients ORR (%) Median PFS (months) Median 
TTP 
(months) 
Criteria 
P 
PNETs 
 
 
Moertel et al[35] 
105 
 
Streptozocin + 
Doxorubicin 
 
69 
20.0 
NS 
.001 
Streptozocin + 
Fluorouracil 
 
45 
6.9 
Raymond et al[53] 171 
 
 Sunitinib 
 
9 
11.4 
RECIST 
< .001 
 Placebo 
 
0 
5.5 
Yao et al[55] 
410 
 
 Everolimus 
 
 
11.0 
RECIST 
< .001 
 Placebo 
 
 
4.6 
Carcinoid tumors  
 
Rinke et al[71] 
90 
 
 Octreotide LAR 
 
2 
14.3 
WHO 
< .001 
 Placebo 
 
2 
6.0 
Pavel et al[72] 
429 
 
 Everolimus + 
octreotide LAR 
 
 
16.4 
RECIST 
.026 
 Placebo + 
octreotide LAR 
 
 
11.3 
Kulke et al[63] 
 
 
 Sunitinib 
41 
2.4 
10.2 
RECIST 


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13 
Abbreviations: PNETs, pancreatic neuroendocrine tumors; ORR, overall response rate; PFS, progression-free survival; TTP, time 
to progression; RECIST, Response Evaluation Criteria in Solid Tumors; LAR, long-acting release; NS, Nonstandard (includes 
computed tomography scan, radioisotope scan, physical exam, or hormonal response)  
1.2.2 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® was approved for adults with advanced renal cell carcinoma (RCC) after failure of 
treatment with sunitinib or sorafenib 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. 
Everolimus acts as a signal transduction inhibitor. Everolimus selectively inhibits mTOR 
(mammalian target of rapamycin), specifically targeting the mTOR-raptor signal transduction 
complex. mTOR is a key serine-threonine kinase in the PI3K/AKT signaling cascade, which is 
known to be dysregulated in a wide spectrum of human cancers[73]. 
Everolimus is being investigated as an anticancer agent based on its potential to act 
x directly on the tumor cells by inhibiting tumor cell growth and proliferation; 
x 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). 
1.2.2.1 mTOR pathway and everolimus 
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[74]. 


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1.2.2.2 Non-clinical experience 
Everolimus inhibits the proliferation of a range of human tumor cell lines in vitro including cell 
lines originating from lung, breast, prostate and colon cancer, 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 (Everolimus Investigator’s Brochure, 2013). 
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 Investigator’s Brochure, 2013). 
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) (Everolimus 
Investigator’s Brochure, 2013). 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 (Everolimus 
Investigator’s Brochure, 2013). 
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 
(Everolimus Investigator’s Brochure, 2013). 
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 (Everolimus Investigator’s Brochure, 2013). 
All significant adverse events observed in toxicology studies with everolimus in mice, rats, 
monkeys and mini-pigs were consistent with its anticipated pharmacological action as an anti-
proliferative and immunosuppressant and at least in part reversible after a 2 or 4-week recovery 
period with the exception of the changes in male reproductive organs, most notably testes. 
In vitro genotoxicity studies covering relevant genotoxicity end-points showed no evidence of 
clastogenic or mutagenic activity. 
In male fertility studies in rats, testicular morphology was affected at 0.5 mg/kg and above, and 
sperm motility, sperm head count and plasma testosterone levels were diminished at 5 mg/kg 


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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. 
1.2.2.3 Clinical Experience  
1.2.2.3.1 Phase 1 Studies 
In a phase 1 dose escalation study of 92 patients which evaluated both daily and weekly doses, 
the maximum tolerated doses for everolimus monotherapy were determined to be 70 mg/week 
and 10 mg/day. In another dose escalation study of 55 subjects, again evaluating both daily and 
weekly doses, the MTDs were determined to be 50 mg/week or 10 mg/day. In this study, data 
suggested that a dose greater than or equal to 10 mg/day was required for complete inhibition of 
the downstream effectors of mTOR. Based on these results, monotherapy everolimus doses of 10 
mg/day and 70 mg/week were recommended for Phase II and III studies. Daily doses provided 
more complete suppression than weekly dosing[75]. Results from a Japanese Phase I study 
confirmed that everolimus 10 mg/day was the optimum daily monotherapy dose to implement in 
pivotal studies in Japan. 
1.2.2.3.2 Phase 2 NET studies 
A phase II trial of everolimus in combination with long-acting octreotide in patients with 
advanced low- to intermediate-grade NETs (30 carcinoid and 30 islet cell tumors) demonstrated 
a partial response rate of 20% and median progression-free survival (PFS) of 15 months[76]. A 
follow up phase II trial, which randomized patients with metastatic pancreatic NETs (who 
experienced progression on or after chemotherapy) to everolimus or everolimus in combination 
with long-acting octreotide showed a significantly longer median PFS in patients receiving 
combination therapy as compared to everolimus alone (16.7 months versus 9.7 months)[77]. 
Most recently, a multicenter double-blind placebo-controlled phase III trial (RADIANT-3) 
comparing everolimus to placebo in 410 patients with progressive, advanced low- or 
intermediate-grade NETs showed that median PFS was improved with everolimus (11.0 months 
versus 4.6 months)[55]. The results of these studies have led to the approval of everolimus by the 
FDA for the treatment of progressive, unresectable, locally advanced or metastatic, low- or 


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intermediate grade PNETs. Unfortunately, none of these clinical trials evaluated what pathways 
or genes were altered in patient tumor samples. 
1.2.3 Sunitinib 
Sunitinib malate is a small molecule kinase inhibitor with activity against a number of tyrosine 
kinase receptors, including VEGFR, PDGFR, KIT, RET, and FMS-like tyrosine kinase-3 
(FLT3)[78, 79]  
Mechanism of Action 
Tumor VEGF expression has been associated clinically with disease prognosis in many different 
types of malignancies. VEGF expression is increased by diverse stimuli including proto-
oncogene activation and hypoxia, with the hypoxic state frequently arising in solid tumors 
because of inadequate perfusion. In addition to its angiogenic role, VEGF also profoundly 
increases the permeability of the vasculature thereby, potentially contributing to tumor 
progression. A leaky tumor endothelium enhances nutrient and catabolite exchange and 
represents less of a barrier to tumor cell migration and intravasation during metastasis. Two 
high-affinity receptors for VEGF with associated tyrosine kinase (TK) activity have been 
identified in human vascular endothelium; VEGFR-1/Flt-1 and VEGFR-2/kinase insert domain-
containing receptor (KDR). Although the relative contributions of KDR and Flt-1 signaling in 
mediating tumor progression have not been clearly elucidated, a number of studies suggest that 
KDR performs a predominant role.  
In addition to VEGF receptor signaling, increasing evidence implicates PDGFR signaling in 
tumor angiogenesis. Recent nonclinical evidence suggests that inhibition of PDGFR signaling 
augments the antitumor and anti-angiogenic effects of VEGFR inhibitors. In addition, PDGF 
signaling is implicated in the autocrine growth of tumor cells and in the recruitment and 
regulation of tumor fibroblasts.  
Upon chronic oral dosing, sunitinib is expected to inhibit PDGF- and VEGF-driven angiogenesis 
and as a consequence, limit solid tumor growth. Because angiogenesis is necessary for the 
growth and metastasis of solid tumors, and VEGF is believed to have a pivotal role in this 
process, sunitinib treatment may have broad-spectrum clinical utility[80, 81]. Sunitinib also 
exerts direct antitumor activity on cells that express target receptor tyrosine kinases (RTKs) 
associated with tumor cell proliferation, such as KIT, PDGFR, and RET.  
1.2.3.1 Non-clinical Experience 
1.2.3.1.1 Specificity and Efficacy Studies 
Non-clinical data from in vitro and in vivo studies have demonstrated sunitinib selectively inhibits 
the Class 3 and Class 5 RTKs, including receptors for VEGF (VEGFR), KIT, FLT-3, and PDGFR 
(Investigator’s Brochure, 2014). Specifically, receptor phosphorylation inhibition studies have shown 
that sunitinib inhibits KIT-ligand-induced phosphotyrosine levels in a dose-dependent manner with 
IC50 values of 0.001-0.01 mcM in vitro and reduced PDGFR-β phosphotyrosine levels in vivo[82]. 
Sunitinib also selectively inhibited proliferation of human umbilical vein endothelial cells (HUVEC) 
stimulated with VEGF (IC50=0.04 mcM) compared to FGF-stimulated proliferation (IC50=0.7 
mcM)[78].  
In animal efficacy studies, sunitinib showed broad antitumor activity in mouse xenograft models 
against a variety of human tumor cell lines including colorectal cancer (HT-29, Colo205), non-small 
cell lung cancer (H460), breast cancer (MDA-MB-435), melanoma (A375), epidermoid cancer 


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(A431), and glioma (SF763T)[78]. Sunitinib has also demonstrated antitumor activity against other 
breast 
cancer 
models 
(MMTV-v-Ha-ras 
transgenic 
mouse 
mammary 
carcinoma 
and 
dimethylbenzanthracene [DMBA]-induced rat mammary carcinomas)[83]. In an animal model of 
KIT-expressing small cell lung cancer (SCLC; NCI-H526), sunitinib administration resulted in 
greater tumor growth inhibition than did imatinib[82].  
Combination studies of sunitinib with docetaxel, 5-fluorouracil (5-FU), or doxorubicin resulted in 
significantly enhanced growth inhibition of human MX-1 breast cancer xenografts compared to 
levels of inhibition with either sunitinib or the cytotoxic agent alone[83]. Moreover, the combination 
therapies each led to a significantly increased survival compared to either single agent alone[83]. 
Significantly delayed tumor growth has also been demonstrated in combination studies of sunitinib 
and cisplatin in NCI-H526 SCLC xenografts[82]. 
1.2.3.1.2 Toxicology Studies 
Single- and multiple-dose toxicology studies were conducted in mice, rats, rabbits, dogs, and 
monkeys (Sunitinib Investigator’s Brochure, 2014). The acute oral maximally-tolerated dose 
(MTD) for mice, rats, and dogs was greater than the maximum dose of 500 mg/kg. The MTD in 
monkeys was greater than the 1200 mg/kg maximum dose tested, but emesis occurred at doses 
≥50 mg/kg. Treatment-related effects in the lymphoid tissue, bone marrow, adrenal glands, and 
bone growth plate were seen in rat repeated-dose studies with gastrointestinal tract, reproductive 
organ, kidney, pancreas, and pituitary effects reported at the highest dose. Death was observed at 
the highest dose level of 240 mg/kg/day. Gastrointestinal disturbances (diarrhea, loss of appetite, 
emesis) as well as hematologic disturbances also occurred in an 8-week study in female 
monkeys. Other toxicities seen in monkeys included mild elevations in AST, ALT, and 
creatinine kinase (CK), adrenal gland cortex hemorrhage, acinar degranulation of the salivary 
glands, decreased erythropoiesis in the bone marrow, and lymphoid atrophy. Possible 
impairment of immune function in the highest dose group was manifested as cytomegalovirus 
and bacterial infections.  
There is an indication that repeated high doses of sunitinib may lead to cardiac 
function/contractility changes as confirmed by altered ECG and MUGA or echocardiographic 
parameters and increased cardiac Troponin I and/or T in single animals that died or were 
euthanized early due to a moribund condition. These changes appear to be primarily functional 
and reversible. Due to the poor clinical condition of these animals, it appears that the cardiac 
changes were not a direct result of sunitinib treatment, but rather resulted from an important, 
non-compensated volume loss and additional suppression of heart function due to chronotropic 
incompetence and possible myocardial involvement of uncertain etiology. Data from this study 
indicate that functional cardiac changes were induced primarily at the highest dose of sunitinib.  
Sunitinib was found to be negative for genotoxicity in vivo and in vitro (Sunitinib Investigator’s 
Brochure, 2014). Wound-healing studies showed a subtle transient delay in skin wound healing 
in mice treated continuously for up to 5 weeks with supratherapeutic doses of sunitinib at 80 
mg/kg/day. However, it was determined that this alteration in wound healing has minimal 
biologic significance (Sunitinib Investigator’s Brochure, 2014).  
1.2.3.1.3 Pharmacokinetics 
Single-dose pharmacokinetics (PK) was evaluated in mice, rats, at oral doses of 20, 40, 80, and 
160 mg/kg (Investigator’s Brochure, 2014). At these doses, the respective Tmax values were 3, 3, 
0.5, and 6 hours respectively, while maximum plasma concentration (Cmax) values were 420, 


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708, 877, and 1670 ng/mL, respectively. In monkeys, t1/2α and t1/2β at a dose of 6 mg/kg PO were 
18 and 16 hours, respectively. Repeat-dose PK studies indicated that increases in exposure were 
not consistently proportional to dose. Steady state plasma concentrations were reached after 28 
days of dosing with little change in levels thereafter. Sunitinib appeared to readily distribute into 
the CNS in mice and to a lesser extent in rats and monkeys.  
Sunitinib metabolism is predominantly mediated by CYP3A4 and produces an active metabolite, 
SU012662. This metabolite and sunitinib were the only major drug-related compounds found in 
the systemic circulation in mice, rats, monkeys and humans. Sunitinib and its major metabolite 
are highly (90-98%) protein bound in mouse, rat, monkey, and human plasma. IC50 values 
measured in vitro are expected to be reached with the currently recommended 50 mg dose. 
Sunitinib and SU012662 are not potent inducers or inhibitors of major CYP450 enzymes. 
Therefore, they are both predicted to have a low potential to cause clinically relevant drug-drug 
interactions mediated by CYP450 enzymes and efflux transporters. However, concurrent 
treatment with CYP3A4 inducers and inhibitors may affect sunitinib metabolism. 
1.2.3.2 Clinical Experience 
1.2.3.2.1 Phase 1 
In an early phase 1 study designed to investigate dosing regimen and scheduling (in human 
subjects, the results of clinical pharmacology studies demonstrate that Cmax and area under the 
concentration-time curve (AUC) increased in a proportional manner after single doses of 50 to 
350 mg as well as after multiple doses of 25-100 mg), 41 patients with a variety of advanced 
solid tumors received sunitinib administered on a schedule of 2 weeks of treatment followed by 2 
weeks off (2/2 schedule) or 4 weeks on with 2 weeks off (4/2 schedule)[84]. Doses evaluated on 
the 2/2 schedule (n=23) included 50 mg every other day (n=3), 50 mg daily (n=15), or 75 mg 
daily (n=5); the 18 patients enrolled in the 4/2 schedule received 25 mg daily (n=3) or 50 mg 
daily (n=15). The most frequent adverse events (AEs) were constitutional (fatigue/asthenia), 
gastrointestinal (nausea, vomiting, diarrhea) and hematologic (neutropenia, thrombocytopenia). 
Most of the AEs were grade 1 or 2, although at 75 mg daily, grade 3 and 4 fatigue/asthenia were 
dose limiting but readily reversible on discontinuation of treatment. There were 4 partial 
responses (PRs) assessed by RECIST and 22 patients with stable disease (SD) among the 41 
patients.  
A phase 1 dose-escalation study in 28 patients with advanced tumors evaluated sunitinib doses of 
30 mg/m2 every other day, and doses of 30, 42, or 59 mg/m2 daily on the 4/2 schedule[85]. Grade 
3 fatigue and hypertension were dose limiting at 59 mg/m2 as well as grade 2 bullous skin 
toxicity, and the MTD was defined as 42 mg/m2 daily. Based on these and other reversible AEs 
in the 12 patients treated at the MTD, the recommended phase 2 dose on the 4/2 schedule was 
determined to be 50 mg/day. Responses determined by RECIST were seen in 6 of 23 evaluable 
patients: 3 in RCC, 1 in NET, 1 in GIST, and 1 in adenocarcinoma of unknown primary. Tumor 
responses in patients treated at higher doses were often associated with reduced intratumoral 
vascularization and central tumor necrosis, leading to organ perforation in one patient and fistula 
in another. These observations suggest the possible necessity for careful tumor density 
monitoring to detect early evidence of necrosis.  
Two phase 1 studies have been conducted in AML, the first with the primary endpoint of 
evaluation of the inhibition of FLT3 phosphorylation and the second designed as a conventional 
dose-escalation study[79, 86]. O’Farrell and colleagues[79] studied FLT3 phosphorylation in 29 


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AML patients who received a single dose of sunitinib at doses ranging from 50-350 mg. Over 
50% of patients showed strong inhibition of Flt3 phosphorylation at doses of 200 mg and higher. 
As anticipated from nonclinical data, patients with FLT3 internal tandem duplication (ITD) 
mutations were more sensitive than those with wild-type Flt3 (FLT3-WT) as shown by 100% 
inhibition in FLT3-ITD compared to 50% in FLT3-WT. This study also gave evidence of 
downstream signal inhibition (STAT5 and ERK pathways), with STAT5 levels reduced 
primarily in FLT3-ITD patients while ERK inhibition occurred in the majority of patients 
independently of FLT3 inhibition. The dose-escalation study enrolled 15 patients with refractory 
or resistant AML who were treated with sunitinib on either the 4/2 or 4/1 schedule at a starting 
dose of 50 mg/day. Dose-limiting AEs (grade 4 fatigue and hypertension) occurred in both 
patients treated at 75 mg/day, and one of these patients (who had received prior mitoxantrone) 
developed cardiac failure. The 75-mg dose level was therefore terminated and 50 mg/day was 
considered to be the MTD. All four patients with FLT3 mutations had morphologic or partial 
responses compared to 2 of 10 evaluable patients with wild-type FLT3. Responses, although 
longer in patients with mutated FLT3, were of short duration.  
Preliminary results from phase 1 studies exploring the combination of sunitinib with 
chemotherapeutic agents like capecitabine[87], pemetrexed[88], docetaxel[89], gemcitabine[90], 
carboplatin/paclitaxel[91], and metronomic cyclophosphamide/ methotrexate[92] in patients with 
various solid tumors have been presented. The MTD of sunitinib on the 4/2 schedule with 
docetaxel (60 mg/m2) was 25 mg daily; with capecitabine (1000 mg/m2), it was 37.5 mg daily. 
The MTD of sunitinib on the 2/1 schedule with docetaxel (75 mg/m2) was 37.5 mg daily and 
with capecitabine (1000 mg/m2) was 50 mg daily. The MTD for sunitinib as continuous daily 
dosing (CDD) with capecitabine (1000 mg/m2) was 37.5 mg daily and for pemetrexed (500 
mg/m2) was 37.5 mg daily. Reported DLTs included febrile neutropenia, fatigue, hand-foot 
syndrome, gastrointestinal hemorrhage, cerebral hemorrhage, and ischemic optic neuropathy.  
1.2.3.2.2 Phase II and Phase III in NET 
A phase II trial in patients with advanced NETs who received sunitinib demonstrated a median 
time to tumor progression of 7.7 and 10.2 months in patients with pancreatic NETs and carcinoid 
tumors, respectively[63]. A follow-up randomized, double-blind phase III trial comparing the 
response of 86 randomly selected patients given sunitinib with that of 85 patients on placebo 
demonstrated significant improvement in median PFS of patients on sunitinib (11.4 months 
versus 5.5 months)[53]. Moreover, patients treated with sunitinib showed early signs of an 
increase in overall survival[54]. Based on these findings sunitinib was approved by the FDA for 
the treatment of progressive, unresectable, locally advanced or metastatic PNETs. Unfortunately, 
none of these clinical trials evaluated what pathways or genes were altered in patient tumor 
samples and whether response to sunitinib was related to the tumor genotype. 
1.2.3.3 Safety Profile 
Sunitinib is reasonably well tolerated, with asthenia, hypertension, dermatitis, and mild 
myelosuppression as the most common AEs.[93] Additionally, the inhibition of TKRs by agents 
such as sunitinib can result in cutaneous AEs such as acral erythema, subungual splinter 
hemorrhages, modification of hair and skin pigmentation, mucositis, and (occasionally) 
periocular edema[94, 95]. Hand-foot skin reaction, a group of signs and symptoms that can 
affect, usually bilaterally, the hands and/or feet of patients, has occurred in patients receiving 
sunitinib. A recent analysis of dermatological AEs in patients receiving sunitinib therapy has 


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reported that all-grade hand-foot skin reactions occurred in 19% of patients (5% grades 3-4), skin 
discoloration in 28% (no grades 3-4), dry skin in 16% (1% grades 3-4), skin rash in 13% (1% 
grades 3-4), dermatitis in 8% (2% grades 3-4), hair color changes in 10% (no grades 3-4), 
alopecia in 6% (no grades 3-4), and phototoxicity in <0.1% (no grades 3-4)[96]. 
1.2.4 Rationale 
The approval, by the FDA, of sunitinib and everolimus for the treatment of unresectable, locally 
advanced or metastatic NETs is a remarkable milestone in the field of medical therapy of 
malignant NETs[53-55]. However, there is important management issue that need to be 
addressed: While the choice of targeted therapies in other malignancies is driven by the findings 
of the precise molecular alterations present in the tumor, no such study has been done in 
malignant NETs. This is particularly important given that the survival of patients with malignant 
NETs appears to be different based on the driver mutation(s) present in the tumor and low- or 
intermediate grade tumors can have a relatively indolent growth[58]. 
Surgical resection alone is a valuable treatment option for patients with early-stage disease; 
however, the extent, timing and effect of surgical intervention for advanced, metastatic NETs 
remain controversial and difficult to estimate. NETs most commonly metastasize to the loco-
regional lymph nodes and liver and 25% to 93% of patients will develop liver metastases 
throughout the course of their disease[38, 43]. Prospective randomized data on the treatment of 
liver metastases of NETs are lacking and there is also considerable debate regarding the optimal 
surgical management[42]. In general, the surgical strategies proposed by different groups can be 
classified into: 1) resection of the primary tumor and loco-regional metastases (intra-abdominal 
debulking), 2) resection of isolated liver metastases, or 3) synchronous resection of primary and 
liver metastases. 
Although not supported by randomized clinical trial data, currently it is advocated that surgery 
should be undertaken only if metastatic disease is confined to the liver and if 90% or more of the 
tumor mass, including liver metastases, can be successfully removed[47]. However, most 
patients will present with multiple bilobar liver metastases, and altogether only 5–10% will have 
apparently solitary or dominant liver metastases amenable to surgical resection[43, 97]. 
Furthermore, recurrence after surgery is common and a significant number of patients with 
advanced NETs undergoing debulking surgery will have residual disease and suffer from 
complications associated with hormonal hypersecretion and or tumor progression[43, 48, 49]. 
The role of surgical tumor debulking less than the traditionally accepted 90% of tumor mass is 
currently unknown and it is not clear if adjuvant therapy in this patient population will render 
favorable outcomes.  
Although improving OS is the ultimate goal for any cancer therapy, the variable, and at times 
long, survival time in many patients with NETs makes OS a less suitable initial end point to 
study for the proposed strategy of targeted therapy [49, 71]. In this regard, using PFS as a 
primary end point poses less significant scientific challenges and is attractive from both an 
ethical and feasibility standpoint[49]. Such an approach will allow us to generate enough data to 
determine whether a larger study is warranted using genotype targeted therapy.  


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2 
Eligibility assessment and enrollment 
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Progressive, histologically or cytologically diagnosed low or intermediate grade, 
neuroendocrine tumors confirmed by the Laboratory of Pathology, NCI or a pathology 
laboratory at the enrolling institution. Disease progression is defined according to 
RECIST criteria for progression of disease (see Section 6.3) or any new lesions seen on 
68-Gallium DOTATATE within 18 months prior to enrolment (per PI discretion and if 
68-Gallium DOTATATE is performed at the enrolling institution). 
2.1.1.2 Age t 18 years, because the incidence and prevalence of metastatic pancreatic and 
gastrointestinal neuroendocrine tumors in the pediatric patient population is exceedingly 
rare (children are excluded from this study, but will be eligible for future pediatric 
trials). 
2.1.1.3 Patients must have measurable disease according to RECIST criteria (see Section 6.3) 
on anatomic imaging studies (CT scan or MRI).  
2.1.1.4 Willingness to undergo tumor biopsy if the patient does not have a known familial 
cancer syndrome (MEN1, VHL and NF1) or archival tissue available. 
2.1.1.5 ECOG performance status <2 (see Appendices 
2.1.1.6 Appendix A). 
2.1.1.7 Patients must have normal organ and bone marrow function as defined below:  
- 
hemoglobin 
 
 
> 9 g/dL* 
- 
leukocytes 
 
 
>3,000/mcL* 
- 
absolute neutrophil count 
>1,500/mcL* 
- 
platelets 
 
 
> institutional lower limit of normal*  
- 
total bilirubin  
 
within normal institutional limits 
- 
AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of normal 
(≤5 x ULN in patients with liver metastases) 
- 
creatinine 
 
 
within normal institutional limits 
  
 
 
 
 
 
OR 
- 
creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal. 
- 
INR 
≤2; 
*If a patient’s bone marrow function falls below the indicated values and it is not 
thought to be related to prior treatments a hematology consult will be ordered. If 
Hematology deems the patients safe to proceed with treatment they will be allowed to 
enroll on study. In such cases, the patient’s absolute neutrophil count must be > 
1,000/mcl, hemoglobin must be > 7.5 g/dL and the platelet count must be > 75,000 
mcL. Each patient will also be seen by a medical oncologist at follow-up visits if 
possible. 


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22 
2.1.1.8 Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides 
≤2.5x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient 
can only be included after initiation of appropriate lipid lowering medication; 
2.1.1.9 Women of childbearing potential (WOCBP) or partners of WOCBP participating in this 
study must agree to use highly effective contraception while on treatment and for at 
least 8 weeks after end of treatment, because the effects of sunitinib and everolimus on 
the developing human fetus are unknown. Should a woman become pregnant or suspect 
she is pregnant while she or her partner is participating in this study, she should inform 
her treating physician immediately. 
Highly effective contraception methods include combination of: 
a. Any two of the following: 
x Use of oral, injected or implanted hormonal methods of contraception or; 
x Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
x Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/ 
vaginal 
suppository; 
b. Total abstinence or; 
c. 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 enrollment. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she 
considered not of child-bearing potential. 
2.1.1.10 Must have fully recovered from toxicities of any prior treatment with cytotoxic drugs, 
radiotherapy, surgery, or other anti-cancer modalities (returned to baseline status as 
noted before most recent treatment or ≤ grade 1). 
2.1.1.11 Ability of subject to understand and the willingness to sign a written informed consent 
document. 
2.1.2 Exclusion Criteria 
2.1.2.1 Uncontrolled hypertension (>150/100 mmHg). 
2.1.2.2 Prior external beam radiation therapy to the target lesion(s) within 1 months prior to 
enrollment 
2.1.2.3 Prior systemic chemotherapy or therapy with one of the investigational agents within 1 
month prior to enrollment.  
2.1.2.4 Patients who had therapy with one of the investigational agents more than 1 month prior 
to enrollment in whom tumor genotyping show assignment to the same investigational 
agent. 
2.1.2.5 Patients who are receiving any other investigational agents. 
2.1.2.6 Patients with known brain metastases will be excluded from this clinical trial because of 
their poor prognosis and because they often develop progressive neurologic dysfunction 
that would confound the evaluation of neurologic and other adverse events. 


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23 
2.1.2.7 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to sunitinib or everolimus. 
2.1.2.8 Patients who have any severe and/or uncontrolled medical conditions such as: 
a. unstable angina pectoris, symptomatic congestive heart failure, myocardial 
infarction ≤6 months prior to start of everolimus, serious uncontrolled cardiac 
arrhythmia, or any other clinically significant cardiac disease 
b. symptomatic congestive heart failure of New York heart Association Class III or 
IV 
c. active (acute or chronic) or uncontrolled severe infection, liver disease such as 
cirrhosis, decompensated liver disease 
d. known severely impaired lung function  
e. QTc interval > 450 msec for males or > 470 msec for females 
f. active, bleeding diathesis; 
g. psychiatric illness/social situations that would preclude informed consent, limit 
compliance with study requirements  
2.1.2.9 Pregnant or nursing patients will be excluded from the study, because the effects of 
sunitinib and everolimus on the developing human fetus are unknown. Because there is 
an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with sunitinib or everolimus, breastfeeding should be 
discontinued if the mother is treated with sunitinib or everolimus (See also Appendix 
B).  
2.1.2.10 Current treatment with therapeutic doses of Coumadin-derivative anticoagulants (low 
dose Coumadin up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed). 
2.1.2.11 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with study agents.  
2.1.2.12 Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome, 
or the inability to take oral medication 
2.1.2.13 Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. 
Patients with a known history or diagnosis of diabetes mellitus who are on therapy and 
have had good blood sugar control may be included even if the HbA1c is > 8% because 
this value can take up to 3-4 months to normalize; 
2.1.2.14 Patients who have received live attenuated vaccines within 1 week of start of 
everolimus and during the study. Patient should also avoid close contact with others 
who have received live attenuated vaccines. Examples of live attenuated vaccines 
include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, 
varicella and TY21a typhoid vaccines 
2.1.2.15 Patients who are on chronic treatment with corticosteroids or other immunosuppressive 
agents (topical or inhaled corticosteroids are allowed) 
2.1.2.16 Patients with a history of non-compliance to medical regimens or who are considered 
potentially unreliable or will not be able to complete the entire study 
2.1.2.17 Patients who are taking medications that are strong inhibitors of CYP3A4 or PgP and 
need to remain on these medications. For a current table of Substrates, Inhibitors and 
Inducers 
please 
access 
the 
following 


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24 
website:http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResourc
es/DrugInteractionsLabeling/ucm093664.htm 
2.1.2.18 Patients who have a history of another primary malignancy from which the patient has 
been disease free for < 3 years at the time of enrolment, with the exceptions of: a patient 
with a familial cancer syndrome-associated NETs including MEN1, VHL, NF-1, and 
TS 
2.2 
SCREENING EVALUATION 
Within 4 weeks prior to enrollment  
x Confirmation of progressive, histologically or cytologically diagnosed low or 
intermediate grade, neuroendocrine tumors locally invasive or metastatic confirmed 
by the Laboratory of Pathology and the Department of Radiology, NCI or a pathology 
laboratory and radiology department at the enrolling institution (any time prior to 
enrollment). 
x Brain MRI or CT (if clinically indicated)  
x 68-Gallium DOTATATE scan per PI discretion 
x Contrast enhanced CT scan or MRI of the chest, abdomen and pelvis (CT C/A/P)  
x Bone scan for patients in whom bone metastases are suspected 
x FDG PET scan  
x HIV antibody  
x 24-urine collection and measurement of urinary creatinine, total protein and albumin, 
and serum creatinine measurement 
Within 2 weeks prior to enrollment  
x Laboratory Evaluations 
o CBC with differential and platelets  
o Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 
(bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium 
total, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Total 
Protein 
o INR 
o Lipid panel (fasting) 
o Hemoglobin A1C 
x Complete history and physical examination including height, weight, vital signs and 
ECOG status  
x 12 lead ECG  
Within 3 days prior to enrollment  
x Serum or urine beta-HCG (in women of childbearing potential)  


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25 
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 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.  
2.3.1 Treatment Assignment Procedures (For registration purposes only): 
Cohorts 
Number Name 
Description 
1 
Cohort 1 
Subjects with wild type NETs or mutations in 
MEN1/PDGFR/KIT/FLT3 or mutations not known to 
be specifically targeted by sunitinib or everolimus  
2 
Cohort 2 
Subjects with NETs and mutations in 
NF1/PTEN/PI3K/AKT/mTOR/VH/TP53L but not in 
MEN1/PDGFR/KIT/FLT3 
 
Arms 
Number Name 
Description 
1 
Arm 1 
Sunitinib 
2 
Arm 2 
Everolimus 
Arms Assignments 
Subjects in Cohorts 1 will be directly assigned to Arm 1. 
Subjects in Cohorts 2 will be directly assigned to Arm 2. 
Subjects who develop disease progression or unacceptable treatment-related toxicity during 
treatment in either Arm 1 or Arm 2 will cross-over to the other Arm. 
2.4 
BASELINE EVALUATION 
Studies do not need to be repeated if they have already been performed for screening within the 
required baseline timeframe. 
Within 4 weeks prior to study drug initiation 
x Echocardiogram in patients with Carcinoid tumors. 
x Patients must provide archival tissue or undergo image guided tumor biopsy for 
genotyping (patients with known familial cancer syndrome (MEN1, VHL and NF1) 
are excluded) 


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26 
x Patients who present with evidence of cardiac or pulmonary risk factors will undergo 
a cardiac evaluation prior to biopsy/surgical intervention according to standard 
clinical practice 
x 30 mL of peripheral blood for research  
x 2-13 mL saliva for research studies 
x Hepatitis B and C serology and viral load (if positive serology)  
Within 2 weeks prior to study drug initiation 
x Laboratory Evaluations  
o Chromogranin A. 
o Only in patients known to have functioning NETs or with a prior history of 
elevation of secreting biomarkers: vasoactive intestinal polypeptide (VIP), 
serotonin (urinary 5-HIAA), gastrin, somatostatin, fasting insulin, C-peptide 
(proinsulin) or glucagon.    
x CT C/A/P or MRI 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
In this Phase II trial, patients first will undergo tumor genotyping from their archival tumor tissue 
samples. Patients who do not have archival tumor tissue samples available, will have image 
guided tumor biopsy. Patients with VHL and MEN1 will not undergo tumor biopsy. 
 Based on the tumor genotype or germline mutation status, patients will be treated with sunitinib 
(Arm 1) (for mutations in MEN1/PDGFR/KIT/FLT3) or everolimus (Arm 2) (for mutations in 
NF1/PTEN/PI3K/AKT/mTOR/VH/TP53L) daily in 28 day cycles (Figure 2, Table 3). Patients 
will receive long-acting octreotide (for symptoms associated with hormonal hypersecretion). 
Patients who have gene mutations not known to be specifically targeted by sunitinib or 
everolimus or with more than one mutation will be assigned to sunitinib (Arm 1) (Table 3, 
Appendix C and Appendix D).  
If a patient has two mutations (one in the sunitinib-MEN1/PDGFR/KIT/FLT3 and another in the 
everolimus group- NF1/PTEN/PI3K/AKT/mTOR/VHL/TP53, the patient will be assigned to 
sunitinib (Arm 1).  
3.1.1 Cross-over 
Patients who develop disease-progression or unacceptable treatment-related toxicity on either 
sunitinib or everolimus will cross-over to the other drug.  
Patients must start cross-over within 3 months of discontinuation of the first line of treatment. 
Unacceptable toxicity must have resolved to CTCAE Grade 1 or baseline. 
Before cross-over eligibility must be confirmed (tests do not need to be repeated if they have 
already been performed within the required timeframe): 
 Within 4 weeks prior: 


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27 
x CT C/A/P or MRI 
Within 2 weeks prior: 
x Physical examination including weight, vital signs and ECOG status 
x Laboratory Evaluations  
o CBC with differential and platelets  
o Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 
(bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium 
total, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Total 
Protein  
During cross-over treatment patients will have regular study assessments as described in Study 
Calendar Error! Reference source not found.  
3.1.2 Long term follow up 
After discontinuation from the study, the subjects will be contacted at 3 months intervals to 
obtain information about subsequent treatment(s) and survival status by phone or e-mail. 
 


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Figure 2. Study flow chart and treatment selection based on tumor genotype. 
 
CR-complete response, PR-partial response, SD-stable disease, PD-disease progression 
 
Treatment will continue until disease progression, unacceptable treatment-related toxicity, or 
consent withdrawal. Response to treatment (CR/PR/SD) will be assessed using RECIST v1.1 
(See Section 6.3) every 3 months after initiation of treatment. 
 
3.2 
STUDY DRUG ADMINISTRATION 
3.2.1 Sunitinib Treatment and dose 
Patients on Arm 1 will be treated with oral sunitinib at a starting dose of 37.5 mg once daily. 
Patients will take sunitinib once daily in the morning, with or without food, as desired. Patients 
should be advised to drink plenty of water or take rehydration fluids to avoid dehydration if 
Subjects with low- or intermediate grade, locally invasive/metastatic neuroendocrine tumors 
of the gastrointestinal tract and pancreas and measurable disease who meet study eligibility 
criteria 
Long-acting octreotide for symptoms control (if indicated) with sunitinib for mutations in 
MEN1/PDGFR/KIT/FTL3, everolimus for mutations in 
NF1/PTEN/PI3K/AKT/mTOR/VHL/TP53 or assignment to sunitinib for mutations in the 
remaining genes sequenced or wild type tumors (see Table 3) 
 
CR, PR or SD 
Continue on current regimen 
PD 
Cross-over to other arm or 
Off study if patient received therapy 
in both arms 
Response assessment every 3 months 


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diarrhea occurs. If a dose is missed the subject will be instructed to take the next dose as 
scheduled. 
3.2.1.1 Because hypertension is a known and potentially serious adverse event associated with 
sunitinib maleate treatment, patients will have their blood pressure monitored and 
recorded at baseline and weekly during sunitinib treatment either at the doctor’s office 
or using any calibrated electronic device (such as those found at a local drug store or 
pharmacy). Appendix E detail the collection and recording of blood pressure related 
information.  
3.2.1.2 Patients with bulky solid tumors should be monitored closely for pneumothorax, 
intestinal fistulae, or intestinal perforation in the event of rapid tumor destruction. 
3.2.1.3 Patients should be alerted to the possibility that sunitinib capsules can cause a yellow 
discoloration of the skin on direct contact. If this happens, the patient should wash 
immediately with soap and water.  
3.2.1.4 Thyroid function (free T4, T3 and TSH) will be monitored at every cycle). 
3.2.2 Everolimus Treatment and dose 
Patients on Arm 2 will be treated with oral everolimus at a starting dose of 10 mg once daily.  
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. 


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Table 3. Choice of targeted therapy driven by the findings of the precise molecular 
alterations based on common mutations that occur in NETs. 
Study Agent 
Mutations * 
Affected Pathways 
 
Everolimus 
PTEN 
PI3K/AKT/mTOR 
 
PI3K 
PI3K/AKT/mTOR 
 
AKT 
PI3K/AKT/mTOR 
 
mTOR 
PI3K/AKT/mTOR 
 
VHL 
Hypoxia induced PI3K/AKT/mTOR 
 
TSC1 
PI3K/AKT/mTOR 
 
TSC2 
PI3K/AKT/mTOR 
 
NF1 
TSC2/mTOR, Hypoxia induced 
neoangiogenesis 
 
Sunitinib 
MEN1 
Cell growth, cell cycle and genome 
instability 
 
FLT3 
Cell survival, proliferation, and 
differentiation 
 
PDGFR 
Cell proliferation, cell migration, 
neoangiogenesis 
 
ATM 
 
 
KIT 
Cell survival, proliferation, and 
differentiation 
 
ATRX 
Cell survival, proliferation, and 
differentiation 
 
 
 
 
 
*Mutations in genes not listed above or that are wildtype will be treated with sunitinib (see Appendix C for list of 
other genes that will be genotyped). Germline DNA will be obtained for comparison to tumor genotype data for 
every patient. Also, some patients with known familial cancer syndromes (MEN1 and VHL) will be included in the 
study and tumor biopsy for the sole purpose of agent selection in these patients will not be performed. 
 
3.2.3 CCR Self-Administered Study Drugs Policy 
All oral self-administered investigational agents will be properly accounted for, handled, and 
disposed in accordance with existing federal regulations and principles of Good Clinical 
Practice. All oral study drugs will be recorded in the patient diary found in Appendix F. This 
will be used as a memory aide for subjects. The clinical research team will maintain the primary 
source record.  
Subjects should be asked to bring the diary as well as unused study agent and empty containers 
with them at each study visit. If a subject goes off study while at home, the research nurse will 
ensure and document the return of the unused oral investigational agents from the participant. 
Unused investigational study agents will be disposed and destroyed per CC pharmacy SOPs. 
3.3 
DOSE MODIFICATIONS/DOSE DELAY 
Patients are allowed to remain off treatment for up to 12 weeks.  
Patients requiring >12 weeks of study medication dose interruption due to persistent toxicity will 
be either crossed over to the other arm or discontinued from the treatment. 
3.3.1 Sunitinib 
Subjects experiencing severe toxicity (see dose modification Table 5 below) will have 1-week 
treatment rests inserted into the regimen as needed and may dose reduce depending on individual 


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tolerability. The dose of 37.5 mg may be reduced to 25 mg daily, which is the minimum dose 
acceptable for daily dosing of sunitinib. Intra-patient re-escalation of study medication back to 
previous dose is permitted at the discretion of the investigator and considering the patient’s 
clinical status. 
Subjects not experiencing a response by RECIST criteria and experiencing only Grade ≤1 non-
hematological or Grade ≤2 hematological toxicity within the first 8 weeks of treatment may dose 
escalate to 50 mg daily at any time after 8 weeks. If dose is escalated or reduced, treatment will 
continue to be on a continuous daily dosing schedule. 
The doses of study medication may be modified as outlined in Table 4. 
Table 4: Sunitinib Dose levels 
Dose Level 
Daily Dose 
Dispensed As 
-1 
25 mg* 
1 x 25 mg capsule 
or 
2 x 12.5 mg capsule 
0 (Starting Dose Level) 
37.5 mg 
3 x 12.5 mg capsule 
+1 
50 mg 
1 x 50 mg capsule 
or 
2 x 25 mg capsules) 
*Patients will not be treated at less than 25 mg per day. If a dose reduction is required at this level, the 
subject will be removed from study therapy 
 
Intrapatient dose reduction by 1 dose level (to 25 mg/day, or to 37.5 mg/day if the subject has 
been receiving 50 mg/day) may be required depending on the type and severity of toxicity 
encountered. In Table 5 is an outline of the recommended dose modifications for study 
treatment-associated toxicity that will be used in this protocol. 
 
Table 5. Dose Modifications for Sunitinib - Associated Toxicity 
Toxicity 
Grade 1/21 
Grade 3 
Grade 4 
Hypertension  
See Table 6  
See Table 6 
See Table 6 
Other Non-
hematologic 
Continue at 
the same 
dose level. 
x 
Withhold dose until 
toxicity is Grade ≤1 or 
has returned to baseline, 
then resume treatment at 
the same dose level.  
x 
If the toxicity recurs with 
Grade 3 severity (except 
hepatotoxicity), at the 
discretion of the 
investigator, reduce the 
dose by 1 level.  
x 
If ASL/ALT or bilirubin 
elevation recurs with 
grade 3 severity, the 
patient will be removed 
from the study. 
Withhold dose until toxicity is 
Grade ≤1 or has returned to 
baseline, then reduce the dose 
by 1 level and resume 
treatment, or discontinue at the 
discretion of the investigator 


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Toxicity 
Grade 1/21 
Grade 3 
Grade 4 
Hematologic 
Continue at 
the same 
dose level. 
Withhold dose until toxicity 
is Grade ≤2 or has returned to 
baseline, then resume 
treatment at the same dose 
level2. If the toxicity recurs 
with Grade 3 severity, at the 
discretion of the investigator, 
reduce the dose by 1 level 
Withhold dose until toxicity is 
Grade ≤2 or has returned to 
baseline, then reduce the dose 
by 1 level and resume 
treatment2 
1If after the first 8 weeks there is no response according to RECIST and toxicity remains ≤ non-
hematological Grade 1 or ≤ hematological Grade 2 dose escalation to 50 mg/day may be considered. 
2 Patients who develop grade 4 hyperuricemia or grade 3 hypophosphatemia without clinical 
symptoms may continue study treatment without interruption at the discretion of the investigator. 
Nausea, vomiting, or diarrhea must persist at grade 3 or 4 despite maximal medical therapy. Patients 
who develop Grade 3 or 4 lymphopenia may continue study treatment without interruption. 
Complicated neutropenia includes duration of Grade 4 longer than 7 days or concurrent fever or 
infection. 
 
 
3.3.1.1 Dose Modification for Sunitinib related hypertension 
Increases in blood pressure (BP) and cases of hypertension have been associated with many 
drugs acting on the VEGF pathway. The proposed mechanism for this increase is through 
inhibition of VEGF-induced peripheral vasodilation. Hypertension following sunitinib treatment 
has rarely been seen in animal studies or clinical trials. Dose modification guidelines are 
provided below and will be used in this protocol. Please see Section 4.1.1 for medical 
management guidelines. 
 
Table 6 
Recommended Dose Modification Hypertension Monitoring and 
Management 
Grade 
(CTCAE v4) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Sunitinib 
Dose 
Modification 
Persistent Grade 1 
Pre-hypertension 
Systolic 120-139 
Diastolic 80-90 
 
 
Standard  
No change 
Persistent Grade 2- 
Moderate 
Systolic 140-159  
Diastolic 90-99  
  
Protocol-specific 
guidance supersedes any 
other management 
guidelines, including 
Step 1) Initiate LA DHP CCB 
treatment and if needed, after 
24-48 hr. Rx, increase dose in 
stepwise fashion every 24-48 
hours until BP is controlled or 
at max dose of Rx 
 
Step 2) If BP still not 
controlled, add another 
BP should be 
monitored as 
recommended by the 
treating physician  
No change except 
as described in 
step 4 


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Grade 
(CTCAE v4) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Sunitinib 
Dose 
Modification 
CTCAE v4  
antihypertensive Rx, a BB, 
ACE1, ARB, or ABB; increase 
dose of this drug as described 
in step 1  
 
Step 3) If BP still not 
controlled, add 3rd drug from 
the list of antihypertensives in 
step 2; increase dose of this 
drug as described in step 1 
 
Step 4) If BP still not 
controlled, consider either 1 
dose reduction of sunitinib or 
stopping sunitinib  
 
NOTE: Stopping or reducing 
the dose of sunitinib is 
expected to cause a decrease 
in BP the treating physician 
should monitor the patient for 
hypotension and adjust the 
number and dose of 
antihypertensive 
medication(s) accordingly. 
 


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Grade 
(CTCAE v4) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Sunitinib 
Dose 
Modification 
Persistent Grade 3 
Severe  
Systolic >160 
Diastolic >100  
 
Protocol-specific 
guidance supersedes any 
other management 
guidelines, including 
CTCAE v4 
HOLD sunitinib until systolic 
BP <159 and diastolic BP <99.  
 
 
BP management is identical to 
that for Grade 2 (see steps 1-4 
above) with 2 major 
exceptions:  
1) If systolic BP >180 or 
diastolic BP >110 and the 
patient is symptomatic: 
optimal management with 
intensive IV support in ICU; 
STOP sunitinib and notify 
hospital staff that stopping 
sunitinib may result in a 
decrease in BP 
 and  
2) If systolic BP >180 or 
diastolic BP >110 and the 
patient is asymptomatic, 
2 new anti-hypertensives 
must be given together in 
step 1 (and dose escalated 
appropriately as in step 1). 
 
NOTE: Stopping or reducing 
the dose of sunitinib is 
expected to cause a decrease 
in BP the treating physician 
should monitor the patient for 
hypotension and adjust the 
number and dose of 
antihypertensive 
medication(s) accordingly 
BP should be 
monitored as 
recommended by the 
treating physician 
unless the patient is 
symptomatic with  
systolic BP >180 or 
diastolic BP >110 in 
which case, 
monitoring should be 
intensive. 
 
 
HOLD sunitinib 
until systolic BP 
<159 and diastolic 
BP  
<99. 
 
In most 
circumstances, if 
BP cannot be 
controlled after an 
optimal trial of 
anti-hypertensive 
medications, 
consider either 1 
dose reduction of 
sunitinib or 
stopping sunitinib. 
HOWEVER, 
if the patient 
requires 
hospitalization 
for management 
of symptomatic 
systolic BP >180 
or diastolic BP 
>110, permanently 
discontinue 
sunitinib or if BP 
is controlled, re-
start sunitinib at 1 
lower dose level 
after consultation 
with the study 
Principal 
Investigator 
 
 
 
 
 
Grade 4 
Life-threatening 
consequences of 
hypertension 
 
Optimal management with 
intensive IV support in ICU; 
STOP sunitinib and notify 
hospital staff that stopping 
sunitinib may result in a 
decrease in BP 
Intensive 
Permanently 
discontinue 
sunitinib or if BP 
is controlled, re-
start sunitinib at 1 
lower dose level 
after consultation 
with the study 


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Grade 
(CTCAE v4) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Sunitinib 
Dose 
Modification 
Principal 
Investigator 
 
Abbreviations: dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers (BB), 
angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), alpha beta 
blocker (ABB) 
x *See table below for suggested antihypertensive medications by class 
x If patients require a delay of >2 weeks for management of hypertension, discontinue protocol therapy 
x If patients require >2 dose reductions, discontinue protocol therapy 
x Patients may have up to 2 drugs for management of hypertension prior to any dose reduction in 
sunitinib 
x 24-48 hours should elapse between modifications of anti-hypertensive therapy 
x Hypertension should be graded using CTCAE v4. 
3.3.2 Everolimus 
3.3.2.1 Hepatic impairment dose modifications 
Please see Appendix G for determination of Child-Pugh classifications. 
x Mild hepatic impairment (Child-Pugh A) – the recommended starting dose is 7.5 mg 
daily. 
x Moderate hepatic impairment (Child-Pugh B) – the recommended starting dose is 5 mg 
daily. 
x Severe hepatic impairment (Child-Pugh C) – not recommended. If the desired benefit 
outweighs the risk, a dose of 2.5 mg daily must not be exceeded. 
x Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes 
during treatment. 
3.3.2.2 Dose delay 
Everolimus treatment will be discontinued if a dose interruption exceeds 4 weeks (28 days). 
3.3.2.3 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. Details of study treatment 
schedule adjustments and dose levels are provided in Table 7 
Table 7: Everolimus Dose Levels 
Dose Level 
Daily Dose 
Dispensed As 
0 – Starting dose level for patients 
without hepatic impairment*.  
10 mg 
1 x 10 mg tablets 
or 
2 x 5 mg tablets 
or 
4 x 2.5 mg tablets 
-1 
5 mg 
1 x 5 mg tablets 
or 


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2 x 2.5 mg tablets 
-2 
5 mg every other day‡ 
1 x 5 mg tablets 
or 
2 x 2.5 mg tablets 
*See Section 3.3.2.1 for definition and starting doses for hepatic impairment. 
‡ Patients requiring dose reduction below this level will be removed from the study therapy 
 
If treatment is interrupted due to toxicity, everolimus should not be resumed until recovery to 
grade ≤1, then reintroduce everolimus at the initial dose or lower dose level depending on 
toxicity type and Grade.  
If a patient has already decreased 2 dose levels, no further dose reduction is permitted. Patients 
requiring a third dose reduction will be required to discontinue study treatment. The following 
Table provides the procedure to be followed for dose modification and re-initiation of 
everolimus in the event of toxicities suspected to be related to the study drug. 
Table 8 and Table 9 list the dosing guidelines for everolimus-related non-hematologic and 
hematologic toxicities.  
Management of severe or intolerable adverse drug reactions (ADRs) may require temporary dose 
interruption (with or without dose reduction) of everolimus therapy.  
The following sections summarize recommendations for dose interruption, reduction, or 
discontinuation of everolimus in the management of ADRs. General management 
recommendations are also provided as applicable. Clinical judgment of the treating physician 
should guide the management plan of each patient based on individual benefit/risk assessment. 
Table 8: 
Dosing guidelines for everolimus-related non-hematologic toxicities 
Toxicity 
Action 
Non-Infectious Pneumonitis 
Please refer to 4.1.2.9 
Reactivation of HBV or HCV flare 
Please refer to 4.1.2.10 
AST or ALT elevation 
Grade 1 (> ULN - 3.0 x ULN) 
Grade 2 (> 3.0 - 5.0 x ULN) 
Maintain current dose level 
AST or ALT elevation 
Grade 3 (> 5.0 - 20.0 ULN)* 
Interrupt everolimus administration until resolution to ≤ grade 1 
(or ≤ grade 2 if baseline values were within the range of grade 
2). If resolution occurs within ≤ 7 days, everolimus should be re-
started at the dose level prior to interruption. 
If resolution takes > 7 days, or if event reoccurs within 28 days, 
hold everolimus until recovery to ≤ grade 1 or baseline grade / 
value and reintroduce everolimus at one dose level lower. . 
AST or ALT elevation 
Grade 4 (> 20 x ULN)* 
 
 
 
 
Interrupt everolimus administration until resolution to ≤ grade 1 
(or ≤ grade 2 if baseline values were within the range of grade 
2). If resolution occurs within ≤ 7 days, everolimus should be re-
started at one dose level lower. If resolution takes > 7 days, 
discontinue everolimus. 


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Toxicity 
Action 
Intolerable grade 2 mucositis, or 
grade 3 AE, except hyperglycemia 
or hypertriglyceridemia or 
hypercholesterolemia (see Section 
4.1.2.6) 
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 reoccurs within 28 days, 
hold everolimus until recovery to ≤ grade 1 or baseline grade / 
value and reintroduce everolimus at one dose level lower. 
Any other grade 4 
Hold everolimus until recovery to grade d 1 or baseline value 
Reintroduce everolimus at one dose level lower, if available. 
Grade 3 or 4 clinical liver failure 
(asterixis or encephalopathy/coma) 
Discontinue everolimus 
Recurrence of intolerable grade 2 
mucositis or grade 3 event after 
dose reduction 
Reduce dose to the next lower dose level, if available. The 
lowest possible dose level of everolimus is 2.5 mg daily. Below 
this level, everolimus must be discontinued. If toxicity recurs at 
Grade 3, consider discontinuation 
Recurrence of grade 4 after dose 
reduction 
Discontinue everolimus 
Any non-hematologic toxicity 
requiring everolimus interruption 
for > 28 days 
Discontinue everolimus 
* Should HCV flare be confirmed, the guidelines for flare must take precedence (4.1.2.10) 
 


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Table 9 
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 d1  
If resolution occurs within ≤ 7 days, reintroduce everolimus 
at the dose level prior to interruption. 
If resolution occurs after more than 7 days, or event reoccurs 
within 28 days, reintroduce everolimus at one dose level 
lower. 
Grade 4 thrombocytopenia (platelets < 
25 x109/L) 
Interrupt everolimus until recovery to grade d 1. Then 
reintroduce everolimus at one dose level lower. 
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 reoccurs within 28 
days, reintroduce everolimus at one dose level lower. 
Grade 4 neutropenia or anemia 
Interrupt everolimus until recovery to grade d 1 or baseline 
value. Reintroduce everolimus at one dose level lower.* 
Febrile neutropenia 
Interrupt everolimus until resolution to grade d 1 (or baseline 
value) and no fever. Reintroduce everolimus at one dose level 
lower.* 
Recurrence of grade 3 toxicity after 
dose reduction 
Reduce dose to the next lower dose level, if available. The 
lowest possible dose level of everolimus is 5 mg every other 
day (2.5 mg daily). Below this level, everolimus must be 
discontinued 
*Recurrence of grade 4 toxicity 
(including febrile neutropenia) after 
dose reduction 
Discontinue everolimus  
*Any hematologic toxicity requiring 
everolimus interruption for > 28 
days 
Discontinue everolimus 
 
 


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3.4 
STUDY CALENDAR  
Cycle is 28 days. A time window of up to 7 days before or after the scheduled visit day will be 
permitted in order to accommodate weekends, holidays, travel delays, inclement weather and 
other such unexpected events. 
 
Screening for eligibility 
 
Within 4 weeks prior to enrollment 
x 24-hour urine collection for urine protein, urine 
creatinine and urine albumin 
x HIV antibody 
x Radiological evaluations1 
x Histopathological confirmation of neuroendocrine 
tumors 
Within 2 weeks prior to enrollment 
x Hemoglobin A1C 
x 12- lead ECG 
x CBC, Chemistries2, INR, Lipid panel (fasting) 
x Clinical Assessments3 
Within 3 days prior to enrollment 
x Serum or urine HCG (in women of childbearing 
potential only) 
Enrollment 
x Patient signs consent 
x Advance Directive 4  
Baseline 
Tests need not be repeated if they have been done during the appropriate timeframe at screening 
Within 4 weeks prior to treatment 
initiation 
x Hepatitis B and C Evaluation 
x Echocardiogram (in patients with carcinoid 
tumors only) 
x Image guided tumor biopsy for genotyping 
(patients with known familial cancer syndrome 
(MEN1, VHL and NF1) and with available 
archival tissue are excluded) 
x Cardiac Evaluation (in patients that present with 
cardiac or pulmonary risk factors) 
x 30 mL of peripheral blood for research  
x 2-13 mL saliva for research studies 
Within 2 weeks prior to treatment 
initiation  
x Chromogranin A 
x VIP, urinary 5-HIAA, gastrin, somatostatin, 
fasting insulin, C-peptide (proinsulin) and or 
glucagon only in patients known to have 
functioning NETs or with a prior history of 
elevation of secreting biomarkers.  


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x CT C/A/P or MRI 
Treatment cycles based on tumor genotyping (1 cycle=28 days) 
Cycle 1 
 
Day 1 
within 2 weeks prior to 
treatment  
x Clinical Assessment3 
x CBC, Chemistries2, free T4, T3, TSH 
x Urinalysis 
x 12 lead ECG 
x Concomitant Medications 
x Adverse Events 
x Urine or serum HCG in women of childbearing 
potential (within 3 days before treatment) 
Day 15 
within 1 week prior to 
treatment 
x Clinical assessment3 
x CBC and Chemistries2  
x Urinalysis 
x Concomitant Medications 
x Adverse Events 
Cycle 2 
 
Day 1 
within 1 week prior to 
treatment or cross-over 
treatment 
x Clinical assessment3 
x CBC, Chemistries2, free T4, T3, TSH 
x Urinalysis 
x 12 lead ECG 
x Concomitant Medications 
x Adverse Events 
x Urine or serum HCG in women of childbearing 
potential (within 3 days before study drug 
initiation) 
Day 15 
within 1 week prior to 
treatment 
x CBC, 
x Chemistries, 
x Urinalysis 
x Concomitant Medications 
x Adverse Events 
Cycle N 
 
Day 1 
within 1 week prior to 
treatment or cross-over 
treatment 
x Clinical assessment3 
x CBC, Chemistries2, free T4, T3, TSH 
x Chromogranin A (every 3 months) 
x Urinalysis 
x 12 lead ECG 
x Concomitant Medications 
x Adverse Events 
x Radiological evaluation of treatment response5 
x Urine or serum HCG in women of childbearing 


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potential (within 3 days before study drug 
initiation) 
Safety Follow Up Visit (approximately 30 days after last dose of study drug) 
x Clinical assessment3 
x CBC, Chemistries2, free T4, T3, TSH 
x Urine or serum HCG in women of childbearing potential 
x Urinalysis 
x Radiological evaluation of treatment response5 (not applicable for patients that have 
progressed on 2 drugs) 
x Concomitant Medications 
x Adverse Events  
Long Term Follow up 
Telephone contact or e-mail every 3 months to determine anti-cancer therapy and survival status  


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1 Radiological Evaluations to be completed as part of the screening. 
o Brain MRI or CT (if clinically indicated)  
o 68-Gallium DOTATATE scan per PI discretion 
o Contrast CT scan or MRI of the chest, abdomen and pelvis (CT C/A/P)   
o Bone scan for patients in whom bone metastases are suspected  
o FDG PET scan 
2 Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, 
Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Alkaline Phosphatase, ALT/GPT, 
AST/GOT, Total Bilirubin, Total Protein  
3 Clinical assessments: Complete history (screening only) and physical examination including 
height (screening only), weight, vital signs and ECOG  
4 Filling out of the advanced directives will be offered, but obtaining of it is not required. For 
details see Section 10.3 
5 A CT or MRI of the chest/abdomen/pelvis to reassess treatment response will be done every 3 
months after treatment initiation 
 
3.5 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
3.5.1 Criteria for removal from protocol therapy 
The criteria that take the subject off active protocol therapy include:  
x Progressive disease on each study arm 
x Participant requests to be withdrawn from active therapy 
x Unacceptable Toxicity as defined in Section 3.3 
x Investigator discretion 
x Positive pregnancy test 
In all cases, a safety follow up visit will be conducted within approximately 30 days of the last 
dose of study drug therapy.  
3.5.2 Off-Study Criteria 
The criteria that take the subject off study include: 
x Participant requests to be withdrawn from study* 
x Patient lost to follow up 
x Investigator discretion 
x Screen failure 
x Death 
x PI decision to close the study 


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* If patient is still on active therapy at the time of request, patients will be encouraged to undergo 
a follow up safety visit approximately 30 days from the last dose of study drug prior to being 
removed from the study.  
3.5.3 Off Protocol Therapy and Off Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the website (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed 
and 
sent 
via 
encrypted 
email 
to: 
NCI 
Central 
Registration 
Office 
ncicentralregistration-l@mail.nih.gov. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
4.1 
SUPPORTIVE CARE 
x Long-acting octreotide (Sandostatin® LAR Depot) is a somatostatin analogue which has 
been used in combination with everolimus or sunitinib for symptoms control[49, 57]. 
Common side effects of long-acting octreotide include gallstones (24%), hyperglycemia 
(27%) and hypoglycemia (4%). Octreotide will be only administered to patients with 
carcinoid syndrome for symptom control and patients already on it will be continued on 
the medication. 
x Long-acting octreotide will be administered at a dose of 30 mg intramuscularly every 28 
days for control of carcinoid symptoms or at the dose the patient is already on at 
enrollment. 
x Standard medical therapy will be utilized in the management of everolimus and sunitinib 
toxicity. The sections provide recommendations for management of specific toxicities.  
4.1.1 Management of Sunitinib-Induced Hypertension 
Table 10 
Oral Antihypertensive Medications 
Agents in bold characters are suggested as optimal choices to avoid or minimize potential 
drug-interactions with sunitinib through CYP450. 
Agent 
class 
 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine 
XL 
30 mg daily 
60 mg daily 
90 mg daily 
CYP 3A4 
substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate 
felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate and 
inhibitor 
Selective 
E Blockers 
(BB) 
metoprolol 
25 mg 
twice daily 
50 mg 
twice daily 
100 mg 
twice daily 
CYP 2D6 
substrate 
atenolol 
25 mg daily 
50 mg daily 
100 mg daily 
No 


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Agent 
class 
 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
acebutolol 
100 mg 
twice daily 
200-300 mg 
twice daily 
400 mg 
twice daily 
Yes (CYP450 
unknown) 
bisoprolol 
2.5 mg daily 5-10 mg daily 
20 mg daily 
Yes (CYP450 
unknown) 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
 
captopril 
12.5 mg 3x 
daily 
25 mg 3x 
daily 
50 mg 3x 
daily 
CYP 2D6 
substrate 
enalapril 
5 mg daily 
10-20 mg 
daily 
40 mg daily 
CYP 3A4 
substrate 
ramipril 
2.5 mg daily 
5 mg daily 
10 mg daily 
Yes (CYP450 
unknown) 
lisinopril 
5 mg daily 
10-20 mg 
daily 
40 mg daily 
No 
fosinopril 
10 mg daily 
20 mg daily 
40 mg daily 
Yes (CYP450 
unknown) 
Rarely used: 
perindopril 
 
4 mg daily 
 
none 
 
8 mg daily 
 
Yes, but not 
CYP450 
Rarely used: 
quinapril 
10 mg daily 
20 mg daily 
40 mg daily 
No 
Angiotensin 
II Receptor 
Blockers 
(ARBs) 
losartan 
25 mg daily 
50 mg daily 
100 mg daily 
CYP 3A4 
substrate 
candesartan 
4 mg daily 
8-16 mg daily 
32 mg daily 
CYP 2C9 
substrate 
irbesartan 
75 mg daily 
150 mg daily 
300 mg daily 
CYP 2C9 
substrate 
telmisartan 
40 mg daily 
none 
80 mg daily 
Yes, but not 
CYP450 
valsartan 
80 mg daily 
none 
160 mg daily 
Yes, but not 
CYP450 
D and E 
Blocker 
labetalol 
100 mg twice 
daily 
200 mg twice 
daily 
400 mg twice 
daily 
CYP 2D6 
substrate and 
inhibitor 
 


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4.1.2 Management of specific everolimus 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).  
4.1.2.1 Management of infections 
Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, 
viral or protozoal infections, including infections with opportunistic pathogens. Localized and 
systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, 
such as aspergillosis or candidiasis and viral infections including reactivation of hepatitis B 
virus, have been described in patients taking everolimus Some of these infections have been 
severe (e.g. leading to sepsis, respiratory or hepatic failure) and occasionally have had a fatal 
outcome. 
Physicians and patients should be aware of the increased risk of infection with everolimus Treat 
pre-existing infections prior to starting treatment with everolimus. While taking everolimus, be 
vigilant for symptoms and signs of infection; if a diagnosis of infection is made, institute 
appropriate treatment promptly and consider interruption or discontinuation of everolimus. 
If a diagnosis of invasive systemic fungal infection is made, discontinue everolimus and treat 
with appropriate antifungal therapy. 
Cases of pneumocystis jirovecii pneumonia (PJP), some with a fatal outcome, have been 
reported in patients who received everolimus. PJP may be associated with concomitant use of 
corticosteroids or other immunosuppressive agents. Prophylaxis for PJP should be considered 
when concomitant use of corticosteroids or other immunosuppressive agents are required. 
4.1.2.2 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. 


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4.1.2.3 Management of Hypersensitivity reactions 
Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, 
dyspnea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or 
without respiratory impairment) have been observed with everolimus. 
4.1.2.4 Angioedema with concomitant use of angiotensin-converting enzyme (ACE) inhibitors 
Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema (e.g. 
swelling of the airways or tongue, with or without respiratory impairment). 
4.1.2.5 Renal Failure Events 
Cases of renal failure (including acute renal failure), some with fatal outcome, occurred in 
patients treated with everolimus. Renal function of patients should be monitored particularly 
where patients have additional risk factors that may further impair renal function. 
Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients 
taking everolimus. Monitoring of renal function, including measurement of blood urea nitrogen 
(BUN), urinary protein, or serum creatinine, is recommended prior to the start of everolimus 
therapy and periodically thereafter. 
4.1.2.6 Management of stomatitis / oral mucositis / mouth ulcers 
 


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


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alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., local 
anesthetics such as, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or 
phenol) with or without topical corticosteroids, such as triamcinolone oral paste 0.1% 
(Kenalog in Orabase®). 
3. Agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. These agents should be avoided. 
4. Antifungal agents should be avoided unless a fungal infection is diagnosed. In particular, 
systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) should 
be avoided in all patients due to their strong inhibition of everolimus metabolism, therefore 
leading to higher everolimus exposures. Therefore, topical antifungal agents are preferred if 
an infection is diagnosed.  
4.1.2.7 Management of diarrhea 
Appearance of grade 1-2 diarrhea attributed to study drug toxicity may be treated with supportive 
care such as loperamide, initiated at the earliest onset (for example 4 mg orally followed by 2 mg 
orally every 2 hours until resolution of diarrhea). 
4.1.2.8 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 one dose level lower. 
Manage with appropriate medical therapy and monitor. 
 
Grade 4 
Discontinue everolimus and treat with appropriate 
medical therapy. 
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary habits 
of the patient. Grade 2 or higher hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) or grade 2 
hypertriglyceridemia or higher (>2.5x upper normal limit) should be treated with a 3-hydroxy-3-
methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g. atorvastatin, pravastatin, fluvastatin) or 
appropriate triglyceride-lowering medication, in addition to diet. 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated with 
an increased risk of a rare but serious skeletal muscle toxicity manifested by rhabdomyolysis, 
markedly elevated creatine phosphokinase (CPK) levels and myoglobinuria, acute renal failure 
and sometimes death. The risk versus benefit of using this therapy should be determined for 
individual patients based on their risk of cardiovascular complications of hyperlipidemia. 
Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been reported in 
patients taking everolimus. Monitoring of blood cholesterol and triglycerides prior to the start of 
everolimus therapy and periodically thereafter as well as management with appropriate medical 
therapy is recommended. 


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


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50 
Worst grade 
pneumonitis 
Suggested investigations 
Management of 
pneumonitis 
Everolimus dose adjustment 
Grade 1 
(Asymptoma
tic, 
radiographic 
findings 
only) 
CT scans with lung windows. 
No specific 
therapy is 
required 
No dose adjustment required.  
Initiate appropriate monitoring. 
Grade 2 
(Symptomati
c, 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 
(Symptomati
c, 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. 
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. 
4.1.2.10 Management of hepatitis reactivation / flare 
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving 
chemotherapy[98]. 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[99]. A detailed 
assessment of Hepatitis B/C medical history and risk factors must be done for all patients at 
baseline, with testing performed prior to the first dose of study drug.  


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Monitoring and prophylactic treatment for hepatitis B reactivation 
Table 11 provides detail of monitoring and prophylactic therapy according to the baseline results 
of viral load and serologic markers testing. 
Table 11 
Action to be taken based on screening hepatitis B results 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBsAb 
+ or - 
+ or - 
+ 
and no prior 
HBV 
vaccination 
+ or - 
- 
or + with prior 
HBV vaccination 
HBcAb 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendation 
Prophylaxis treatment 
should be started 1-2 weeks 
prior to first dose of 
everolimus 
 
Monitor HBV-DNA 
approximately every 4-8 
weeks 
No prophylaxis 
 
Monitor HBV-DNA 
approximately every 3-4 weeks  
No specific 
action 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of everolimus. 
For HBV reactivation definition and management guidelines, see Table 12. 


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Table 12 
Guidelines for the management of hepatitis B reactivation 
HBV reactivation (with or without clinical signs and symptoms)* 
For patients with baseline 
results:  
Positive HBV-DNA 
OR 
positive HBsAg 
----------------------------------
---- 
reactivation is defined as: 
[Increase of 1 log in HBV-
DNA relative to baseline 
HBV-DNA value OR new 
appearance of measurable 
HBV-DNA] 
 
Treat: Start a second antiviral medication 
AND 
Interrupt everolimus administration until resolution:  
x 
≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days, everolimus should be re-started 
at one dose lower, if available. (see Table 7 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. Both antiviral therapies should continue at least 4 weeks 
after last dose of everolimus.  
If resolution occurs > 28 days Patients should discontinue everolimus 
but continue both antiviral therapies at least 4 weeks after last dose of 
everolimus. 
For patients with baseline 
results: 
Negative HBV-DNA and 
HBsAg 
AND 
[Positive HBsAb (with no 
prior history of vaccination 
against HBV), OR positive 
HBcAb] 
----------------------------------
--- 
Reactivation is defined as: 
New appearance of 
measurable HBV-DNA 
Treat: Start first antiviral medication 
AND 
Interrupt everolimus administration until resolution: 
x 
≤ undetectable (negative) HBV-DNA levels 
If resolution occurs within ≤ 28 days, everolimus should be re-started 
at one dose lower, if available (see Table 7 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 4.0 - 
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. 
Monitoring for hepatitis C flare 
The following two categories of patients should be monitored every 4–8 weeks for HCV flare: 
x Patients with detectable HCV RNA-PCR test at screening. 
x 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 
13. 


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Table 13 
Guidelines for the management of hepatitis C flare 
Baseline results 
HCV flare definition* 
HCV flare 
management 
Detectable HCV-RNA 
 
> 2 log10 IU/mL increase in HCV-RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher. 
Discontinue everolimus 
Knowledge of past hepatitis C 
infection with no detectable 
HCV-RNA 
New appearance of detectable HCV-
RNA 
AND 
ALT elevation > 5 x ULN or 3 x baseline 
level, whichever is higher. 
Discontinue everolimus 
* All flares of HCV are to be recorded as grade 3 (e.g. CTCAE Version 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). 
4.2 
CONCURRENT MEDICATIONS 
4.2.1 General guidelines 
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. 
4.2.2 Cytochrome P450 and P-glycoprotein inhibitors/inducers/substrates 
Co-administration of everolimus or sunitinib with strong inhibitors of CYP3A4 or PgP should be 
avoided; and may cause increased drug 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: 
x Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
ritonavir) or P-glycoprotein (PgP) inhibitor should be avoided. 
x Co-administration of either study drug with moderate CYP3A4 inhibitors (e.g., 
erythromycin, fluconazole) or PgP inhibitors should be used with caution. If a patient 
requires co-administration of moderate CYP3A4 inhibitors or PgP inhibitors, reduce the dose 
of everolimus by approximately 50%. Additional dose reductions to every other day may be 
required to manage toxicities. If the inhibitor is discontinued, the everolimus dose should be 
returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor after a 
washout period of 2 to 3 days. 


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x 
Grapefruit, Seville oranges, and starfruit affect P450 and PgP activity. Concomitant use 
should be avoided. 
x If patients require co-administration of a strong CYP3A4 inducer with everolimus, consider 
doubling the daily dose of everolimus (based on pharmacokinetic data), using increments of 
5 mg or less. This dose of everolimus is predicted to adjust the AUC to the range observed 
without inducers. However, there are no clinical data with this dose adjustment in patients 
receiving strong CYP3A4 inducers. If the strong inducer is discontinued, consider a washout 
period of at least 3 to 5 days (reasonable time for significant enzyme de-induction), before 
the everolimus dose is returned to the dose used prior to initiation of the strong CYP3A4 
inducer. 
x This dose adjustment of everolimus is intended to achieve similar AUC to the range observed 
without inducers. However, there are no clinical data with this dose adjustment in patients 
receiving strong CYP3A4 inducers. If the strong inducer is discontinued the everolimus dose 
should be returned to the dose used prior to initiation of the strong CYP3A4/PgP inducer. 
Please refer to Table 14 listing relevant inducers and inhibitors of CYP3A and Table 15 for a 
list of relevant substrates, inducers, and inhibitors of PgP. 
4.2.2.1 Everolimus and drugs influencing CYP3A4 enzyme 
Everolimus is a substrate of CYP3A4, and a substrate and moderate inhibitor of the multidrug 
efflux pump, PgP (PgP, MDR1, and ABCB1). Therefore, extent of absorption and subsequent 
elimination of systemically absorbed everolimus may be influenced by products that are 
substrates, inhibitors, or inducers of CYP3A4 and/or PgP. Concurrent treatment with strong 
CYP3A4-inhibitors should be avoided. 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).  
 


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Table 14 
Clinically relevant drug interactions: inducers, and inhibitors of isoenzyme 
CYP3A 
Inducers 
Strong inducers: 
avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St. 
John's wort 
(hypericum perforatum) 
Moderate inducers: 
bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, ritonavir, [talviraline], thioridazine, 
tipranavir 
Weak inducers: 
amprenavir, aprepitant, armodafinil (R-modafinil), bexarotene, clobazam, danshen, dexamethasone, 
Echinacea, garlic (allium sativum), gingko (ginkgo biloba), glycyrrhizin, methylprednisolone, 
nevirapine, oxcarbazepine, pioglitazone, prednisone, [pleconaril], primidone, raltegravir, rufinamide, 
sorafenib, telaprevir, terbinafine, topiramate, [troglitazone] , vinblastine 
Inhibitors 
Strong inhibitors: 
boceprevir, clarithromycin, cobicistat, conivaptan, elvitegravir, indinavir, itraconazole, ketoconazole, 
lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole[100], ritonavir, saquinavir, telaprevir, 
telithromycin, tipranavir, troleandamycin, voriconazole 
Moderate inhibitors: 
Amprenavir, aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, cyclosporine, darunavir, 
diltiazem, dronedarone, erythromycin, fluconazole, fosamprenavir, grapefruit juice (citrus parasidi 
fruit juice), imatinib, schisandra sphenanthera, tofisopam, verapamil 
 
Table 15 
Clinically relevant drug interactions: substrates, inducers, inhibitors of 
PgP and PgP/CYP3A dual inhibitors 
 
Substrates 
colchicine, digoxin, fexofenadine, indinavir, paclitaxel, talinolol, topotecan, vincristine, everolimus 
Inducers 
rifampin, St John’s wort 
PgP Inhibitors and PgP/CYP3A Dual Inhibitors 
amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, 
elacridar, erythromycin, felodipine, fexofenadine, fluvoxamine, ginkgo (ginkgo biloba), indinavir, 
itraconazole, lopinavir, mibefradil, milk thistle (silybum marianum), nelfinavir, nifedipine, 
nitrendipine, paroxetine, quercetin, quinidine, ranolazine, rifampin, ritonavir, saquinavir, Schisandra 
chinensis, St John’s wort (hypericum perforatum), talinolol, Telaprevir, telmisartan, ticagrelor, 
tipranavir, tolvaptan, valspodar, verapamil 
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Oct. 2, 
2011,29-Oct-2012 which summarizes DDI data from three sources including the FDA’s “Guidance for 
Industry, Drug Interaction Studies”, the University of Washington’s Drug Interaction Database, and 
Indiana University School of Medicine's Drug Interaction Table. 


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4.2.3 Vaccinations 
Immunosuppressants may affect the response to vaccination and vaccination during treatment 
with everolimus may therefore be less effective. The use of live vaccines should be avoided 
during treatment with everolimus. For pediatric patients with SEGA that do not require 
immediate treatment, complete the recommended childhood series of live virus vaccinations 
prior to the start of therapy according to local treatment guidelines. Examples of live vaccines 
are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and 
TY21a typhoid vaccines. 
5 
BIOSPECIMEN COLLECTION 
5.1 
SAMPLE COLLECTION FOR GENOTYPING AND RESEARCH STUDIES 
5.1.1 Tumor Sample 
Within 4 weeks prior to initiation of treatment with the respective study agent (everolimus or 
sunitinib), patients who meet eligibility criteria, will undergo biopsy of the primary tumor or any 
metastatic site for molecular analyses. Patients will undergo a percutaneous core needle (16 or 18 
gauge) biopsy of the tumor under local anesthesia if there are no paraffin blocks available of 
tumor sample previously removed or biopsied. These percutaneous biopsies will be performed 
by interventional radiology (CT scan or ultrasound guidance). If needed, patients will be offered 
conscious sedation for the biopsy procedure. Sample collection will be performed according to 
standard operating procedures. Four core needle biopsies will be obtained, three samples will be 
formalin fixed and sent to the Laboratory of Pathology in the NCI for histological study. The 
official pathology report and samples will then be taken to Dr. Paul Meltzer’s laboratory: 
Paul Meltzer, Email: paulmeltzer@mail.nih.gov 
CANCER GENETICS BRANCH 
Bldg. 37/Room 6183, 
Bethesda, MD 20892, 
Phone: 240-760-6136 
The remaining sample will be immediately placed in cryovials, snap frozen on liquid nitrogen or 
dry ice and transported to Dr. Naris Nilubol’s laboratory. 
Fresh tissue samples should be collected into empty, unused cryovials (Nunc catalog #5001-
0012, 5001-1020 or equivalent) on dry ice or liquid nitrogen. Samples may be obtained by FNA 
or core biopsy. 
The interval between sample acquisition and freezing on dry ice must not exceed 30 minutes. 
Frozen, vialed samples should be transferred from dry ice to -80°C (minimum) or liquid nitrogen 
frozen storage within 2 hours. 
Samples will be recorded in LabMatrix and reviewed by the Laboratory of Pathology to confirm 
the diagnosis. The remaining sample will be transported to Dr. Paul Meltzer’s laboratory [Paul 
Meltzer, M.D., Bldg. 37/Room 6138, Bethesda, MD 20892, Phone: 240-760-6136, Email: 
pmeltzer@mail.nih.gov] for tumor genotyping along the saliva DNA. 


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5.1.2 Saliva Collection and Peripheral Blood 
Saliva specimen (2-13 ml) will be obtained for targeted sequencing and comparison to tumor 
sequencing results and mutation calls before treatment. The saliva samples will be collected by a 
saliva collecting kit with complete and detailed instructions for collection available in the kit and 
on manufacturer’s website at http://www.dnagenotek.com/ROW/products/OG500.html (an 
alternative saliva collecting kit can be used if needed). The saliva will be processed by and stored 
in the laboratory of Dr. Paul Meltzer and will be used as an autologous control for future 
genomic studies. 
 
3 mL of saliva will be collected using the Oragene saliva collection kit (DNA Genotek). The 
sample may be collected at any time after informed consent has been obtained, but collection is 
preferred at baseline. 
Ideally, the patient should be advised not to eat or drink anything 30 minutes prior to collection. 
Once the sample is obtained, the top of the device is closed, releasing a preservative, the top is 
removed, and a cap is placed on the tube. 
The date and exact time of the collection should be recorded on the sample. 
Samples will be recorded in LabMatrix. DNA will be extracted from the saliva samples and the 
DNA sample (along with the coded, linked tumor sample) will be transported to Dr. Paul 
Meltzer’s laboratory. Dr. Meltzer will not have access to the sample code key.  
Peripheral blood (30 mL) may be obtained for targeted sequencing and comparison to tumor 
sequencing results and mutation calls after enrollment and before treatment. The blood will be 
processed by and stored in the laboratory of Dr. Paul Meltzer and will be used as an autologous 
control for future genomic studies. 
 
Test/assay 
Volume 
(approx.) 
Type of 
tube 
Collection point  
Location of 
specimen analysis 
Molecular Analysis 4 Core Tumor 
Biopsies 
 
Screening 
Dr. Paul Meltzer’s lab 
Targeted 
Sequencing & 
Autologous 
Control  
2-13 ml Saliva 
Saliva 
Collecting 
Kit 
Baseline 
Dr. Paul Meltzer’s lab 
Targeted 
Sequencing 
30 ml Serum 
 
Baseline 
Dr. Paul Meltzer’s lab 
 
5.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
5.2.1 Procedures for Storage of Specimens in the Laboratory of Dr. Naris Nilubol  
x In patients who undergo biopsy, the samples will be immediately snap frozen in liquid 
nitrogen and transported to the Dr. Naris Nilubol Lab by calling 240-760-6155. Samples 
will be labeled with the date and time of acquisition, the type of tissue and patient study 
ID. Upon receipt in the lab, samples will be bar coded and logged in to the tissue 


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database, LabMatrix. Samples will be stored in -20°C or -80°C freezers until molecular 
analysis. All freezers are monitored and are on separate emergency generator lines. 
x Saliva and serum samples for correlative studies may also be obtained and will be stored 
and tracked in the same manner as tissue samples. 
x At the completion of the protocol, the investigator will dispose of all specimens in 
accordance with the environmental protection laws, regulations and guidelines of the 
Federal Government and the State of Maryland. 
x Samples at NIH will be ordered in CRIS and tracked through a Clinical Trial Data 
Management system. Should a CRIS screen not be available, the CRIS downtime 
procedures will be followed. Samples will not be sent outside NIH without IRB 
notification and an executed MTA. 
x All specimens obtained in the protocol are used as defined in the protocol. Any 
specimens that are remaining at the completion of the protocol will be stored in the 
conditions described below. The study will remain open so long as sample or data 
analysis continues. Samples from consenting subjects will be stored until they are no 
longer of scientific value or if a subject withdraws consent for their continued use, at 
which time they will be destroyed. The PI will report any loss or destruction of samples 
to the NIH IRB as soon as he is made aware of such loss 
x If the patient withdraws consent the participant’s data will be excluded from future 
distributions, but data that have already been distributed for approved research use will 
not be able to be retrieved. 
x The PI will report destroyed samples to the IRB if samples become unsalvageable 
because of environmental factors (ex. broken freezer or lack of dry ice in a shipping 
container) or if a patient withdraws consent. Samples will also be reported as lost if they 
are lost in transit between facilities or misplaced by a researcher. Freezer problems, lost 
samples or other problems associated with samples will also be reported to the IRB, the 
NCI Clinical Director, and the office of the CCR, NCI. 
5.2.2 Procedures for Storage of Tissue Specimens in the Laboratory of Pathology 
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly, and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation. Unutilized excess tissues are stored for up to 
three months, in accordance with College of American Pathologists/Joint Commission on 
Accreditation of Healthcare Organizations (CAP/JCAHO) guidelines, and then discarded. 
Following completion of the diagnostic workup, the slides and tissue blocks are stored 
indefinitely in the LP’s clinical archives. All specimens are catalogued and retrieved utilizing the 
clinical laboratory information systems, in accordance with CAP/JCAHO regulations. The use of 
any stored specimens for research purposes is only allowed when the appropriate IRB approval 
has been obtained. In some cases, this approval has been obtained via the original protocol on 
which the patient was enrolled 


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5.3 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
5.3.1 Description of the scope of genetic/genomic analysis 
o Tumor genotyping: Somatic mutation analysis of tumor biopsy specimens will be 
performed by sequencing 197 driver genes (Appendix C) in a CLIA certified 
genetic laboratory. 
o Germline sequencing for 197 driver genes (Appendix C) will be performed on 
saliva samples or peripheral blood samples in a CLIA certified genetic laboratory  
o Histology: 
Tissues 
may 
be 
examined 
by 
standard 
histology, 
immunohistochemistry and or in situ hybridization in the Laboratory of 
Pathology, NCI. 
5.3.2 Privacy and Confidentiality of medical information/biological specimens 
Fresh tumor and blood samples will be stored in a minus 80-degree freezer. The samples of each 
patient will be assigned a study ID number, and that number will be used in all laboratory 
studies. At no time will patient’s names be used on the blood and tissue samples. The molecular 
studies will be done in the CLIA certified genetic laboratory of Paul Meltzer, MD. Sometimes, 
because a group collaboration or journal policy requires it, a subject’s genetic data may be 
deposited in a database such as dbGaP. Although there is controlled access to such a database, 
such a submission carries theoretical risks of revealing the identity of the subject. This is 
discussed in the consent. 
5.3.3 A Certificate of Confidentiality will be obtained for the study as described in Section 
10.3.1.5.  
5.3.4 Management of Results 
The results of molecular studies will be communicated to the patient. Other than initial 
determination of the presence of particular genetic alteration(s) outlined in Appendix C and 
Appendix D, the results of subsequent molecular studies are for research purposes only and will 
not be communicated to the patient. The exceptions to this are potential incidental findings that 
are deemed medically significant and actionable.  
Subjects, treated in NCI will be contacted if a clinically actionable gene variant is discovered. 
Clinically actionable findings for the purpose of this study are defined as disorders appearing in 
the American College of Medical Genetics and Genomics recommendations for the return of 
incidental findings that is current at the time of primary analysis. (A list of current guidelines is 
maintained 
on 
the 
CCR 
intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). Subjects who 
still remain on the study will be contacted at this time with a request to provide a blood sample to 
be sent to a CLIA certified laboratory.  
5.3.4.1 Genetic counseling in NCI 
If the research findings are verified in the CLIA certified lab, the subject will be offered the 
opportunity to come to NIH (at our expense) to have genetic education and counseling with the 
NCI Genetics Branch to explain this result. If the subject does not want to come to NIH, a 
referral to a local genetic healthcare provider will be provided (at their expense). This is the only 
time during the course of the study that incidental findings will be returned. No interrogations 
regarding clinically actionable findings will be made after the primary analysis  


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6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into a password protected electronic 
system (NCI C3D) and ensuring data accuracy, consistency and timeliness. Clinical data will be 
entered into the NCI C3D electronic database at least once every two weeks when patients are 
enrolled on the trial. Protocol-specific eCRFs will be developed for this trial in C3D. 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. 
The NCI investigators will be responsible for the collection, maintenance, and quality control of 
the study data.  
Labmatrix will be used for sample data collection. Data in this system will be entered by the NCI 
staff.  
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for at least 30 days after removal from study treatment or 
until off-study, whichever comes first. 
 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
x 
Results in discontinuation from the study 
x 
Is associated with clinical signs or symptoms  
x 
Requires treatment or any other therapeutic intervention 
x 
Is associated with death or another serious adverse event, including hospitalization.  
x 
Is judged by the Investigator to be of significant clinical impact 
x 
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. 
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 breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
6.1.1 Source Documents 
The PI will permit trial-related monitoring, audits, IRB review, and regulatory inspection(s), 
providing direct access to source documents. 


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6.1.2 Case Report Forms 
Data may be entered from the source documents directly into eCRFs in C3D for each patient 
enrolled in this study. The principal investigator or research nurse will review the eCRFs for 
completeness and accuracy. Site personnel may also conduct independent audits to ensure 
completeness and accuracy of data in C3D. 
Only the following adverse events will be recorded on the Case Report Form: 
– Grade 2 unexpected events that are possibly, probably or definitely related to the 
study drugs;  
– Grade 3 and 4 events that are possibly, probably or definitely related to the study 
drugs;  
– Grade 5 events regardless of attribution;  
– Serious Events regardless of attribution.  
Patients who meet the standard of care criteria for resection of their disease will undergo a major 
operative procedure and may receive extensive care in the ICU. The principal investigator or 
designee will closely monitor and document the clinical care and treatment of each patient as per 
standard of care at the NIH Clinical Center. As per NIH Clinical Center standards of practice, the 
Occurrence Reporting System will be used to report any clinical events meeting these reporting 
criteria.  
6.1.3 Data Quality Assurance 
The research team will monitor each patient’s dataset throughout the study. Source document 
review will be made against entries on the eCRF and a quality assurance check will be performed 
to ensure that the investigator is complying with the protocol and regulations. In addition, after 
the research team (data managers) completes the CRFs a research nurse or physician at the NCI 
will review and verify the data. 
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
x Coded, linked data in an NIH-funded or approved public repository.  
x Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 
How and where will the data be shared?  
Data will be shared through: 
x An NIH-funded or approved public repository. Clinicaltrials.gov. 
x BTRIS  
x Publication and/or public presentations. 
When will the data be shared?  
x Before publication. 
x At the time of publication or shortly thereafter. 


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6.2.2 Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
6.3 
RESPONSE CRITERIA 
For the purposes of this study, patients should be re-evaluated for response every 12 weeks.  
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). 
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. 
6.3.1 Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with sunitinib or everolimus. 
Evaluable for objective response: Only those patients who according to RECIST guideline 
(version 1.1) have measurable disease present at baseline, have been started on therapy with 
everolimus or sunitinib, 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 been started on therapy 
with everolimus or sunitinib, 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.  
6.3.2 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:  
x By chest x-ray: >20 mm;  
x By CT scan:  
o Scan slice thickness 5 mm or under as >10 mm with CT scan 
o Scan slice thickness >5 mm: double the slice thickness  
x With calipers on clinical exam: >10 mm.   
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Metastatic 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 


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non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
6.3.3 Methods for Evaluation of Measurable Disease 
All measurements will be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations will 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 will be used to characterize each 
identified and reported lesion at baseline and during follow-up.  
Conventional CT: 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. 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. 
Tumor markers: Chromogranin A levels, which represents a constitutive neuroendocrine 
secretory protein, is the most widely accepted biomarker. Chromogranin A was compared to a 
panel of biomarkers and proved to be the most accurate, with a specificity of 85.7% and 
sensitivity of 67.9%[101]. Chromogranin A is elevated in 60- 80% of patients with 
neuroendocrine tumors. The National Cancer Institute (NCI) recommends that serial 


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measurements of CgA be incorporated into prospective clinical trials[49]. Chromogranin A level 
will be checked within 2 weeks prior to treatment, and every 3 months after treatment initiation. 
68-Gallium DOTATATE: We and others have demonstrated that 68-Gallium DOTATATE is 
more sensitive for detecting sites of metastatic disease than anatomic imaging studies [102]. 
Therefore, we will also use 68-Gallium DOTATATE imaging results that show new lesions 
within 18 months follow up time to define progression of disease. All patients must have a target 
lesion as identified by conventional CT or MRI, however, to be eligible for enrollment in the 
study to evaluate response by RECIST criteria. 
6.3.4 Response Criteria 
6.3.4.1 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. 
6.3.4.2 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). 
6.3.4.3 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. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials 
so to assign this category when no lesions can be measured is not advised 
 
 


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6.3.5 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.  
6.3.6 Progression-Free Survival 
PFS is defined as the duration of time from start of each treatment to time of progression or 
death, whichever occurs first. 
6.3.7 Response Review 
Simultaneous review of the patients’ files and radiological images for all responses will be 
reviewed by an expert(s) independent of the study at the study’s completion. 
6.4 
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). 
 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7.1 
DEFINITIONS 
7.1.1 Adverse Event 
Any untoward medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in research, whether or not considered related to the 
subject’s participation in the research. 
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. 


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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 
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: 
x Death, 
x A life-threatening adverse drug experience 
x Inpatient hospitalization or prolongation of existing hospitalization 
x Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
x A congenital anomaly/birth defect. 
x 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. 


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7.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
x 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 
(b) the characteristics of the subject population being studied; AND 
x Is related or possibly related to participation in the research; AND 
x 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 
NIH INTRAMURAL IRB AND CLINICAL DIRECTOR REPORTING 
7.2.1 NIH Intramural IRB and NCI CD Expedited Reporting of Unanticipated Problems and 
Deaths 
The Protocol PI will report in the NIH Problem Form to the NIH Intramural IRB and NCI 
Clinical Director: 
x All deaths, except deaths due to progressive disease  
x All Protocol Deviations 
x All Unanticipated Problems 
x All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
7.2.2 NIH Intramural IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NIH Intramural 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: 
x All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
x All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
x All Grade 5 events regardless of attribution;  
x All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.2.3 NIH Intramural 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 NIH Intramural IRB. 


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7.3 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS  
7.3.1 Novartis 
The Principal Investigator will notify Novartis of each Serious Adverse Event (SAE) as defined 
under 21 CFR 310.305 encountered in the Clinical Trial within 24 hours of becoming aware of it. 
This applies to SAEs which occur after the patient takes the first dose of study drug and 
continues until at least 30 days after the patient has stopped study treatment or until the patient is 
taken off-study, whichever comes first. Information about all SAEs is collected and recorded on 
the Novartis Serious Adverse Event Report Form; all applicable sections of the form must be 
completed in order to provide a clinically thorough report. The PI must assess and record the 
relationship of each SAE to each specific study treatment, complete the SAE Report Form and 
send the completed, signed form along with the Novartis provided fax cover sheet to the Novartis 
Oncology Drug Safety and Epidemiology (DS&E) department by fax (877-778-9739) or email 
(clinicalsafetyop.phuseh@novartis.com) within 24 hours of  PI’s awareness.To ensure patient 
safety, each pregnancy occurring while the patient is on study treatment must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications.  
Pregnancy should be reported by the investigator to the oncology Novartis Drug Safety and 
Epidemiology 
Department 
(DS&E) 
by 
fax 
(877-778-9739) 
or 
email 
(clinicalsafetyop.phuseh@novartis.com). Pregnancy follow-up should include an assessment of 
the possible relationship to the investigational/study treatment and any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
7.3.2 Pfizer 
The Principal Investigator will notify Pfizer of each Serious Adverse Event (SAE) encountered 
in the Clinical Trial within 24 hours of becoming aware of it, even if complete information is not 
yet available. This applies to SAEs which occur after the patient takes the first dose of study drug 
and continues until at least 30 days after the patient has stopped study treatment or is taken off-
study, whichever comes first. Additionally, the Principal Investigator will notify Pfizer of any 
SAE the PI suspects has a causal relationship between the Pfizer Product and the SAE at any 
time after the patient’s last study treatment. Information about all SAEs is collected and recorded 
on the Pfizer-provided Investigator-Initiated Research Serious Adverse Event Form; all 
applicable sections of the form must be completed in order to provide a clinically thorough 
report. The PI must assess and record the relationship of each SAE to each specific study 
treatment, complete the SAE Report Form and send the completed, signed form along with the 
Pfizer Reportable Event Fax Cover Sheet to the Pfizer US Drug Safety Unit fax number 866-
997-8322 within 24 hours of PI’s awareness. To ensure patient safety, the Principal Investigator 
will also report each pregnancy, drug exposure during lactation, occupational exposure, and 
reportable instances of lack of effect as SAEs to Pfizer.   


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7.4 
DATA AND SAFETY MONITORING PLAN 
7.4.1 Principal Investigator/Research Team  
The clinical research team will meet on a weekly 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.  
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  
The primary objective of this trial is to determine PFS of patients with low- or intermediate grade 
NET who receive first-line targeted therapy. This will provide preliminary data to explore 
whether the PFS on first-line therapy in patients treated with sunitinib or everolimus based on 
tumor genotyping may represent a potential improvement over published results with regular 
treatment with everolimus/sunitinib. Secondary objectives include evaluation of response and OS 
as well as safety and exploring the association between tumor genotype and PFS, and response to 
treatment. 
If the findings suggest improved PFS from targeted treatment, a larger randomized trial to 
confirm the findings will be developed. 
Following tumor genotyping, eligible patients will be treated with everolimus (Arm 2) or 
sunitinib (Arm 1). Based on results of the genotyping, enrolled patients will then receive targeted 
treatment with sunitinib (for mutations in MEN1/PDGFR/KIT/FTL3 or everolimus (for mutations 
in NF1/PTEN/ PI3K/AKT/mTOR/VHL). Patients with other different mutations or multiple types 
of mutations will be assigned to receive sunitinib since almost all of these tumors have elevated 
levels of VEGF/VEGFR expression. 
Results from previously published trials[53, 55] both demonstrated approximately 11 months 
PFS in patients similar to the ones to be treated on this protocol. Those patients had not received 
cytoreductive surgery, and also were not assigned to receive treatment on the basis of any tumor 
genotype information. In the context of this trial, the study will be designed to determine if 
meaningful improvement in PFS may be obtained using this focused strategy. For purposes of 
sample size determination, patients will be primarily evaluated based on the treatment received. 
Thus, within each treatment arm, using the method of Brookmeyer and Crowley, with 44 patients 
accrued during a 48-month period (88 total patients for the two arms), and followed for up to an 
additional 12 months (60 months total from entry of the first patient), there would be 80% power 
to test whether the median PFS is consistent with 18 months, and greater than 11 months, with a 
0.10 alpha level one-sided significance test. 
In practice, a Kaplan-Meier curve of PFS will be constructed for each arm and will have the 
median as well as key time points such as 12 and 18 months estimated, along with appropriate 


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80% and 95% confidence intervals to explore whether the present results exceed those from prior 
studies. In addition, the Kaplan-Meier curves for all patients who received either sunitinib and 
everolimus as their treatments may be combined into one pooled Kaplan-Meier curve if the two 
curves for these treatments are sufficiently similar to one another (p>0.30 by a two-tailed log-
rank test). This combined curve will then be evaluated relative to the published median of 11 
months PFS for each arm to provide a more powerful comparison relative to the historically 
expected results. In addition, Kaplan-Meier curves limited to the patients who received targeted 
therapy based solely on mutation status may be constructed for exploratory and descriptive 
purposes. 
Response and overall survival will also be evaluated as secondary endpoints, based on the 
patients treated with sunitinib or everolimus, using all patients receiving treatment. These results 
will be descriptive and may consist of fractions of responses as well as Kaplan-Meier curves for 
survival. The association between genotype and PFS will be explored by evaluating the results 
within a treatment based on the major genotype categories identified. Safety will be evaluated by 
tabulating and reporting the distribution of the worst grade of each type of toxicity found, per 
patient, separately by arm. Should any particular type of toxicity result in 5 or more patients with 
grade 3-4 toxicity, a comparison of the distributions of toxicity between the two arms may be 
performed using a Cochran-Armitage test for trend.  
Because the patients may not end up being assigned in equal proportions to the two arms, and 
because the goal is to have 44 evaluable patients who have received each treatment, additional 
patients beyond the 44 described above may be enrolled on the arm with faster accrual. As such, 
the study will have an accrual ceiling of 120 patients, with accrual ending when there are 44 
evaluable patients on the arm with fewer patients. An amendment may also be needed if a lower 
proportion of patients than expected receive study drug therapy or if a high portion of treated 
patients are not evaluable for response. It is anticipated that 20-30 patients per year may enroll 
onto this trial; thus, accrual may be completed in 4-5 years.  
9 
COLLABORATIVE AGREEMENTS 
9.1 
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA)  
The everolimus used in this trial in NCI will be obtained under a CRADA (02975) with Novartis, 
the manufacturer of the agent. 
9.2 
CLINICAL TRIALS AGREEMENT (CTA) 
The sunitinib used in this trial in NCI will be obtained under CTA with Pfizer (00963-14), the 
manufacturer of the agent.  
10 HUMAN SUBJECTS PROTECTIONS  
10.1 RATIONALE FOR SUBJECT SELECTION 
Subjects from both gender groups and all racial/ethnic groups are eligible for this study if they 
meet the eligibility criteria. Efforts will be made to extend accrual to a representative population. 
10.2  PARTICIPATION OF CHILDREN 
Patients age 18 and older will be eligible for this study. The incidence and prevalence of 
metastatic pancreatic and gastrointestinal neuroendocrine tumors in the pediatric patient 
population is exceedingly rare and this is the rationale for not including this patient population. 


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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 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (Section 10.5), all subjects 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 (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate. For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in NIHMEC Policy 87-4 and 
NIH HRPP SOP 14E 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 Risks/Benefits Analysis 
The risks and benefits of participation for adults who become unable to consent, are no different 
than those described for patients who are less vulnerable. 
10.4.1.1 Risks 
10.4.1.1.1 Study Drug Risks 
The risks of participation in this study are primarily associated with the toxicities of the study 
agents as discussed in Section 11. Both study agents have been approved by the FDA for the 
treatment of progressive, locally advanced or metastatic pancreatic NETs and have been 
available for clinical use since 2011. Patients will be monitored routinely in order to minimize 
the risk of complications. 
10.4.1.1.2 Specimen Collection Risks 
Risks also include those associated with specimen collection include pain, bleeding and the 
possibility of infection at the sampling site. Risk of baseline biopsy: 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 biopsy, immediate medical 
treatment is available at the enrolling center. 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. 
10.4.1.1.3 Risk of Radiation 
This research study involves exposure to radiation from one CT guided biopsy. This radiation 
exposure is not required for medical care and is for research purposes only. The amount of 
radiation received in this study is 0.80 rem which is below the guideline of 5 rem per year 
allowed for research subjects by the NIH Radiation Safety Committee. The average person in the 


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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. More information about radiation is available in the 
pamphlet, An Introduction to Radiation for NIH Research Subjects. 
10.4.1.1.4 Non-Physical Risks of Genetic Research 
x Risk of receiving unwanted information 
Anxiety and stress may arise as a result of the anticipation that unwanted information 
regarding disease related DNA sequencing or disease tendencies, or misattributed paternity. 
Patients will be clearly informed that the data related to DNA sequencing and genetic 
analysis is coded, investigational and will not be shared with patients, family members or 
health care providers. 
x Risk related to possibility that information may be released 
This includes the risk that data related to genotype, DNA sequencing or risk for disease 
tendency or trait can be released to members of the public, insurers, employers, or law 
enforcement agencies. Although there are no plans to release results to the patients, family 
members or health care providers, this risk will be included in the informed consent 
document. 
x Risk to family or relatives 
Family members or relatives may or may not want to be aware of familial tendencies or 
genetic risks of disease which may cause anxiety about possible future health problems. As 
previously noted, patients will be given the option in the consent document to be notified of 
any medically significant and actionable incidental findings.  
10.4.1.1.5 Certificate of Confidentiality 
As part of study efforts to provide confidentiality of subject information, this study will obtain a 
Certificate of Confidentiality which helps to prevent forced disclosure of personally identifiable 
research information. The Certificate of Confidentiality allows investigators on this trial to refuse 
to disclose identifying information related to the research participants, should such disclosure 
have adverse consequences for subjects or damage their financial standing, employability, 
insurability or reputation. The informed consent includes the appropriate coverage and 
restrictions of the Certificate of Confidentiality. 
10.4.1.2 Benefits 
Subjects participating in the study may benefit from the study drugs, both of which are indicated 
in the use of the diseases. Additional possible benefits are tumor shrinkage and reduced 
morbidity.  
10.5 CONSENT PROCESS AND DOCUMENTATION 
All patients who are being considered for this trial will undergo informed consent prior to being 
enrolled on the trial. The PI or associate investigator will perform the consenting process. 
Patients and family members when applicable will be asked to read the consent and will be 
encouraged to ask questions. It will be stated clearly that participation in the research study is 
voluntary and that participants can withdraw from the study without losing benefits they would 
otherwise be entitled to. Patients will be enrolled after the consent document has been signed. 
The informed consent process will be documented in the patient’s medical record and on the 


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informed consent document. This process will be performed by the local Principal Investigator or 
designee. 
10.5.1 Procedure for Consent via Telephone 
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.  
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. 
11 PHARMACEUTICAL INFORMATION  
11.1 SUNITINIB  
11.1.1 Source  
Sunitinib is manufactured by Pfizer and will be provided to the NIH CC Pharmacy under a 
CRADA.  
11.1.2 Toxicity  
(Please see package insert for a complete list of toxicities) 
In over 10,000 subjects with solid malignant tumors diarrhea (52.4%), fatigue (49.0%), nausea 
(42.7%), decreased appetite (38.5%), vomiting (33.9%), palmar-plantar erythrodysaesthesia 
syndrome (28.7%), hypertension (27.6%), stomatitis (26.0%), dysgeusia (25.9%), and mucosal 
inflammation (25.7%) were the most commonly reported treatment emergent adverse events. 
Overall, 60.3% experienced treatment-related AEs of Grade 3, 4, or 5 severity; Grade 3 in 46.9% 
of subjects, Grade 4 and grade 5 in 11.9% and1.6% of subjects respectively. The most commonly 
reported were neutropenia (13.5%), fatigue (9.2%), thrombocytopenia (8.6%), palmar-plantar 
erythrodysaesthesia syndrome (7.4%), diarrhea (6.3%), hypertension (5.5%), and asthenia 
(5.0%). 
Neutropenia (0.3%), fatigue (8.8%), palmar-plantar erythrodysaesthesia syndrome (7.4%), 
thrombocytopenia (6.8%), diarrhea (6.1%); and hypertension (5.4%) were the most commonly 
reported treatment-related AEs of Grade 3 severity. Neutropenia (3.2%), thrombocytopenia 
(1.8%), and anemia (0.9%) were the most commonly reported treatment-related AEs of Grade 4 
severity. Pulmonary embolism, cardiac failure, death, cerebral hemorrhage, renal failure, 
myocardial infarction, hepatic failure, gastrointestinal hemorrhage, multi-organ failure, 
respiratory failure, pneumonia, septic shock, cardiac arrest, sepsis, sudden death, tumor 
hemorrhage, and hemorrhage, were among the Grade 5 treatment-related AEs reported in at least 
3 subjects. 
Boxed Warning: 
SUTENT has been associated with hepatotoxicity, which may result in liver failure or death. 
Liver failure has been observed in clinical trials (7/2281 [0.3%]) and post-marketing experience. 


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Liver failure signs include jaundice, elevated transaminases and/or hyperbilirubinemia in 
conjunction with encephalopathy, coagulopathy, and/or renal failure. Monitor liver function tests 
(ALT, AST, bilirubin) before initiation of treatment, during each cycle of treatment, and as 
clinically indicated. SUTENT should be interrupted for Grade 3 or 4 drug-related hepatic adverse 
events and discontinued if there is no resolution. Do not restart SUTENT if patients subsequently 
experience severe changes in liver function tests or have other signs and symptoms of liver 
failure. 
Safety in patients with ALT or AST >2.5 × ULN or, if due to liver metastases, >5.0 × ULN has 
not been established. 
11.1.3 Formulation and preparation  
Sunitinib malate capsules consist of hard gelatin capsules containing sunitinib malate equivalent 
to 12.5, 25 and 50 mg sunitinib together with mannitol, croscarmellose sodium, povidone, and 
magnesium stearate.  
11.1.4 Stability and Storage  
Sunitinib – will be stored in a closed container at room temperature (15 to 30°C), away from 
heat, moisture, and direct light. 
11.1.5 Administration procedures 
Please see Section 3.2.1 
11.1.6 Incompatibilities  
Co-administration of sunitinib with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, 
itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, voriconazole) may increase sunitinib concentrations. Grapefruit may also increase 
plasma concentrations of sunitinib. A dose reduction for sunitinib should be considered when it 
must be co-administered with strong CYP3A4 inhibitors. 
11.2 EVEROLIMUS 
11.2.1 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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11.2.2 Chemical structure  
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
 
 
11.2.3 Source  
Everolimus will be manufactured and provided to the NIH CC Pharmacy by Novartis under a 
Clinical Trials Agreement.  
11.2.4 Toxicity  
(Please see package insert for a complete list of toxicities) 
Toxicity information is based on pooled safety data in cancer patients receiving everolimus 
(N=2470) in clinical studies including randomized, double-blind, placebo- or active comparator- 
controlled phase-III trials and phase-II studies related to the approved indications in oncology. 
The most common ADRs (incidence ≥1/10 and suspected to be related to treatment by the 
investigator) from the pooled safety data were (in decreasing order): stomatitis, rash, fatigue, 
diarrhea, infections, nausea, decreased appetite, anemia, dysgeusia, pneumonitis, hyperglycemia, 
weight decreased, pruritus, asthenia, peripheral edema, hypercholesterolemia, epistaxis, and 
headache. 
The most common grade 3/4 adverse drug reactions (incidence ≥1/100 to <1/10 and suspected to 
be related to treatment by the investigator) were stomatitis, anemia, hyperglycemia, fatigue, 
infections, pneumonitis, diarrhea, asthenia, thrombocytopenia, neutropenia, dyspnea, 
lymphopenia, proteinuria, hemorrhage, hypophosphatemia, rash, hypertension, aspartate 
aminotransferase (AST) increased, alanine aminotransferase (ALT) increased and pneumonia. 
The most common adverse events were stomatitis (in 64% of the patients in the everolimus 
group vs. 17% in the placebo group), rash (49% vs.10%), diarrhea (34% vs. 10%), fatigue (31% 
vs. 14%), and infections (23% vs. 6%). The most common grade 3 or 4 drug-related adverse 
events were anemia, hyperglycemia, stomatitis, thrombocytopenia, diarrhea, hypophosphatemia, 
and neutropenia[55]. 
 
11.2.5 Formulation and preparation  
Dosage forms: 
x Tablets will be supplied in 2.5 mg, 5 


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mg, and 10 mg formulations 
x Dispersible tablets (also referred to as 
‘tablets for oral suspension’): 2 mg, 3 
mg and 5 mg. The dispersible tablet is 
prepared as a suspension of undissolved 
medicine that is mixed with water, and 
then taken by mouth. The suspension 
can be prepared in an oral syringe or 
small drinking glass. 
Composition/excipients: 
x Tablets: Everolimus drug substance, 
butylhydroxytoluene/butylated 
hydroxytoluene (BHT), magnesium 
stearate, lactose anhydrous/Anhydrous 
lactose, lactose monohydrate, 
hypromellose/hydroxypropyl 
methylcellulose, crospovidone 
x Dispersible tablets: Everolimus drug 
substance, 
butylhydroxytoluene/butylated 
hydroxytoluene (BHT), magnesium 
stearate, lactose monohydrate, 
hypromellose/hydroxypropyl 
methylcellulose, crospovidone, silica 
colloidal anhydrous /colloidal silicon 
dioxide, mannitol/D-mannitol, cellulose 
microcrystalline/microcrystalline 
cellulose The excipients comply with the 
requirements of the applicable 
compendial monographs European 
Pharmacopeia (Ph. Eur.), Unites States 
Pharmacopeia / National Formulary 
(USP/NF). 
 
 
11.2.6 Stability and Storage  
Everolimus tablets and everolimus tablets for oral suspension are stored at 25°C (77°F); with 
excursions permitted between 15°–30°C (59°–86°F). Store everolimus in the original container, 
and protect from light and moisture. 
11.2.7 Administration procedures 
See Section 3.2.2 
11.2.8 Hazards and precautions 
The extent of absorption of everolimus through topical exposure is not known. Therefore, 
caregivers are advised to avoid contact with suspensions of everolimus tablets or dispersible 
tablets. Wash hands thoroughly before and after preparation of either suspension. 


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11.2.9 Incompatibilities  
Co-administration of everolimus with strong CYP3A4-inhibitors (e.g., ketoconazole, 
itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) and 
strong CYP3A4 inducers (e.g., rifampin, rifabutin) is not recommended without close monitoring 
of everolimus whole blood trough concentrations. Grapefruit and grapefruit juice inhibit 
cytochrome P450 3A4 and P-gp activity and should therefore be avoided with concomitant use 
of everolimus. Please refer to Section 4.2.2 


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70. Fjallskog, M.L., et al., Expression of molecular targets for tyrosine kinase receptor 
antagonists in malignant endocrine pancreatic tumors. Clinical cancer research : an official 
journal of the American Association for Cancer Research, 2003. 9(4): p. 1469-1473. 
71. Rinke, A., et al., Placebo-controlled, double-blind, prospective, randomized study on the 
effect of octreotide LAR in the control of tumor growth in patients with metastatic 
neuroendocrine midgut tumors: a report from the PROMID Study Group. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology, 2009. 27(28): p. 
4656-4663. 
72. Pavel, M.E., et al., Everolimus plus octreotide long-acting repeatable for the treatment of 
advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a 
randomised, placebo-controlled, phase 3 study. Lancet, 2011. 378(9808): p. 2005-2012. 
73. Boulay, A. and H.A. Lane, The mammalian target of rapamycin kinase and tumor growth 
inhibition. Recent Results Cancer Res, 2007. 172: p. 99-124. 
74. Cohen, H.T. and F.J. McGovern, Renal-cell carcinoma. N Engl J Med, 2005. 353(23): p. 
2477-90. 
75. Tanaka, C., et al., Identifying optimal biologic doses of everolimus (RAD001) in patients 
with cancer based on the modeling of preclinical and clinical pharmacokinetic and 
pharmacodynamic data. J Clin Oncol, 2008. 26(10): p. 1596-602. 
76. Yao, J.C., et al., Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to 
intermediate-grade neuroendocrine tumors: results of a phase II study. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology, 2008. 26(26): p. 
4311-4318. 
77. Yao, J.C., et al., Daily oral everolimus activity in patients with metastatic pancreatic 
neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology, 2010. 
28(1): p. 69-76. 
78. Mendel, D.B., et al., In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor 
targeting vascular endothelial growth factor and platelet-derived growth factor receptors: 
determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res, 2003. 
9(1): p. 327-37. 
79. O'Farrell, A.M., et al., SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent 
activity in vitro and in vivo. Blood, 2003. 101(9): p. 3597-605. 
80. Gan, H.K., B. Seruga, and J.J. Knox, Sunitinib in solid tumors. Expert Opin Investig Drugs, 
2009. 18(6): p. 821-34. 
81. Chow, L.Q. and S.G. Eckhardt, Sunitinib: from rational design to clinical efficacy. J Clin 
Oncol, 2007. 25(7): p. 884-96. 
82. Abrams, T.J., et al., SU11248 inhibits KIT and platelet-derived growth factor receptor beta 
in preclinical models of human small cell lung cancer. Mol Cancer Ther, 2003. 2(5): p. 471-
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83. Abrams, T.J., et al., Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a 
single agent and in combination with "standard of care" therapeutic agents for the treatment 
of breast cancer. Mol Cancer Ther, 2003. 2(10): p. 1011-21. 
84. Rosen, L., M. Mulay, and J. Long, Phase I trial of SU011248, a novel tyrosine kinase 
inhibitor in advanced solid tumors. . J Clin Oncol, 2008. 21(23s): p. suppl; abst 284. 
85. Faivre, S., et al., Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral 
multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol, 2006. 24(1): p. 
25-35. 
86. Fiedler, W., et al., A phase 1 study of SU11248 in the treatment of patients with refractory or 
resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the 
disease. Blood, 2005. 105(3): p. 986-93. 
87. Sweeney, C.J., et al., A phase I study of sunitinib plus capecitabine in patients with 
advanced solid tumors. J Clin Oncol, 2010. 28(29): p. 4513-20. 
88. Chow, L., D.L. Yonker, and S.A. Laurie, Sunitinib (SU) in combination with pemetrexed (P) 
in patients (pts) with advanced solid malignancies: a phase I dose escalation study. J Clin 
Oncol, 2008. 26(15s): p. suppl; abstr 3560. 
89. Traynor, A.M. and J.H. Schiller, Phase I dose-escalation and pharmacokinetic (PK) study of 
sunitinib (SU) plus docetaxel (D) in patients (pts) with advanced solid tumors (STs). J Clin 
Oncol, 2008. 26(15s): p. suppl; abstr 3564. 
90. Brell, J.M., et al., Phase I study of sunitinib malate continuously dosed and standard-
infusion gemcitabine in solid tumors. . J Clin Oncol, 2008. 26(15s): p. suppl; abst 13533. 
91. Heath, E.I. and J.R. Cohen, Phase I study of sunitinib in combination with carboplatin (C) 
plus paclitaxel (P) in patients (pts) with advanced solid tumors (STs). J Clin Oncol, 2008. 
26(15s): p. suppl; abstr 3565. 
92. Chien, A.J., et al., Phase I/II study of sunitinib (SU) in combination with metronomic dosing 
of cyclophosphamide (C) and methotrexate (M) in patients (pts) with metastatic breast 
cancer (MBC). J Clin Oncol, 2010. 28(15s): p. suppl; abstr 1067. 
93. Stadler, W.M., New targets, therapies, and toxicities: Lessons to be learned. J Clin Oncol, 
2006. 24(1): p. 4-5. 
94. Robert, C., et al., Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet 
Oncology, 2005. 6(7): p. 491-500. 
95. Suwattee, P., et al., Sunitinib: a cause of bullous palmoplantar erythrodysesthesia, 
periungual erythema, and mucositis. Arch Dermatol, 2008. 144(1): p. 123-5. 
96. Rosenbaum, S.E., et al., Dermatological reactions to the multitargeted tyrosine kinase 
inhibitor sunitinib. Support Care Cancer, 2008. 16(6): p. 557-66. 
97. Akerstrom, G. and P. Hellman, Surgery on neuroendocrine tumours. Best practice & 
research.Clinical endocrinology & metabolism, 2007. 21(1): p. 87-109. 
98. Yeo, W., et al., Hepatitis B reactivation in patients with hepatocellular carcinoma 
undergoing systemic chemotherapy. Ann Oncol, 2004. 15(11): p. 1661-6. 
99. Loomba, R., et al., Systematic review: the effect of preventive lamivudine on hepatitis B 
reactivation during chemotherapy. Ann Intern Med, 2008. 148(7): p. 519-28. 
100. 
Krishna, G., 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 
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101. 
Bajetta, E., et al., Chromogranin A, neuron specific enolase, carcinoembryonic antigen, 
and hydroxyindole acetic acid evaluation in patients with neuroendocrine tumors. Cancer, 
1999. 86(5): p. 858-865. 
102. 
Sadowski, S.M., et al., Prospective Study of 68Ga-DOTATATE Positron Emission 
Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic 
Neuroendocrine Tumors and Unknown Primary Sites. J Clin Oncol, 2016. 34(6): p. 588-96. 
 


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


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13.2 APPENDIX B: PREGNANCY AND ASSESSMENTS OF FERTILITY 
There are no adequate data from the use of everolimus in pregnant women. Studies in animals 
have shown reproductive toxicity effects including embryo-toxicity and feto-toxicity. The 
potential risk for humans is unknown. Everolimus should not be given to pregnant women unless 
the potential benefit outweighs the potential risk to the fetus. If a pregnancy occurs while on 
study treatment, the newborn will be followed for at least 12 months. 
It is not known whether everolimus is excreted in breast milk. However, in animal studies 
everolimus and/or its metabolites readily passed into the milk of lactating rats. Women taking 
everolimus should therefore not breast-feed. 
Women of childbearing potential 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 8 weeks after stopping 
treatment. Highly effective contraception is defined as either: 
x Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
[Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception] 
x Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least six weeks before taking study treatment. In case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment 
x Male partner sterilization (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate). [For female subjects on the study, the vasectomised male partner 
should be the sole partner for that subject]. 
x Use of a combination of any two of the following (a+b or a+c or b+c): 
a. Use of oral, injected, implanted or other hormonal methods of contraception 
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 
x In case of use of oral contraception, women should have been stable on the oral agent before 
taking study treatment. 
Male Contraception 
Sexually active males must use a condom during intercourse while taking the drug and for 8 
weeks after stopping treatment and should not father a child in this period. 
A condom is required to be used also by vasectomised men in order to prevent delivery of the 
drug via seminal fluid. 
Female partners of male patients must also be advised to use one of the following contraception 
methods: Use of (1) oral, injected, implanted or other hormonal methods of contraception, or (2) 
intrauterine device (IUD) or intrauterine system (IUS), or (3) prior male/female sterilization. 
Fertility 
 


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The potential for everolimus to cause infertility in male and female patients is unknown. 
However, menstrual irregularities, secondary amenorrhea and associated luteinizing hormone 
(LH)/follicle stimulating hormone (FSH) imbalance has been observed. 
Based on non-clinical findings, male and female fertility may be compromised by treatment with 
everolimus. 
 


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13.3 APPENDIX C: PANEL OF 197 GENES TESTED FOR IN CLINICAL MOLECULAR PROFILING 
CORE (CLIA-COMPLIANT). GENES IMPLICATED IN NETS ARE IN BOLD. 
 
 
Genes  
 
ABL1 
DMBT1 
KRAS 
RNF2 
ACN9 
DNMT3A 
KRT20 
RPS15 
ACVR1B 
DPYD 
MAGI1 
RUNX1 
AKT1 
EGF 
MAP2K4 
SCLC1 
ALK 
EGFR 
MEN1 
SDHA 
APC 
EGR3 
MET 
SDHAF1 
ARHGEF2 
EIF4G2 
MGMT 
SDHAF2 
ARID1A 
EML4 
MIB1 
SDHB 
ASXL1 
ENO1 
MKI67 
SDHC 
ATM 
ENO2 
MLH1 
SDHD 
ATRX 
ERBB2 
MPL 
SELT 
BAG3 
ERBB3 
MSH2 
SETD2 
BAI3 
ERBB4 
MSH6 
SLC38A1 
BAP1 
ERG 
MUC1 
SLC6A2 
BCAN 
EZH2 
MUC17 
SLTM 
BCL2 
F10 
MUC2 
SMAD4 
BRAF 
FAM123B 
MUC3A 
SMARCA4 
BRCA1 
FBXW7 
MUTYH 
SMARCB1 
BRCA2 
FGFR1 
MVP 
SMO 
CA12 
FGFR2 
MYC 
SMOX 
CA9 
FGFR3 
MYD88 
SMUG1 
CALU 
FH 
NAT1 
SOCS1 
CARD11 
FHIT 
NAT2 
SRC 
CBL 
FLCN 
NES 
SST 
CCND1 
FLT3 
NF1 
STC1 
CD34 
FOXL2 
NF2 
STK11 
CDC73 
FZR1 
NOTCH1 
SUFU 
CDH1 
GATA1 
NOTCH2 
SYP 
CDK4 
GATA2 
NPM1 
TCF7L2 
CDKN2A 
GATA3 
NRAS 
TET2 
CDX2 
GFAP 
PBRM1 
TFE3 
CEACAM7 
GNA11 
PCNA 
TFEB 
CEBPA 
GNAQ 
PDGFRA 
TMEM97 
CES3 
GNAS 
PDZD4 
TNFAIP3 
CHDM 
GRP 
PGR 
TNFSF13 
CRLF2 
GSTM1 
PHOX2B 
TP53 


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CSF1R 
HIVEP3 
PIK3CA 
TPD52L2 
CSF3 
HNF1A 
PMS2 
TPM4 
CTNNA1 
HRAS 
PPP2R1A 
TSC1 
CTNNB1 
IDH1 
PRCC 
TSC2 
CUL2 
IDH2 
PRKAR1A 
TSHR 
CYLD 
IFNA1 
PTCH1 
TYK2 
CYP1A1 
IGKV1D-43 
PTEN 
VHL 
DAXX 
IL2 
PTGS2 
VIM 
DCC 
ITGB5 
PTPN11 
WT1 
DES 
JAK1 
RB1 
WTS 
DIRAS1 
JAK2 
REEP5 
XRCC1 
DIRC2 
JAK3 
RET 
ZNF135 
DKK3 
KDR 
RNF139 
 
DLD 
KIT 
 
 
 
 


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13.4 APPENDIX D: PATHWAY ANALYSIS OF 193 MAPPED GENES USING INGENUITY PATHWAY 
ANALYSIS* 
Ingenuity 
Canonical 
Pathways 
Molecules 
 
 
AMPK Signaling 
SRC,TSC1,PIK3CA,PPP2R1A,GNAS,AKT1,STK11,TSC2,SMARCA4,ATM,PRKAR1A 
Angiopoietin 
Signaling 
PIK3CA,AKT1,NRAS,PTPN11,HRAS,KRAS,ATM 
EGF Signaling 
MAP2K4,SRC,PIK3CA,JAK1,AKT1,EGF,HRAS,ATM,EGFR 
Endothelin-1 
Signaling 
BRAF,MYC,SRC,PIK3CA,GNAS,NRAS,GNA11,GNAQ,HRAS,KRAS,PTGS2,ATM 
Ephrin A Signaling 
PIK3CA,PTPN11,ATM 
Ephrin B Signaling 
GNAS,CBL,GNA11,GNAQ,HRAS,CTNNB1 
Ephrin Receptor 
Signaling 
SRC,GNAS,AKT1,NRAS,PTPN11,GNA11,ABL1,GNAQ,EGF,HRAS,KRAS,JAK2 
ErbB Signaling 
MAP2K4,PIK3CA,AKT1,NRAS,ERBB4,EGF,HRAS,KRAS,ERBB3,ERBB2,ATM,EGFR 
ErbB2-ErbB3 
Signaling 
PIK3CA,NRAS,TYK2,HRAS,KRAS,ERBB3,CCND1,PTEN,MYC,AKT1,ERBB2,JAK3,A
TM 
ErbB4 Signaling 
PIK3CA,AKT1,NRAS,ERBB4,HRAS,KRAS,ATM 
ERK/MAPK 
Signaling 
BRAF,MYC,SRC,PIK3CA,PPP2R1A,NRAS,HRAS,KRAS,ATM,PRKAR1A 
ERK5 Signaling 
MYC,SRC,AKT1,NRAS,PTPN11,GNAQ,EGF,HRAS,KRAS,EGFR 
Erythropoietin 
Signaling 
SOCS1,SRC,PIK3CA,AKT1,NRAS,CBL,HRAS,KRAS,JAK2,ATM 
Inhibition of 
Angiogenesis by 
TSP1 
MAP2K4,TP53,AKT1,KDR 
Insulin Receptor 
Signaling 
TSC1,PIK3CA,JAK1,NRAS,HRAS,KRAS,JAK2,PTEN,AKT1,CBL,PTPN11,TSC2,PRKA
R1A,ATM 
mTOR Signaling 
TSC1,PIK3CA,PPP2R1A,AKT1,NRAS,EIF4G2,STK11,TSC2,RPS15,HRAS,KRAS,ATM 
p38 MAPK 
Signaling 
MAP2K4,TP53,MYC,DAXX 
PDGF Signaling 
MYC,MAP2K4,SRC,PIK3CA,NRAS,JAK1,TYK2,PDGFRA,ABL1,HRAS,KRAS,JAK2,J
AK3,ATM 
PI3K/AKT 
Signaling 
TP53,TSC1,PIK3CA,JAK1,NRAS,TYK2,HRAS,KRAS,JAK2,CCND1,PTEN,BCL2,PPP2
R1A,AKT1,TSC2,PTGS2,JAK3,CTNNB1 
Protein Kinase A 
Signaling 
GNAS,PTCH1,GNAQ,HNF1A,PTEN,BRAF,PTPN11,DCC,SMO,SMAD4,PTGS2,CTNN
B1,TCF7L2,PRKAR1A 
PTEN Signaling 
PIK3CA,NRAS,FGFR1,HRAS,FGFR2,KRAS,CCND1,PTEN,BCL2,FGFR3,MAGI1,CBL,
AKT1,PDGFRA,KDR,EGFR 
Role of Tissue 
Factor in Cancer 
TP53,SRC,PIK3CA,NRAS,GNA11,GNAQ,HRAS,KRAS,JAK2,PTEN,F10,AKT1,PTPN1
1,ITGB5,EGFR,ATM 
VEGF Family 
Ligand-Receptor 
Interactions 
PIK3CA,AKT1,NRAS,HRAS,KRAS,KDR,ATM 
VEGF Signaling 
SRC,PIK3CA,AKT1,NRAS,PTPN11,HRAS,KRAS,KDR,ATM,BCL2 
Wnt/β-catenin 
Signaling 
TP53,CDKN2A,SRC,GNAQ,CCND1,HNF1A,APC,ACVR1B,MYC,CDH1,PPP2R1A,AK
T1,DKK3,SMO,CTNNB1,TCF7L2 
 


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13.5 APPENDIX E: COLLECTION/RECORDING OF BLOOD PRESSURE INFORMATION 
1.0 
General Guidelines 
1.1 Frequency of monitoring. Blood pressure (BP) should be monitored at baseline, and 
then at every clinic visit, as well as at home during weeks when there is no clinic visit.  
1.2 Data recording. All required data should be recorded in the appropriate CRF or on the 
patient’s blood pressure monitoring diary, as appropriate. The following data are 
required at baseline and at each subsequent assessment: 
x Assessment date and time 
x Pulse 
x Systolic and diastolic BP  
 
1.3 Risk factors for hypertension (assess and record data in baseline history/physical CRF) 
x Diabetes (type 1 or type 2) 
x Renal disease (specify on CRF) 
x Endocrine condition associated with HTN (specify on CRF) 
x Use of steroids or NSAIDs (specify all concomitant meds) 
x Underlying cardiovascular condition – specify (i.e., ischemic heart disease) 
 
 
2.0 
Baseline data collection (at study entry) 
2.1 All patients 
x Current BP 
x Proteinuria, if present 
 
2.2 Patients with preexisting hypertension (i.e., those for whom “hypertension” is entered 
as a concomitant condition at study entry, or those who are currently receiving therapy 
with antihypertensive medication) – also record: 
x Date of HTN diagnosis (original) 
x Type HTN (essential or secondary) 
x CTCAE grade of HTN (at time of study entry) 
x Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of the 
following: 
- 
Antihypertensive agents taken at study entry 
- 
Antihypertensive agents taken in past (e.g., discontinued for toxicity, lack 
of efficacy) 
 
3.0 
Follow up BP data collection (during study) 
3.1 All patients (at each clinic visit) 
x Current BP 
x Proteinuria, if present 
 
3.2 Patients with treatment-emergent hypertension [defined as BP increase of >20 mmHg 
(diastolic) OR systolic BP >139 OR diastolic BP > 90 (if previously normal or grade 1 
per CTCAE v4) – record at time of hypertension diagnosis and at all subsequent clinic 
visits: 
x BP changes from baseline (or from previous assessment) (specify CTCAE 


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grade changes) 
x Hypertension-related symptoms as reported by patient (e.g., headache) 
x Other relevant changes associated with development of hypertension (e.g., 
ECG abnormalities) 
x Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of 
currently prescribed antihypertensive agents 
 
3.3 Patients with pre-existing hypertension at study entry – record at each clinic visit 
x BP changes from previous clinic visit (specify CTCAE grade changes) 
x Hypertension-related symptoms reported by patient (e.g., headache) 
x Other relevant changes associated with development of hypertension (e.g., 
ECG abnormalities) 
x Changes in antihypertensive medications since last assessment (e.g., dose 
change, add/discontinue drug) 
 
*Classes of antihypertensive drugs include ACE inhibitors, calcium channel blockers, alpha 
blockers, beta blockers, diuretics, angiotension II receptor antagonists. 
 


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13.6 APPENDIX F: PATIENT DRUG ADMINISTRATION DIARY 
13.6.1 Sunitinib 
Patient Name _________________________________ Study ID __________________ 
Please complete this form and return to the research nurse or doctor every cycle 
You will take: Sunitinib        Dose: _____ mg each morning with or without food. Be advised to drink 
plenty of water while you are on sunitinib. 
You will only need to take your blood pressure once per week. Please be sure you are seated when you 
take the measurement. 
DAY DATE 
TIME  TAKEN Blood Pressure 
COMMENTS (side effects or 
missed doses) 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 


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27 
 
 
 
 
28 
 
 
 
 
 


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13.6.2 Everolimus 
Patient Name _________________________________ Study ID __________________ 
Please complete this form and return to the research nurse or doctor every cycle 
You will take: Everolimus        Dose: ________.  
DAY DATE 
TIME  TAKEN COMMENTS (side effects or missed doses) 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
 
 
 
14 
 
 
 
15 
 
 
 
16 
 
 
 
17 
 
 
 
18 
 
 
 
19 
 
 
 
20 
 
 
 
21 
 
 
 
22 
 
 
 
23 
 
 
 
24 
 
 
 
25 
 
 
 
26 
 
 
 
27 
 
 
 
28 
 
 
 
 
Patient Signature:____________________________________ 


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13.7 APPENDIX G: CHILD PUGH SCORE 
Parameter 
1 point 
2 points 
3 points 
Total bilirubin (mg/dl) 
<2 
2-3 
>3 
Serum albumin, (g/dl) 
>3.5 
2.8-3.5 
<2.8 
PT INR 
<1.7 
1.71-2.30 
> 2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy None 
Grade I-II (or suppressed with 
medication) 
Grade III-IV (or 
refractory) 
Points are assigned based on the above parameters and totaled. Based on totals the following 
categories are assigned. 
Points 
Child Pugh Class 
5-6 
A 
7-9 
B 
10-15 
C 
 
 

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
15-C-0040 
PRINCIPAL INVESTIGATOR: 
Naris Nilobul, M.D. 
STUDY TITLE:  
A Phase II Trial of Mutation-Targeted Therapy with Sunitinib or Everolimus in Patients 
with Advanced Low-or Intermediate Grade Neuroendocrine Tumors of the 
Gastrointestinal Tract and Pancreas  
Continuing Review Approved by the IRB on 07/09/18 
Amendment Approved by the IRB on  02/20/19 (J) 
             Date posted to web:  03/07/19 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time. In either 
case, you will not lose any benefits to which you are otherwise entitled. However, to receive 
care at the NIH, you must be taking part in a study or be under evaluation for study 
participation. 
You may receive no benefit from taking part. The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical 
or research treatments they would want to receive (such as blood transfusions). If you have such 
beliefs, please discuss them with your NIH doctors or research team before you agree to the study. 
Now we will describe this research study. Before you decide to take part, please take as much time 
as you need to ask any questions and discuss this study with anyone at NIH, or with family, friends 
or your personal physician or other health professional.  
Why is this study being done?  
Patients with advanced neuroendocrine tumors (NETs) have several treatment options available. 
Surgery to reduce the size of the tumor(s) has been somewhat successful in cases where the size 
of the tumor(s) can be reduced tenfold or more. However, less than half of patients with advanced 
NETs can meet this potentially curative threshold, and of those that do, the tumors tend to come 
back after surgery. Patients with NETs that do not undergo surgery have been treated using 
chemotherapy. Nevertheless, it is not known to what extent surgery that reduces but does not 
remove all of the disease will result in any benefit to patients. Additionally, it is not known whether 
this surgery in combination with chemotherapy might improve outcomes.  


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-0040 
CONTINUATION: page 2 of 19 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 
 
In this study, we will determine if two drugs, sunitinib and everolimus, in sequence (one after the 
other) and assigned based on the genetics of your tumor result in a longer time between treatment 
and the worsening of your cancer. 
The study drug, everolimus, is supplied by Novartis Pharmaceuticals Corporation. The study drug, 
sunitinib, is supplied by Pfizer. Both have been approved by the US FDA for treatment of NETs. 
Both are considered to be targeted therapy, in that they work by interrupting specific pathways that 
are necessary to the survival of a tumor. Not everyone’s tumor depends on the same pathways, so 
in this study, your tumor will be tested to determine what type of mutation you have so that we 
will know which pathway is affected and assign you to the drug that targets the pathway your 
tumor depends on. You will be switched to the other drug if your tumor worsens or if you 
experience intolerable side effects related to the first drug. 
Why are you being asked to take part in this study? 
You are being asked to participate in this study because you have been diagnosed with an advanced 
low or intermediate grade gastrointestinal or pancreatic neuroendocrine tumor. 
How many people will take part in this study?  
Up to 120 subjects at the National Cancer Institute and Rush University Medical Center will take 
part in this study. 
Description of Research Study 
Before you begin the study 
Before you begin this study, you will have several exams and tests to make sure you are eligible 
for this study.  The exams and tests are part of regular cancer care and may be done even if you 
do not join the study.  If you recently had some of the tests, they may not need to be repeated. 
The research team will explain these exams and tests to you. You will have: 
• History and physical exam 
• Review of histological samples, current medications, and past treatments 
• Electrocardiogram  
• Routine blood work 
• Viral blood tests 
• Tumor measurements using special x-rays called computerized tomography (CT or CAT 
scans), positron emission tomography (PET) scan or magnetic resonance imaging (MRI) 
of your brain, chest, abdomen, and pelvis areas, bone scan.  
• Urine tests 


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-0040 
CONTINUATION: page 3 of 19 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 
 
• Pregnancy test. 
During the study 
You will undergo the following studies to help us monitor your health and tumor size/number at 
the beginning of and throughout the course of the study. The first time a test is done, it will be 
before you have taken any study drug, but after you have signed the consent. This is called a 
baseline study. The baseline study may not have to be repeated if you have already had it done at 
screening. Your doctor will let you know. 
Evaluations during the study: 
• Physical Exam+  
• Vital Signs+ 
• Routine blood and urine tests+ 
• Tests for Hepatitis B and C# 
• ~ 6 teaspoons of blood for genetic studies# (see discussion in Research Studies section 
below) 
• Echocardiogram (if you have a carcinoid tumor) 
• CT scan or MRI of chest, abdomen and pelvis to evaluate your disease‡ 
• 12 lead ECG* 
• Tests to determine the types of hormones your tumors are secreting# 
• Pregnancy test (in women that can have children only) * 
• Evaluation of your heart (in patients at risk for heart and lung disease) # 
• We will ask you to provide tumor tissue from prior biopsy or surgery. If this is not available 
or it is of poor quality for tumor analysis, you will be asked to undergo a mandatory biopsy 
so that we can determine what type of mutation you have. Patients that are known to have 
a familial cancer syndrome in which the mutation is known will not have to have a biopsy# 
#Baseline only 
+Baseline, ~day 1 of each 28-day cycle, ~day 15 of cycles 1 and 2 
*Approximately every 28 days (every cycle) 
‡Baseline and every 3 cycles after you have started treatment 
 
Taking the study drug: 
You will begin taking your assigned study medication after baseline studies are complete. 
During the study, you must talk to the study doctor before you take any drug other than the study 
drugs. This includes alternative or herbal medicines, and vitamins. Please avoid eating 


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-0040 
CONTINUATION: page 4 of 19 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 
 
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 the study drugs. 
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 may also 
ask you to stop taking your study drug for a brief time. If this happens, you will always 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. 
While you are taking assigned study drug, you will be asked to keep track of this drug and of any 
side effects you experience while taking it. A patient diary will be provided for this purpose. Please 
bring the diary will you at each study visit along with any unused capsules/tablets or empty 
containers. 
You will continue to take assigned study drug (sunitinib or everolimus) until you experience any 
intolerable side effects or until your disease worsens. In this case you will then switch to taking 
the other study drug (sunitinib or everolimus). You will be removed from study therapy for 
worsening disease or intolerable side effects only if your disease has worsened or you have 
intolerable side effects to both drugs in the study. 
Before switching to another drug, some eligibility evaluations might be repeated.  
Sunitinib 
Those patients assigned to sunitinib will take the drug by mouth once per day with or without food. 
Please note that a yellow discoloration of the skin area may result following direct contact with 
the capsules. Wash the exposed area with soap and water immediately. 
You will also be asked to keep track of your blood pressure at least once per week. Please, record 
the results in the patient diary provided for this purpose.  
Everolimus 
Those patients assigned to everolimus will take the drug by mouth once per day (or once every 
other day if your dose has been reduced). 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 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 drug 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. 
 


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-0040 
CONTINUATION: page 5 of 19 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 studies 
We will conduct genetic studies on the blood, saliva and tumor samples that you have provided in 
order to test for genes that are known to be associated with cancer. You will be informed of the 
results of these specific studies as they will determine your initial treatment.  
Your blood may be further tested in the future for additional genes that may cause NETs or other 
cancer. When we are conducting these tests, it is possible that we could identify possible changes 
in other parts of your DNA that are not related to this research. These are known as “incidental 
medical findings”. 
However, the analyses that we perform in our laboratory are for research purposes only; they are 
not nearly as sensitive as the tests that are performed in a laboratory that is certified to perform 
genetic testing. Changes that we observe unrelated to our research may or may not be valid. 
Therefore, we do not plan to inform you of the results of testing on your tissue and blood that is 
performed in our research lab. However, in the unlikely event that we discover a finding that is 
believed to be clinically important based on medical standards at the time that we first analyze 
your results, we will contact you. This could be many years in the future. We will ask you to have 
an additional tube of blood drawn to verify the findings we have seen in our lab. If the results are 
verified, you will be re-contacted and offered a referral to a genetic healthcare provider to discuss 
the results. 
Please also review the privacy risks associated with genetic testing in Privacy Risks section of the 
consent. 
When you are finished taking the drugs (treatment) 
Approximately 30 days after the last day you will take any study drug, you will be seen for a follow 
up safety visit. At this visit, you have the following tests:  
• Physical Exam 
• Vital Signs 
• Routine blood and urine tests 
• CT scan or MRI of chest, abdomen and pelvis to evaluate your disease. If you are being 
removed from the study due to worsening of your  disease, this will not be done. 
• Tests to determine the types of hormones your tumors are secreting 
• Pregnancy test (in women that can have children only) 
After this safety follow up visit, we will contact you by telephone or e-mail every 3 months to 
determine your health status and any new cancer treatments that you have begun. 


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-0040 
CONTINUATION: page 6 of 19 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 or sunitinib are not known. 
If you are a woman who can become pregnant, you must use a highly effective method of 
contraception while receiving any study drug, 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.  
• 
Female sterilization, when you have been already surgically sterilized prior to the 
study by surgical removal of both 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. Your Study Doctor will medically follow your pregnancy until delivery to 
monitor you and your child`s safety.  


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-0040 
CONTINUATION: page 7 of 19 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. Consent from your partner will be needed to allow your Study Doctor to medically follow 
this pregnancy until delivery to monitor the mother`s and child`s safety. 
Risks or Discomforts of Participation 
If you choose to take part in this study, there is a risk that: 
• You may lose time at work or home and spend more time in the hospital or doctor’s office 
than usual 
• You may be asked sensitive or private questions which you normally do not discuss 
The study drugs may affect how different parts of your body work such as your liver, kidneys, 
heart, and blood. The study doctor will be testing your blood and will let you know if changes 
occur that may affect your health. 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
Listed below are the most common and serious side effects of the study drugs that the 
researchers know about. There might be other side effects that researchers do not yet know 
about. If important new side effects are found, the study doctor will discuss these with you. 


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-0040 
CONTINUATION: page 8 of 19 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 
 
Sunitinib: 
COMMON, SOME MAY BE SERIOUS                                         
In 100 people receiving sunitinib malate, more than 20 and up to 100 may have: 
• Pain 
• Diarrhea, nausea, vomiting 
• Sores in mouth (which may cause difficulty swallowing) 
• Tiredness 
• Loss of appetite 
• Changes in taste 
• Sore throat 
 
 
OCCASIONAL, SOME MAY BE SERIOUS                                     
In 100 people receiving sunitinib malate, from 4 to 20 may have: 
• Anemia which may require blood transfusion 
• Blurred vision with chance of blindness 
• Bloating, constipation, heartburn, passing gas 
• Dry mouth, skin 
• Chills, fever 
• Swelling of arms, legs 
• Bruising, bleeding, weight loss 
• Infection, especially when white blood cell count is low 
• Dehydration 
• Dizziness, headache 
• Difficulty sleeping 
• Cough, shortness of breath 
 
• Nose bleed 
 
• Hair loss, rash, skin changes  
• Redness, pain or peeling of palms and soles  
• Change in hair color  
• High blood pressure   
 
 
 
 
 
 
 
 


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-0040 
CONTINUATION: page 9 of 19 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 
 
 
RARE, AND SERIOUS 
In 100 people receiving sunitinib malate, 3 or fewer may have: 
• Blood clot which may cause confusion, paralysis, swelling, pain, or shortness of 
breath  
• Heart failure which may cause shortness of breath, swelling of ankles, and tiredness 
• A tear or hole in the stomach that may require surgery 
 
• Liver damage which may cause yellowing of eyes and skin, swelling 
• Change in the heart rhythm 
 
• Kidney damage which may require dialysis   
• Damage to organs which may cause loss of teeth or change in thinking 
• Brain damage which may cause headache, seizure, blindness (also known as 
Reversible Posterior Leukoencephalopathy Syndrome) 
• Severe skin rash with blisters and can involve inside of mouth and other parts of 
the body 
Everolimus 
COMMON, SOME MAY BE SERIOUS                                         
In 100 people receiving everolimus, more than 10 and up to 100 may have: 
• Sores in mouth which may cause difficulty swallowing (up to ½ of subjects 
experience this) 
• Fatigue 
• Weakness 
• 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 
• Nosebleeds 
• Cough 
• Shortness of breath 
• Headache 
• High levels of blood sugar – which could lead to diabetes 
• High levels of lipids (cholesterol) 
• Change in taste 
• Low levels of red blood cells 
• Infections 


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-0040 
CONTINUATION: page 10 of 19 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 
 
• Spontaneous bleeding or bruising 
• Inflammation in the lungs (generally mild) 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving everolimus, from 1 to 10 may have: 
• Dry mouth 
• Dehydration 
• Skin changes (acne, rash, redness, dryness or irritation, itching and skin 
inflammation) 
• Abdominal pain 
• Stomach virus 
• Constipation and passing gas 
• 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 
• Low white blood cells which may lead to infection 
• Liver damage 
• Lowering of the blood cells that help the blood to clot (which could cause you to 
bleed more easily 
• lowering of the protein in your blood (hemoglobin) that helps carry oxygen; this 
could lead to anemia. 
 
 
RARE, AND SERIOUS 
In 100 people receiving everolimus, fewer than 1 may have: 
• 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.) 
• Severe decrease in red blood cells or all blood cells  


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-0040 
CONTINUATION: page 11 of 19 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 
 
• Loss of taste, rash of small blisters, bronchitis 
• Coughing up of blood 
• Swelling of the tissue just beneath the top layer of skin  
• Congestive heart failure (fluid build-up and shortness of breath)  
• Non-cardiac chest pain  
• Impaired wound healing 
• Increased daytime urination 
• Changes in menstrual period (female patients only) 
• Changes in fertility  
 
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 had or 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 also contribute to increased levels of an enzyme called blood lactate 
dehydrogenase which gives information about the health of certain organs. 
 
If you experience any hypersensitivity or signs of serious allergic reaction such as rash, itching, 
hives, difficulty breathing or swallowing, dizziness, please contact your doctor. 
Research Procedure Risks 
Blood Draw 
Side effects of blood draws include pain and bruising in the area where the needle was placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop. 
Saliva collection  
There are no physical risks or discomforts associated with saliva collection. 
Tumor biopsy 
If you do not have a tissue sample available, and do not have a hereditary cancer syndrome of 
known mutation, we will collect a small piece of tumor tissue from you. A hollow needle is used 
to withdraw small cylinders (or cores) of tissue from your tumor using a CT scan or ultrasound for 
guidance. The needle is put in 3 to 6 times to get the samples, or cores. This procedure usually 
causes only brief discomfort at the site from which the biopsy is taken and you will be offered 
medication to help numb the pain. Biopsy collection may cause bruising and bleeding, but usually 
does not leave scars. Rarely infection may occur at the needle site. 


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-0040 
CONTINUATION: page 12 of 19 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 
 
Radiation Risks from CT guided biopsy 
This research study involves exposure to radiation from one CT guided tumor biopsy. 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 0.80 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. 
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. If you are breast 
feeding and the protocol involves injection of radioactive material you will not be permitted to 
participate. It is best to avoid radiation exposure to unborn or nursing infants since they are more 
sensitive to radiation than adults. 
 
Privacy Risks 
The following general points are indirectly related to your participation in the research study. 
1. Unanticipated medical information: During the course of this investigation, it is possible 
(although not likely) that we will obtain unanticipated information about your health or 
genetic background.  
2. Release of medical records. In the course of applying for certain types of insurance (e.g., 
medical insurance, life insurance, or disability insurance), people are often asked to sign forms 
that authorize insurance companies to obtain their medical records. If you sign such a release 
form at some point in the future, it is possible that the insurance company would present this 
signed release form to the Clinical Center of the National Institutes of Health. In that event, 
the National Institutes of Health would comply with your request to provide the insurance 
company with your medical record. It is possible that information contained in your medical 
record might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. Your employability may also be affected. 


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-0040 
CONTINUATION: page 13 of 19 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 
 
3. Release of genetic information:  
• Your privacy is very important to us and we will use many safety measures to protect your 
privacy. However, in spite of all of the safety measures that we will use, we cannot 
guarantee that your identity will never become known. Although your genetic information 
is unique to you, you do share some genetic information with your children, parents, 
brothers, sisters, and other blood relatives. Consequently, it may be possible that genetic 
information from them could be used to help identify you. Similarly, it may be possible 
that genetic information from you could be used to help identify them.  
• While the controlled-access databases developed for this project will not contain 
information that is traditionally used to identify you, such as your name, address, telephone 
number, or social security number, people may develop ways in the future that would allow 
someone to link your genetic or medical information in our databases back to you. For 
example, someone could compare information in our databases with information from you 
(or a blood relative) in another database and be able to identify you (or your blood relative). 
It also is possible that there could be violations to the security of the computer systems 
used to store the codes linking your genetic and medical information to you. 
• Since some genetic variations can help to predict the future health problems of you and 
your relatives, this information might be of interest to health providers, life insurance 
companies, and others. Patterns of genetic variation also can be used by law enforcement 
agencies to identify a person or his/her blood relatives. Therefore, your genetic information 
potentially could be used in ways that could cause you or your family distress, such as by 
revealing that you (or a blood relative) carry a genetic disease. 
• There also may be other privacy risks that we have not foreseen. 
There are state and federal laws that protect against genetic discrimination. There is also a federal 
law called the Genetic Information Nondiscrimination Act (GINA). In general, this law makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information. However, it does not protect you against 
discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not apply to members of the United States military, to veterans 
obtaining health care through the Veteran’s Administration or the Indian Health Service. Lastly, 
GINA does not forbid insurance medical underwriting based on your current health status. 
Potential Benefits of Participation 
The aim of this study is to see if this experimental treatment will have any effect on the length of 
time that it takes your disease to worsen. 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 


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-0040 
CONTINUATION: page 14 of 19 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 
 
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 
Instead of being in this study, you have these options: 
• Expectant management without particular care or treatment for your cancer 
• 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. 
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 with the second of the two study drugs assigned 
• 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 
• if you become pregnant 
• if he/she decides to close the study 
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 Pfizer and 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. Unless and 
until you do withdraw your consent to participate in this study, it will remain valid and effective. 


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-0040 
CONTINUATION: page 15 of 19 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?  
For purposes of this study, NCI and Dr. Nilobul will use medical information collected or created 
as part of the study, such as medical records and test results, which identifies you by name or in 
another way. Your consent to participate in the study means you agree that NCI and Dr. Nilobul 
may obtain your medical information that they request for study purposes from your physicians 
and your other health care providers. You are also agreeing that NCI and Dr. Nilobul may use and 
share this information with the parties described below. In addition, you agree that, during the 
study, you may not have access to some of your medical information obtained or created as part 
of this study. You will be allowed to access this information once the study is finished.  
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 Institutes of Health Intramural Institutional Review Board 
• Qualified representatives from Pfizer and Novartis, the pharmaceutical companies who 
supply sunitinib and everolimus respectively, or its authorized representatives 


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-0040 
CONTINUATION: page 16 of 19 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 
 
Portions of your samples, genomic data, and health information will be stored for an unlimited 
period of time to be used in future research. Your individual genomic data and health information 
will be put in a controlled-access database. This means that only researchers who apply for and 
get permission to use the information for a specific research project will be able to access the 
information. Your genomic data and health information will not be labeled with your name or 
other information that could be used to identify you. Researchers approved to access information 
in the database have agreed not to attempt to identify you. 
 
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.  
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The researchers 
can use this Certificate to legally refuse to disclose information that may identify you in any 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for example, 
if there is a court subpoena. The researchers will use the Certificate to resist any demands for 
information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
• will be used for auditing or program evaluation internally by the NIH; or  
• must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
• is necessary for your medical treatment and you have consented to this disclosure;  
• is for other research.  
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible threat 
of harm to self or others. 


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-0040 
CONTINUATION: page 17 of 19 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 
 
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 everolimus 
developed by Novartis through a joint study with your researchers and the company. Novartis also 
provides financial support for this study. 
Pfizer is providing sunitinib for this study to NIH without charge. No NIH employee involved in 
this study receives any payment or other benefits from Pfizer. 
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 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-0040 
CONTINUATION: page 18 of 19 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, Naris Nilubol, M.D., Building 10, Room 4-5932, Telephone: 240-760-6154. 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-0040 
CONTINUATION: page 19 of 19 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 JULY 09, 2018 THROUGH JULY 08, 2019.  
 
  
 
 
  
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name