untitled h1
untitled h2

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 1  
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.
untitled h1
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.
untitled h1
eligibility

x Patients with:  
o progressive, histologically or cytologically diagnosed low or intermediate grade locally advanced or metastatic NETs.  
o Age t 18 years
untitled h1
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.
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.  
3  
| TABLE OF CONTENTS                                                                                                 |                                                                                                                                                                  |
|-------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| PRÉCIS .                                                                                                          |                                                                                                                                                                  |
| TABLE OF CONTENTS                                                                                                 |                                                                                                                                                                  |
| l                                                                                                                 | INTRODUCTION .                                                                                                                                                   |
| Study Objectives .                                                                                                |                                                                                                                                                                  |
| 1.1                                                                                                               | Primary Objective: ..................................................................................................................................... 8       |
| 1.1.1                                                                                                             |                                                                                                                                                                  |
| 1.1.2                                                                                                             | Secondary Objectives:  ....................................................................................................................................... 8 |
| 1.2                                                                                                               | Background and Rationale                                                                                                                                         |
| Neuroendocrine tumors                                                                                             |                                                                                                                                                                  |
| 1.2.1                                                                                                             |                                                                                                                                                                  |
| 1.2.2                                                                                                             | Everolimus .                                                                                                                                                     |
| 1.2.3                                                                                                             | SUNITIES IN THE SURESTING INTERACTION IN THE SURESTING OF THE SURESTING                                                                                          |
| 1.2.4                                                                                                             | RATIONALE                                                                                                                                                        |
| 2                                                                                                                 | ELIGIBILITY ASSESSMENT AND ENROLLMENT ............................................................................. 21                                           |
| Eligibility criteria .                                                                                            |                                                                                                                                                                  |
| 2.1                                                                                                               |                                                                                                                                                                  |
| 2.1.1                                                                                                             | Inclusion Criteria .                                                                                                                                             |
| 2.1.2                                                                                                             | Exclusion Criteria .                                                                                                                                             |
| 2.2                                                                                                               | Screening Evaluation .                                                                                                                                           |
| 2.3                                                                                                               | Registration Procedures                                                                                                                                          |
| 2.3.1                                                                                                             | Treatment Assignment Procedures (For registration purposes only):                                                                                                |
| Baseline Evaluation                                                                                               |                                                                                                                                                                  |
| 2.4                                                                                                               |                                                                                                                                                                  |
| 3                                                                                                                 | STUDY IMPLEMENTATION .                                                                                                                                           |
| Study Design                                                                                                      |                                                                                                                                                                  |
| 3.1                                                                                                               |                                                                                                                                                                  |
| 3.1.1                                                                                                             | C Coss-over                                                                                                                                                      |
| 3.1.2                                                                                                             | Long term follow up                                                                                                                                              |
| 3.2                                                                                                               | Study Drug Administration                                                                                                                                        |
| Sunitinib Treatment and dose .                                                                                    |                                                                                                                                                                  |
| 3.2.1                                                                                                             |                                                                                                                                                                  |
| 3.2.2                                                                                                             | Everolimus Treatment and dose                                                                                                                                    |
| 3.2.3                                                                                                             | CR Self-Administered Study Drugs Policy ........................................................................... 30                                           |
| Dose Modifications/Dose Delay                                                                                     |                                                                                                                                                                  |
| 3.3                                                                                                               |                                                                                                                                                                  |
| 3.3.1                                                                                                             | Sunitinib                                                                                                                                                        |
| 3.3.2                                                                                                             | Everolimus .                                                                                                                                                     |
| 3.4                                                                                                               | S Study Calendar                                                                                                                                                 |
| 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 .                                                                                                                                             |
| Off Protocol Therapy and Off Study Procedure ................................................................. 43 |                                                                                                                                                                  |
| 3.5.3                                                                                                             |                                                                                                                                                                  |
| 4                                                                                                                 | CONCOMITANT MEDICATIONS/MEASURES .                                                                                                                               |
| Supportive Care                                                                                                   |                                                                                                                                                                  |
| 4.1                                                                                                               |                                                                                                                                                                  |
| 4.1.1                                                                                                             | Management of Sunitinib-Induced Hypertension ............................................................... 43                                                  |
untitled h1
abbreviated title targeted rx in

| Version Date: 01/15/2019                                                                                         |                                                                                                                    |                 |
|------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------|-----------------|
| 4.1.2                                                                                                            | Management of specific everolimus toxicities .................................................................. 45 |                 |
| 4.2                                                                                                              | Concurrent medications .                                                                                           |                 |
| 4.2.1                                                                                                            | General guidelines .                                                                                               |                 |
| 4.2.2                                                                                                            | Cytochrome P450 and P-glycoprotein inhibitors/inducers/substrates ................... 53                           |                 |
| 4.2.3                                                                                                            | Vaccinations                                                                                                       |                 |
| S                                                                                                                | BIOSPECIMEN COLLECTION                                                                                             |                 |
| Sample collection for genotyping and research Studies                                                            |                                                                                                                    |                 |
| 5.1                                                                                                              |                                                                                                                    |                 |
| 5.1.1                                                                                                            | T TUMOR SAMPLE                                                                                                     |                 |
| 5.1.2                                                                                                            | Saliva Collection and Peripheral Blood .                                                                           |                 |
| 5.2                                                                                                              | Sample Storage, Tracking and Disposition                                                                           |                 |
| Procedures for Storage of Specimens in the Laboratory of Dr. Naris Nilubol ...... 57                             |                                                                                                                    |                 |
| 5.2.1                                                                                                            |                                                                                                                    |                 |
| 5.2.2                                                                                                            | Procedures for Storage of Tissue Specimens in the Laboratory of Pathology ...... 58                                |                 |
| 5.3                                                                                                              | Samples for Genetic/Genomic Analysis .                                                                             |                 |
| Description of the scope of genetic/genomic analysis ........................................................ 59 |                                                                                                                    |                 |
| 5.3.1                                                                                                            |                                                                                                                    |                 |
| 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.                                                                                                |                                                                                                                    |                 |
| 5.3.4                                                                                                            | Management of Results                                                                                              |                 |
| DATA COLLECTION AND EVALUATION .                                                                                 |                                                                                                                    |                 |
| 6                                                                                                                | 6.1                                                                                                                | DATA COLLECTION |
| SOURCE DOCUMENTS .                                                                                               |                                                                                                                    |                 |
| 6.1.1                                                                                                            |                                                                                                                    |                 |
| 6.1.2                                                                                                            | Case Report Forms                                                                                                  |                 |
| 6.1.3                                                                                                            | DATA QUALITY Assurance .                                                                                           |                 |
| 6.2                                                                                                              | DATA SHARING Plans                                                                                                 |                 |
| 6.2.1                                                                                                            | Human Data Sharing Plan                                                                                            |                 |
| 6.2.2                                                                                                            | Genomic Data Sharing Plan                                                                                          |                 |
| 6.3                                                                                                              | Response Criteria                                                                                                  |                 |
| Definitions                                                                                                      |                                                                                                                    |                 |
| 6.3.1                                                                                                            |                                                                                                                    |                 |
| 6.3.2                                                                                                            | Disease Parameters .                                                                                               |                 |
| 6.3.3                                                                                                            | Methods for Evaluation of Measurable Disease ................................................................ 63   |                 |
| 6.3.4                                                                                                            | Response Criteria                                                                                                  |                 |
| Duration of Response                                                                                             |                                                                                                                    |                 |
| 6.3.5                                                                                                            |                                                                                                                    |                 |
| 6.3.6                                                                                                            | Progression-Free Survival                                                                                          |                 |
| 6.3.7                                                                                                            | Response Review                                                                                                    |                 |
| 6.4                                                                                                              | TOXICITY Criteria                                                                                                  |                 |
| SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN                                                    |                                                                                                                    |                 |
| 7                                                                                                                | ..                                                                                                                 |                 |
| 7.1                                                                                                              | Definitions                                                                                                        |                 |
| 7.1.1                                                                                                            | A Adverse Event                                                                                                    |                 |
| 7.1.2                                                                                                            | Suspected adverse reaction .                                                                                       |                 |
| 7.1.3                                                                                                            | Unexpected adverse reaction                                                                                        |                 |
| 7.1.4                                                                                                            | Serious                                                                                                            |                 |  
| Version Date: 01/15/2019                                                             |                                                                                                                                 |
|--------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------|
| 7.1.5                                                                                | Serious Adverse Event                                                                                                           |
| 7.1.6                                                                                | Disability                                                                                                                      |
| 7.1.7                                                                                | Life-threatening adverse drug experience .                                                                                      |
| Protocol Deviation (NIH Definition)                                                  |                                                                                                                                 |
| 7.1.8                                                                                |                                                                                                                                 |
| 7.1.9                                                                                | Non-compliance (NIH Definition)                                                                                                 |
| 7.1.10                                                                               | Unanticipated Problem                                                                                                           |
| 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 .                                                                         |                                                                                                                                 |
| 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                                                                              |
| 7.3                                                                                  | Safety Reporting Criteria to the Pharmaceutical Collaborators                                                                   |
| 7.3.1                                                                                | Novartis                                                                                                                        |
| 7.3.2                                                                                | Pfizer .                                                                                                                        |
| 7.4                                                                                  | DATA And Safety Monitoring Plan                                                                                                 |
| 7.4.1                                                                                | Principal Investigator/Research Team ....................................................................................... 70 |
| 8                                                                                    | STATISTICAL CONSIDERATIONS                                                                                                      |
| 9                                                                                    | COLLABORATIVE AGREEMENTS .                                                                                                      |
| 9.1                                                                                  | Cooperative Research and Development Agreement (CRADA) ......................................... 71                             |
| 9.2                                                                                  | Clinical Trials Agreement (CTA)                                                                                                 |
| 10 HUMAN SUBJECTS PROTECTIONS                                                        |                                                                                                                                 |
| 10.1 Rationale For Subject Selection                                                 |                                                                                                                                 |
| 10.2  Participation of Children                                                      |                                                                                                                                 |
| 10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT ........................... 72 |                                                                                                                                 |
| 10.4  Evaluation of Benefits and Risks/Discomforts .                                 |                                                                                                                                 |
| 10.4.1                                                                               | Risks/Benefits Analysis                                                                                                         |
| 10.5 Consent Process and Documentation                                               |                                                                                                                                 |
| 10.5.1                                                                               | Procedure for Consent via Telephone                                                                                             |
| 1 PHARMACEUTICAL INFORMATION                                                         |                                                                                                                                 |
| 1.1 Sunitinib                                                                        |                                                                                                                                 |
| S SOURCE .                                                                           |                                                                                                                                 |
| 11.1.1                                                                               |                                                                                                                                 |
| 11.1.2                                                                               | T Toxicity .                                                                                                                    |
| 11.1.3                                                                               | Formulation and preparation                                                                                                     |
| 11.1.4                                                                               | Stability and Storage                                                                                                           |
| Administration procedures                                                            |                                                                                                                                 |
| 11.1.5                                                                               |                                                                                                                                 |
| 11.1.6                                                                               | Incompatibilities                                                                                                               |
| 1.2 Everolimus .                                                                     |                                                                                                                                 |
| 11.2.1                                                                               | D Drug substance                                                                                                                |
| 11.2.2                                                                               | C Chemical structure .                                                                                                          |
| 11.2.3                                                                               | S 76                                                                                                                            |
| 11.2.4                                                                               | TOXICITY                                                                                                                        |  
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 (CLIAcompliant). 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
untitled h1
1 introduction 1.1 study objectives

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).
untitled h1
1.2 background and rationale 1.2.1

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, longacting somatostatin analogues play a central role in the treatment of hormonal symptoms produced by NETs but do not have significant antitumor activity[13, 16].
untitled h1
epidemiology

The annual incidence of NETs has been increasing in the United States and worldwide[2, 7, 1720]. 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].
untitled h1
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  Ki67Index  (%)b                                                    |                                                 |                           |                                                                                                  |                |
|----------------------------------------------------|-------------------------------------------------|---------------------------|--------------------------------------------------------------------------------------------------|----------------|
| Differentiation &  Mitotic Count  Grade (/10 HPF)a | Traditional                                     | ENETS/WHO  Classification | Moran et al[30]                                                                                  |                |
| Classification                                     |                                                 |                           |                                                                                                  |                |
| Well  differentiated  Low grade (grade  1) < 2     | ≤ 2                                             | Carcinoid,                | islet  Neuroendocrine                                                                            | Neuroendocrine |
| cell, PNET                                         | tumor, grade 1                                  | carcinoma, grade 1        |                                                                                                  |                |
| Carcinoid,  atypical  carcinoidc ,                 | islet                                           |                           |                                                                                                  |                |
| cell, PNET                                         |                                                 |                           |                                                                                                  |                |
| Intermediate grade  (grade 2) 2-20                 | 3-20                                            | Neuroendocrine            | Neuroendocrine                                                                                   |                |
| tumor, grade 2                                     | carcinoma, grade 2                              |                           |                                                                                                  |                |
| Poorly  differentiated                             | Neuroendocrine  carcinoma, grade 3,  small cell |                           |                                                                                                  |                |
| Large-cell  neuroendocrine  carcinoma              | Neuroendocrine  carcinoma, grade 3,  small cell |                           |                                                                                                  |                |
| High grade (grade  3) > 20                         | > 20                                            | Small-cell  carcinoma     | Neuroendocrine  carcinoma, grade 3,  large cell  Neuroendocrine  carcinoma, grade 3,  large cell |                |  
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.
untitled h1
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].
untitled h1
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.
untitled h1
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, VHL, DAX, ATRX, *TP53* and *CDKN1B*. These mutations are present in 87% of pancreatic neuroendocrine tumors and in 60% of gastrointestinal neuroendocrine tumors.
untitled h1
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]. 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**).
untitled h1
key drivers of angiogenesis growth

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 |  
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)
untitled h1
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 receptorpositive, 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).
untitled h1
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].
untitled h1
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 antiangiogenic 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 antiproliferative and immunosuppressant and at least in part reversible after a 2 or 4-week recovery period with the exception of the changes in male reproductive organs, most notably testes. In vitro genotoxicity studies covering relevant genotoxicity end-points showed no evidence of clastogenic or mutagenic activity. In male fertility studies in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm head count and plasma testosterone levels were diminished at 5 mg/kg which corresponded to 0.7 times the estimated clinical exposure at 10 mg/day, and caused a decrease in male fertility. There was evidence of reversibility. Female fertility was not affected, but everolimus caused an increase of pre-implantation loss in female rats at doses > 0.1 mg/kg, suggesting it could also potentially impact fertility in females. Everolimus crossed the placenta and was toxic to the conceptus. In rats, everolimus caused embryo/fetotoxicity at systemic exposure below the planned therapeutic level comprising mortality and reduced fetal weight. The incidence of skeletal variations and malformations at 0.3 and 0.9 mg/kg (e.g. sternal cleft) was increased. In rabbits, embryo toxicity was evident by an increase in late resorptions. Effects of everolimus on the pre- and postnatal development of rats were limited to slightly affected body weight and survival in the F1-generation at ≥0.1 mg/kg, and did not indicate a specific toxic potential. The potential reproductive risk for humans is unknown. However, due to the observed malformations in rats, everolimus should be considered potentially teratogenic. Everolimus should not be given to pregnant women unless the potential benefit outweighs the potential risk for the fetus. Women of childbearing potential should be advised to use highly effective contraception methods while they are receiving everolimus and up to 8 weeks after treatment has been stopped. It is not known whether everolimus is excreted in human milk. In animal studies, everolimus and/or its metabolites were readily transferred into the milk of lactating rats. Therefore women who are taking everolimus should not breastfeed.
untitled h1
1.2.2.3 clinical experience 1.2.2.3.1 phase

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.
untitled h1
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 intermediate grade PNETs. Unfortunately, none of these clinical trials evaluated what pathways or genes were altered in patient tumor samples.
untitled h1
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]
untitled h1
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 protooncogene 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 domaincontaining 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.
untitled h1
1.2.3.1 non-clinical experience 1.2.3.1.1 specificity

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
(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].
untitled h1
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).
untitled h1
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, 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.
untitled h1
1.2.3.2 clinical experience 1.2.3.2.1 phase

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 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.
untitled h1
1.2.3.2.2 phase ii and phase

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.
untitled h1
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 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].
untitled h1
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 locoregional 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.
untitled h1
2 eligibility assessment and enrollment

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.  
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.
untitled h1
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.
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  
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
untitled h1
2.2 screening evaluation within 4

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
untitled h1
within 2 weeks prior to

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)
untitled h1
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**):  
| 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                                             |
untitled h1
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.
untitled h1
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)
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
untitled h1
3 study implementation 3.1 study

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).
untitled h1
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:
untitled h1
x ct c/a/p or mri

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.  
Figure 2. Study flow chart and treatment selection based on tumor genotype.  
Subjects with low- or intermediate grade, locally invasive/metastatic neuroendocrine tumors of the gastrointestinal tract and pancreas and measurable disease who meet study eligibility  
  
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.
untitled h1
3.2 study drug administration 3.2.1

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 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.  
| alterations based on common mutations that occur in NETs.                                                            |                                                      |                                                    |
|----------------------------------------------------------------------------------------------------------------------|------------------------------------------------------|----------------------------------------------------|
| Study Agent                                                                                                          | Mutations *                                          | Affected Pathways                                  |
| 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                                        |                                                    |
| Everolimus                                                                                                           | NF1                                                  | TSC2/mTOR, Hypoxia induced neoangiogenesis         |
| MEN1                                                                                                                 | Cell growth, cell cycle and genome  instability      |                                                    |
| FLT3                                                                                                                 | Cell survival, proliferation, and  differentiation   |                                                    |
| PDGFR                                                                                                                | Cell proliferation, cell migration,  neoangiogenesis |                                                    |
| ATM                                                                                                                  |                                                      |                                                    |
| Sunitinib                                                                                                            | 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 |                                                      |                                                    |  
*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.
untitled h1
3.2.3 ccr self-administered study drugs

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.
untitled h1
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  
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 nonhematological 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 x 25 mg capsule        |
| -1                                                                                                                                                       | 25 mg*     | or                                     |
| 2 x 12.5 mg capsule                                                                                                                                      |            |                                        |
| 0 (Starting Dose Level)                                                                                                                                  | 37.5 mg    | 3 x 12.5 mg capsule  1 x 50 mg capsule |
| +1                                                                                                                                                       | 50 mg      | 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 Nonhematologic                                                                   | Continue at  the same  dose level.                                                                                                            | 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 |             |
| 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.                               |                                                                                                                                                                                       |             |  
| 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 |
| 1 If after the first 8 weeks there is no response according to RECIST and toxicity remains ≤ nonhematological 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.             |                                    |                                                                                                                                                                                                                                              |                                                                                                                                 |
untitled h1
3.3.1.1 dose modification for sunitinib

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.  
| Management                                                                                                                                             |                                                                                                                                                                               |                                                                    |                                           |
|--------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|-------------------------------------------|
| Grade                                                                                                                                                  | Antihypertensive                                                                                                                                                              | Blood Pressure                                                     | Sunitinib                                 |
| (CTCAE v4)                                                                                                                                             | Therapy                                                                                                                                                                       | Monitoring                                                         | 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 | BP should be  monitored as  recommended by the  treating physician | No change except  as described in  step 4 |
| Step 2) If BP still not  controlled, add another                                                                                                       |                                                                                                                                                                               |                                                                    |                                           |  
| Grade        | Antihypertensive                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Blood Pressure   | Sunitinib   |
|--------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------|-------------|
| (CTCAE v4)   | Therapy                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Monitoring       | 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. |                  |             |  
| Version Date: 01/15/2019 Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Antihypertensive                                                                                                                                          | Blood Pressure                                                                                                                                                                                        | Sunitinib                                                       |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|
| (CTCAE v4)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Therapy                                                                                                                                                   | Monitoring                                                                                                                                                                                            | Dose                                                            |
| Modification                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                           |                                                                                                                                                                                                       |                                                                 |
| Persistent Grade 3  Severe  Systolic >160  Diastolic >100                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | HOLD sunitinib until systolic  BP <159 and diastolic BP <99.                                                                                              | 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. |
| 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). |                                                                                                                                                           |                                                                                                                                                                                                       |                                                                 |
| Protocol-specific  guidance supersedes any  other management  guidelines, including  CTCAE v4                                                                                                                                                                                                                                                                                                                                                                                                                                                | 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, restart sunitinib at 1  lower dose level  after consultation  with the study  Principal  Investigator                                                                                                                                                           |                                                                                                                                                                                                       |                                                                 |
| 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                                                                                                                                                                                                                                                                                                |                                                                                                                                                           |                                                                                                                                                                                                       |                                                                 |
| 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, restart sunitinib at 1  lower dose level  after consultation  with the study                                                                 |  
| Grade                                                                                            | Antihypertensive   | Blood Pressure   | Sunitinib   |
|--------------------------------------------------------------------------------------------------|--------------------|------------------|-------------|
| (CTCAE v4)                                                                                       | Therapy            | Monitoring       | Dose        |
| Modification                                                                                     |                    |                  |             |
| Principal  Investigator                                                                          |                    |                  |             |
| Abbreviations: dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers (BB), |                    |                  |             |  
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**  
| Dose Level                           | Daily Dose                                 | Dispensed As         |
|--------------------------------------|--------------------------------------------|----------------------|
| 0 - Starting dose level for patients | 10 mg                                      | 1 x 10 mg tablets    |
| without hepatic impairment*.         | or 2 x 5 mg tablets  or 4 x 2.5 mg tablets |                      |
| -1                                   | 5 mg                                       | 1 x 5 mg tablets  or |  
| 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                                                           | Interrupt everolimus administration until resolution to ≤ grade 1  (or ≤ grade 2 if baseline values were within the range of grade |
| Grade 3 (> 5.0 - 20.0 ULN)*                                                    | 2). If resolution occurs within ≤ 7 days, everolimus should be restarted 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                                                           | Interrupt everolimus administration until resolution to ≤ grade 1                                                                  |
| Grade 4 (> 20 x ULN)*                                                          | (or ≤ grade 2 if baseline values were within the range of grade 2). If resolution occurs within ≤ 7 days, everolimus should be restarted at one dose level lower. If resolution takes > 7 days,  discontinue everolimus.                                                                                                                                    |  
| 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 restarted 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                                                                                                          | Discontinue everolimus                                                                                                                                                                                                             |
| (asterixis or encephalopathy/coma)  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                                                                                                             | Discontinue everolimus                                                                                                                                                                                                             |
| reduction  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)                                                    |                                                                                                                                                                                                                                    |  
| Table 9                                                                                | Dosing guidelines for Everolimus-related hematologic toxicities                                                                                                                                                                          |
|----------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Toxicity                                                                               | Action                                                                                                                                                                                                                                   |
| Grade 2 thrombocytopenia (platelets                                                    | No action                                                                                                                                                                                                                                |
| <75, ≥ 50x109/L) Grade 3 thrombocytopenia (platelets                                   | Interrupt everolimus until resolution to grade d1                                                                                                                                                                                        |
| <50, ≥ 25 x109/L)                                                                      | 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 <                                                  | Interrupt everolimus until recovery to grade d 1. Then                                                                                                                                                                                   |
| 25 x109/L)                                                                             | reintroduce everolimus at one dose level lower.                                                                                                                                                                                          |
| Grade 3 neutropenia or anemia                                                          | Interrupt everolimus until resolution to grade ≤1 or baseline                                                                                                                                                                            |
| (neutrophil <1, ≥0.5 x109/L)                                                           | 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                                                   | Reduce dose to the next lower dose level, if available. The                                                                                                                                                                              |
| dose reduction                                                                         | 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                                                                                                                                                                                                                   |
untitled h1
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 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 4 weeks prior to enrollment                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | x                     | Hemoglobin A1C                                                |
| x                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | 12- lead ECG          |                                                               |
| Within 2 weeks prior to enrollment                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | 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 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 4 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. Within 2 weeks prior to treatment  initiation |                       |                                                               |  
| x                                                                                                                                                                                                                                                                                                                                          | CT C/A/P or MRI                                                                                      |                      |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------|----------------------|
| Treatment cycles based on tumor genotyping (1 cycle=28 days) 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 1  within 2 weeks prior to  treatment |                                                                                                      |                      |
| Cycle 1                                                                                                                                                                                                                                                                                                                                    | x                                                                                                    | Clinical assessment3 |
| x                                                                                                                                                                                                                                                                                                                                          | CBC and Chemistries2                                                                                 |                      |
| x                                                                                                                                                                                                                                                                                                                                          | Urinalysis                                                                                           |                      |
| x                                                                                                                                                                                                                                                                                                                                          | Concomitant Medications                                                                              |                      |
| x                                                                                                                                                                                                                                                                                                                                          | Adverse Events                                                                                       |                      |
| Day 15                                                                                                                                                                                                                                                                                                                                     |                                                                                                      |                      |
| within 1 week 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 study drug  initiation) |                      |
| Day 1                                                                                                                                                                                                                                                                                                                                      |                                                                                                      |                      |
| within 1 week prior to  treatment or cross-over  treatment                                                                                                                                                                                                                                                                                 |                                                                                                      |                      |
| Cycle 2                                                                                                                                                                                                                                                                                                                                    | x                                                                                                    | CBC,                 |
| x                                                                                                                                                                                                                                                                                                                                          | Chemistries,                                                                                         |                      |
| x                                                                                                                                                                                                                                                                                                                                          | Urinalysis                                                                                           |                      |
| x                                                                                                                                                                                                                                                                                                                                          | Concomitant Medications                                                                              |                      |
| x                                                                                                                                                                                                                                                                                                                                          | Adverse Events                                                                                       |                      |
| Day 15                                                                                                                                                                                                                                                                                                                                     |                                                                                                      |                      |
| within 1 week prior to  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                                                          |                      |
| Day 1                                                                                                                                                                                                                                                                                                                                      |                                                                                                      |                      |
| Cycle N                                                                                                                                                                                                                                                                                                                                    | within 1 week prior to  treatment or cross-over  treatment                                           |                      |  
potential (within 3 days before study drug  
   
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
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
untitled h1
3.5 criteria for removal from

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
* 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.
untitled h1
4 concomitant medications/measures 4.1 supportive

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  
| Agent                       | Initial      | Intermediate   | Maximum     | Hepatic            |            |
|-----------------------------|--------------|----------------|-------------|--------------------|------------|
| class                       | Agent        | dose           | dose        | dose               | metabolism |
| Dihydropyridine  CalciumChannel  Blockers                             |              |                |             |                    |            |
| (DHP CCB)                   | nifedipine   | 30 mg daily    | 60 mg daily | 90 mg daily        | CYP 3A4    |
| XL                          | 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    |              |                |             |                    |            |
| metoprolol                  | 25 mg        | 50 mg          | 100 mg      | CYP 2D6            |            |
| twice daily                 | twice daily  | twice daily    | substrate   |                    |            |
| Selective  E Blockers  (BB) | atenolol     | 25 mg daily    | 50 mg daily | 100 mg daily       | No         |  
Agents in bold characters are suggested as optimal choices to avoid or minimize potential drug-interactions with sunitinib through CYP450.  
| Version Date: 01/15/2019 Agent                       | Initial      | Intermediate   | Maximum      | Hepatic                  |                    |
|------------------------------------------------------|--------------|----------------|--------------|--------------------------|--------------------|
| class                                                | Agent        | dose           | dose         | dose                     | metabolism         |
| acebutolol                                           | 100 mg       | 200-300 mg     | 400 mg       | Yes (CYP450              |                    |
| twice daily                                          | twice daily  | twice daily    | unknown)     |                          |                    |
| bisoprolol                                           | 2.5 mg daily | 5-10 mg daily  | 20 mg daily  | Yes (CYP450  unknown)    |                    |
| captopril                                            | 12.5 mg 3x   | 25 mg 3x       | 50 mg 3x     | CYP 2D6                  |                    |
| daily                                                | daily        | daily          | substrate    |                          |                    |
| enalapril                                            | 5 mg daily   | 10-20 mg       | 40 mg daily  | CYP 3A4                  |                    |
| daily                                                | substrate    |                |              |                          |                    |
| ramipril                                             | 2.5 mg daily | 5 mg daily     | 10 mg daily  | Yes (CYP450  unknown)    |                    |
| Angiotensin  Converting  Enzyme  Inhibitors  (ACEIs) | lisinopril   | 5 mg daily     | 10-20 mg     | 40 mg daily              | No                 |
| daily                                                |              |                |              |                          |                    |
| 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:                                         | 10 mg daily  | 20 mg daily    | 40 mg daily  | No                       |                    |
| quinapril  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       |                    |
| Angiotensin  II Receptor  Blockers  (ARBs)           | 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     |                    |
| labetalol                                            | 100 mg twice | 200 mg twice   | 400 mg twice | CYP 2D6                  |                    |
| D and E Blocker                                      | daily        | daily          | daily        | substrate and  inhibitor |                    |
untitled h1
4.1.2 management of specific everolimus

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 noncumulative.  
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).
untitled h1
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.
untitled h1
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. 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).