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abbreviated title ph2sunitinib-thymoma/thymic ca ctep

Title: A Phase II Study of Sunitinib in Patients with Advanced Relapsed or Refractory Thymoma or Thymic Carcinoma with at Least One Prior Line of Platinum-Based Systemic Chemotherapy Coordinating Center: Center for Cancer Research/ National Cancer Institute 10 Center Drive Bethesda, MD 20892 NCI Principal Investigator: Arun Rajan, MD A-F
Thoracic and GI Malignancies Branch/CCR/NCI Bldg 10-CRC RM 4-5330 MSC 1465 10 Center Drive Bethesda, MD 20892-1465 Telephone: 240 760-6236 Email: rajana@mail.nih.gov
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nci lead associate investigator

Anish Thomas, MD DTB/CCR/NCI A- F
Bldg 10-CRC RM 4-5330 MSC 1465 10 Center Drive Bethesda, MD 20892-1465 Telephone: 240-760-6241 E-mail: anish.thomas@nih.gov  
| NIH Associate Investigators: Jane Trepel, DTB, CCR, NCI F 10 Center Drive, Room 12C432A  Bethesda, MD 20814 Phone: 301-496-1547  Email: trepelj@mail.nih.gov   | Corrine Keen, RN, OCD, CCR, NCI A, B, C 10 Center Drive, Room 8D44B  Bethesda, MD 20814 Phone: 240-760-6097  Email: ck232s@nih.gov       |
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| Raffit Hassan, MD, TGMB, CCR, NCI A-F Building 10, Room 4-5330  Bethesda, MD 20892 Phone: 240-760-6232  Email: hassanr@mail.nih.gov                            | Arlene Berman, RN, OCD, CCR, NCI A, B, C 10 Center Drive, Room 8D44  Bethesda, MD 20814 Phone: 240-760-6096  Email: arleneb@mail.nih.gov |  
| Paul Meltzer, MD, GB, CCR, NCI F 37 Convent Drive  Building 37, Room 6138  Bethesda, MD 20814 Phone: 240-760-6136  Email: pmeltzer@mail.nih.gov   | Linda Sciuto, RN, OCD, CCR, NCI A, B, C 10 Center Drive, Room 13N230  Bethesda, MD, 20814 Phone: 240-760-6117  Email: lsciuto@mail.nih.gov   |
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| Eva Szabo, MD, DCP, NCI A- F 9609 Medical Center Drive, Room 5E102  Bethesda, MD 20852  Phone: 240-276-7011  Email: azaboe@mail.nih.gov           | Christine Alewine, MD, LMB, CCR, NCI A-F 37 Convent Drive, Room  Bethesda, MD, 20814 Phone: 240-760-6146  Email: alewinecc@mail.nih.gov      |  
| Statistician:                            | Seth M. Steinberg, PhD OCD/CCR/NCI F 9609 Medical Center Drive, Room 2W334 MSC 9716  Rockville, MD 20850-9716  Telephone: 240-276-5563 E-mail: steinbes@mail.nih.gov   |
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| Referral Contact and  Study Coordinator: | Arlene Berman, RN A, B, C 10 Center Drive, Room 12N226  Bethesda, MD 20814  Phone: 240-760-6096  Fax: 301-480-2590  Email: arleneb@mail.nih.gov                        |  
Investigator Role Code Key A. Obtain information by intervening or interacting with living individuals for research purposes B. Obtaining identifiable private information about living individuals C. Obtaining the voluntary informed consent of individuals to be subjects D. Makes decisions about subject eligibility E. Studying, interpreting, or analyzing identifiable private information or data/specimens for research purposes F. Studying, interpreting, or analyzing coded, linked data or specimens for research purposes G. Some/all research activities performed outside NIH
Drug Sponsor: CTEP \# 9174 NCI Supplied Agent: Sunitinib malate (NSC 736511, IND \# 74019)
Protocol Type: Interventional/ Version \#19/ Version Date: 04/30/2020  
| Affiliated Institution   | Indiana University Simon Cancer Center                                                                                                                                                                                    |
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|                          | Federal Wide Assurance Number (FWA) # 00003544                                                                                                                                                                            |
| Lead Site Investigator:  | Patrick J. Loehrer, Sr., MD  Director, Indiana University Simon Cancer Center  535 Barnhill Drive, Room 473  Indianapolis, IN 46202-5289  Telephone: 317-274-3539  Fax: 317-278-4190  E-mail: ploehrer@iupui.edu          |
| IRB/Research Contacts:   | Jessica Sastre Regulatory Compliance Coordinator  Clinical Trials Office 535 Barnhill Drive, RT380  Indianapolis, IN 46202  Phone: 317.278.5615  Fax: 317.274.8022  jsastre@iu.edu                                        |
| Pharmacy Contact:        | Bonnie Klank, PharmD  Investigational Drug Services  IUSCC Room C2102  550 N. University Blvd.  Indianapolis, IN 46202  Direct Line: 317-948-6881;  IDS Main: 317-944-1900; Fax: 317-948-1697  Email: bklank@iuhealth.org |
|                          | IDS@iuhealth.org                                                                                                                                                                                                          |
| Research Nurse:          | A. John Spittler RN, BSN  GI Oncology and Thymoma Clinical Research Nurse  535 Barnhill Drive  Indianapolis, IN 46202  Telephone: 317-274-0771  Fax: 317-274-8007                                                         |
|                          | E-mail: ajspittl@iupui.edu                                                                                                                                                                                                |
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precis background

Platinum-based chemotherapy is the standard of care for advanced unresectable thymoma and thymic carcinoma. However over 50% of these patients may fail initial therapy and therefore require second-line therapy. New therapeutic options are needed for patients who have disease progression on or after platinum-containing therapy. Results obtained from protocol 12-C-0118 so far have shown impressive clinical activity of sunitinib in patients with recurrent thymic carcinoma with an objective response rate of 23% and disease control rate of 91% which is unprecedented for this histology. Treatment at a dose of 50 mg once daily for four weeks followed by 2 weeks off was poorly tolerated. Twenty five out of 41 patients needed dose reductions due to development of intolerable adverse events.
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objectives primary objective

- To evaluate the objective response rate (PR+CR) for sunitinib in patients with relapsed or refractory thymoma or thymic carcinoma
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main eligibility

- Patients with histologically confirmed thymoma (Group 1 only) or thymic carcinoma who have previously been treated with at least one platinum-containing chemotherapy regimen with progressive disease prior to study entry
- Measurable disease by RECIST 1.1 criteria
- Adequate renal, hepatic and hematopoietic function
- No major surgery, radiotherapy, chemotherapy or biologic therapy within 28 days of sunitinib
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design

- In the first group (Group 1), sunitinib will be administered orally using a continuous schedule at 50 mg per day for 4 weeks with 2 weeks off to constitute a 6-week cycle (Schedule 4/2) until disease progression or development of intolerable side-effects.  
- In the second group (Group 2), sunitinib will be administered orally using a continuous schedule at 50 mg per day for 2 weeks with 1 week off to constitute a 3-week cycle (Schedule 2/1) until disease progression or development of intolerable side-effects.  
- Toxicity will be assessed every cycle by CTCAE Version 5.0
- Tumor response assessments by RECIST 1.1 criteria will be performed every cycle for Group 1 and every other cycle for Group 2 (every 6 weeks) for patients receiving treatment for less than one year, and every two cycles for Group 1 and every four cycles for Group 2 (every 12 weeks) for patients who have been receiving treatment one year or longer.  
- Exploratory studies include evaluation of serum VEGFR2, PLGF, IL-4, IL-12, HGF, and b-FGF (Group 1 only); and circulating tumor cells, endothelial progenitors, and mature apoptotic endothelial cells (both groups). In Group 2, regulatory T cells (Tregs), exhausted CD8 T cells, myeloid-derived suppressor cells (MDSCs), and Th1/Th2 T cell populations will also be evaluated. Where tumor samples are available, intra-tumoral immune infiltrate will be assessed (both groups). Exploratory studies apply to NCI only.
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table of contents

SUMMARY OF PROTOCOL CHANGES  
| Precis 4                                                                                                                  |                                                                                                                                                                     |                  |
|---------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------|
| TABLE OF CONTENTS                                                                                                         |                                                                                                                                                                     |                  |
| 1                                                                                                                         | OBJECTIVES .......................................................................................................................................................8 |                  |
| 1.1                                                                                                                       | Primary Objectives                                                                                                                                                  |                  |
| 1.2                                                                                                                       | Secondary Objectives                                                                                                                                                |                  |
| 1.3                                                                                                                       | Exploratory Objectives ...........................................................................................................8                                 |                  |
| 2                                                                                                                         | BACKGROUND AND RATIONALE                                                                                                                                            |                  |
| Thymoma and Thymic Carcinoma .......................................................................................8     |                                                                                                                                                                     |                  |
| 2.1                                                                                                                       |                                                                                                                                                                     |                  |
| 2.2                                                                                                                       | Sunitinib Malate                                                                                                                                                    |                  |
| 2.3                                                                                                                       | RATIONALE                                                                                                                                                           |                  |
| Exploratory Studies Background ........................................................................................25 |                                                                                                                                                                     |                  |
| 2.4                                                                                                                       |                                                                                                                                                                     |                  |
| 3                                                                                                                         | PATIENT SELECTION                                                                                                                                                   |                  |
| 3.1                                                                                                                       | Eligibility Criteria .........................................................................................................................27                    |                  |
| 3.2                                                                                                                       | Exclusion Criteria ....................................................................................................................29                           |                  |
| 3.3                                                                                                                       | Inclusion of Women and Minorities .................................................................................31                                               |                  |
| 4                                                                                                                         | REGISTRATION PROCEDURES ........................................................................................................32                                  |                  |
| 4.1                                                                                                                       | Coordinating Center                                                                                                                                                 |                  |
| 4.2                                                                                                                       | Participating Site .......................................................................................................................32                        |                  |
| 4.3                                                                                                                       | Treatment Initiation Timeline ...........................................................................................32                                         |                  |
| S                                                                                                                         | TREATMENT PLAN.......................................................................................................................................32             |                  |
| 5.1                                                                                                                       | Agent Administration                                                                                                                                                |                  |
| 5.2                                                                                                                       | General Concomitant Medication and Supportive Care Guidelines .......................34                                                                             |                  |
| 5.3                                                                                                                       | D Duration of Therapy                                                                                                                                               |                  |
| 5.4                                                                                                                       | Duration of Follow Up                                                                                                                                               |                  |
| 5.5                                                                                                                       | Criteria for Removal from Study .................................................................................37                                                 |                  |
| DOSING DELAYS/DOSE MODIFICATIONS ...................................................................38                    |                                                                                                                                                                     |                  |
| 6                                                                                                                         | 6.1                                                                                                                                                                 | General Guidance |
| 6.2                                                                                                                       | Treatment delays and modifications for administrative needs ................................38                                                                      |                  |
| 6.3                                                                                                                       | Treatment delays and modifications for medical needs ..............................................39                                                               |                  |
| 6.4                                                                                                                       | Sunitinib Monotherapy Dose Level Reductions (Groups 1 and 2)                                                                                                        |                  |
| 6.5                                                                                                                       | Management of Treatment-Emergent Hypertension .................................................39                                                                   |                  |
| 6.6                                                                                                                       | Dosage Modification Criteria for Other Hematologic and Non¬                                                                                                         |                  |
| Hematologic Adverse Events                                                                                                |                                                                                                                                                                     |                  |
| 6.7                                                                                                                       | Management of Other Clinically Significant Sunitinib-related AEs ....................41                                                                             |                  |
| 7                                                                                                                         | NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING                                                                                                               |                  |  
PLAN .................................................................................................................................................42  
| 7.1   | Definitions 42                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
|-------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 7.2   | OHSRP Office of Compliance and Training / IRB Reporting 42                                                                                                                                                                                                                                                                                                                                                                                                                             |
| 7.3   | NCI Clinical Director Reporting 42                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| 7.4   | IND Sponsor Reporting Criteria 42                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| 7.5   | Routine Adverse Event Reporting 50                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| 7.6   | NIH Required Data and Safety Monitoring Plan 51                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| 8     | PHARMACEUTICAL INFORMATION 51 8.1 Sunitinib [Sunitinib Malate (NSC 736511)] 51 8.2 Agent Ordering and Agent Accountability 53                                                                                                                                                                                                                                                                                                                                                          |
| 9     | BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 54 9.1 Serum VEGFR2, PLGF, IL-4, IL-12, HGF, b-FGF - Group 1 only 54 9.2 Circulating tumor cells, circulating endothelial progenitors, mature  apoptotic endothelial cells, regulatory T cells (Tregs)*, exhausted CD8 T  cells*, myeloid-derived suppressor cells (MDSCs)*, and Th1/Th2 T cell  populations* 54 9.3 Intra-tumoral immune infiltrate, where tumor samples are available 54 9.4 Sample Storage, Tracking and Disposition 55 |
| 10    | DATA COLLECTION AND EVALUATION 55 10.1 Data Collection 55                                                                                                                                                                                                                                                                                                                                                                                                                              |
| 11    | STUDY CALENDAR 56                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| 12    | MEASUREMENT OF EFFECT 61 12.1 Antitumor Effect - Solid Tumors 61                                                                                                                                                                                                                                                                                                                                                                                                                       |
| 13    | DATA REPORTING / REGULATORY REQUIREMENTS 66 13.1 Data Reporting 66                                                                                                                                                                                                                                                                                                                                                                                                                     |
| 14    | CTEP MULTICENTER GUIDELINES 67                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| 15    | CCR MULTI-INSTITUTIONAL GUIDELINES 67 15.1 IRB Approvals 67 15.2 Amendments and Consents 67                                                                                                                                                                                                                                                                                                                                                                                            |
| 16    | COLLABORATIVE AGREEMENTS 67                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| 17    | STATISTICAL CONSIDERATIONS 69 17.1 Study Design/Endpoints 69 17.2 Sample Size/Accrual Rate 71 17.3 Stratification Factors 71 17.4 Analysis of Secondary Endpoints 71 17.5 Reporting and Exclusions 72                                                                                                                                                                                                                                                                                  |
| 18    | HUMAN SUBJECTS PROTECTIONS 72 18.1 Rationale For Subject Selection 72                                                                                                                                                                                                                                                                                                                                                                                                                  |  
| 18.2   | Participation of Children 73                                                |
|--------|-----------------------------------------------------------------------------|
| 18.3   | Participation of Subjects Unable to Give Consent 73                         |
| 18.4   | Evaluation of Benefits and Risks/Discomforts 74                             |
| 18.5   | Risks/Benefits Analysis 74                                                  |
| 18.6   | Consent and Assent Process and Documentation 74                             |
| 19     | REFERENCES 75                                                               |
| 20     | Appendix A: performance status criteria 84                                  |
| 21     | Appendix B: New York Heart Association Classification of Cardiac Disease 85 |
| 22     | Appendix C: Drugs Known to be Metabolized by Selected CYP450 Isoenzymes 86  |
| 23     | Appendix D: Patient's medication diary 88                                   |
| 24     | Appendix E: CTEP MULTICENTER GUIDELINES 92                                  |  
25 Appendix F: Collection/Recording of Blood Pressure Information ..................................94 26 Appendix G: Management of Sunitinib-Induced Hypertension ........................................96 27 Appendix H ......................................................................................................................100 28 Appendix I: LIST OF PRESCRIPTION AND OVER THE COUNTER
MEDICATIONS THAT MAY INTERACT WITH SUNITINIB (SUTENT®) .............104
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1 objectives 1.1 primary objectives

- To evaluate the objective response rate (PR+CR) for sunitinib in patients with relapsed or refractory thymoma (Group 1 only) or thymic carcinoma
- To determine the progression-free survival (PFS) and overall survival (OS) for sunitinib in patients with relapsed or refractory thymoma (Group 1 only) or thymic carcinoma
- To assess safety and tolerability of sunitinib
- To assess the duration of response to sunitinib Peripheral blood will be collected to evaluate serum VEGFR2, PLGF, IL-4, IL-12, HGF, and bFGF (Group 1); and circulating tumor cells, endothelial progenitors, and mature apoptotic endothelial cells at various time points (both groups). For Group 2, regulatory T cells (Tregs), exhausted CD8 T cells, myeloid-derived suppressor cells (MDSCs), and Th1/Th2 T cell populations will also be evaluated at various time points. Where tumor samples are available, intra-tumoral immune infiltrate will be assessed (both groups). Exploratory studies apply to NCI only. Thymoma is the most common tumor in the anterior mediastinum in adults with an incidence of 0.15 cases per 100,000 person years based on National Cancer Institute Surveillance, Epidemiology, and End Results data.1 Although thymomas are histologically benign, they can potentially invade through the capsule, infiltrate surrounding organs and rarely metastasize to distant organs. Thymomas are primary tumors of thymic epithelial cells; but on histology, B and T lymphocytes, intradigitating reticulum cells, macrophages, and myoid cells are also seen. 2,3 World Health Organization (WHO) pathologic classification which takes into account both histologic and morphologic features, is the most widely used classification system of thymomas
(Table 1).4 Proposed in 1999, it and has since then been validated as an indicator of invasiveness, immunologic function and prognosis.  
5-7 This system divides thymomas into two groups based on whether the neoplastic epithelial cells and their nuclei have a spindle and/or oval shape (type A) or whether these cells have a dendritic or plump (epithelioid) appearance (type B). Tumors that combine these two morphologies are designated type AB. Type B tumors are further subdivided into B1, B2, and B3, respectively, on the basis of the proportional increase of the epithelial component and the emergence of atypia of the neoplastic cells. Thymic carcinomas are categorized 8 as type C.  
4 Thymic carcinomas are rare, constituting only 0.06% of all thymic neoplasms. They are typically invasive, have a greater propensity to capsular invasion, metastases and a higher risk of relapse and death. 8-10  
| Table 1: WHO classification of epithelial thymic malignancies WHO type Histologic description A Medullary thymoma AB Mixed thymoma B1 Predominantly cortical thymoma B2 Cortical thymoma B3 Well-differentiated thymomic carcinoma C Thymic carcinoma   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Since most patients do not have nodal disease or metastases, the tumor, node, metastasis staging system is not particularly useful for thymomas. The Masaoka staging which takes into account the extension and invasion of tumor into surrounding organs is the most widely used staging system for thymomas (Table 2).11 Proposed in 1981, it and has since then been found to correlate with overall survival of patients with thymoma and thymic carcinoma. 12,13  
| Table 2: Masaoka staging of thymomas   |                                                                                                                                                                       |
|----------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Masaoka                                | Stage description                                                                                                                                                     |
| Stage Stage I                          | Macro and microscopically encapsulated (tumors invading into but not through the capsule)                                                                             |
| Stage II                               | A. Microscopic transcapsular invasion B. Macroscopic invasion into surrounding fatty tissue or grossly  adherent to but not through mediastinal pleura or pericardium |
| Stage III                              | Macroscopic invasion into neighboring organs (i.e. pericardium, great  vessels, lung)  A. without invasion of great vessels  B. with invasion of great vessels        |
| Stage IV                               | A. Pleural or pericardial dissemination B. Lymphogenous or hematogenous metastases                                                                                    |  
Thymomas are slow growing tumors and a large proportion of patients are asymptomatic at diagnosis, while the rest may present either with symptoms related to a mediastinal mass or with autoimmune paraneoplastic syndromes.14 The latter may be found in up to 50-60% of patients and includes a wide spectrum of disorders: immune mediated cytopenias, hypogammaglobulinemia, pemphigus, systemic lupus erythematosus and neurologic syndromes. Polymyositis, hepatitis, and myocarditis are less frequent autoimmune paraneoplastic syndromes associations of thymoma. However, myasthenia gravis (MG) is the most common paraneoplastic syndrome associated with thymoma, seen in approximately 30–45% of the patients. The etiology of autoimmune phenomenon associated with thymoma is not known. Thymomas tend to grow locally and do not often extend beyond the chest. Although unilateral metastatic pleural depositions are not rare, distant metastases are very uncommon, except in very advanced stages of the disease.14  
| Table 3: Responses to combination chemotherapy and biologic agents in thymic  malignancies Author                                                |                       |                        |     |
|--------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------|------------------------|-----|
| (year of publication)                                                                                                                            | Number of patients    | Drugs                  | ORR |
| Chemotherapy                                                                                                                                     |                       |                        |     |
| Fornasiero (1991) 15                                                                                                                             | 37                    | ADOC                   | 91% |
| 16                                                                                                                                               | 29                    | PAC                    | 50% |
| Loehrer (1994) Giaccone (1996)17                                                                                                                 | 16                    | EP                     | 56% |
| Berruti (1999)18                                                                                                                                 | 16                    | ADOC                   | 81% |
| Loehrer (2001) 19                                                                                                                                | 34                    | VIP                    | 32% |
| Loehrer (2006)20                                                                                                                                 | 27                    | Pemetrexed             | 17% |
| Lemma (2011) 21                                                                                                                                  | 44                    | Carboplatin/Paclitaxel | 32% |
| Biologic agents                                                                                                                                  |                       |                        |     |
| Loehrer (2004) 22                                                                                                                                | 38                    | Octreotide± prednisone | 11% |
| 23                                                                                                                                               | 7                     | Imatinib               | 0   |
| Giaccone (2009) 24                                                                                                                               | 41                    | Belinostat             | 8%  |
| Giaccone (2011) Kurup (2005)25                                                                                                                   | 26                    | Gefitinib              | 4%  |
| Gordon (1995)26                                                                                                                                  | 14                    | Interleukin-2          | 0   |
| Abbreviations: ADOC: Cisplatin, doxorubicin, cyclophosphamide                                                                                    | and vincristine; PAC: |                        |     |
| cisplatin, doxorubicin, and cyclophosphamide; EP: Cisplatin, etoposide; VIP: Etoposide,  ifosfamide, and cisplatin; ORR Objective response rates |                       |                        |     |  
Due to the rare nature of thymic malignancies, there are no definitive trials which guide the management of these patients. Based on retrospective case series, surgery has been established as the mainstay of treatment of non-metastatic thymoma and thymic carcinoma. Given the relatively slow growth of well differentiated thymomas, surgery also has a role in locally advanced tumors that are not radically resectable and in those that have loco-regionally relapsed. Chemotherapy, before and/or after surgery, and radiation therapy (RT) may be useful in selected patients.3 In patients with unresectable or metastatic disease, chemotherapy is the primary treatment modality.2 In general, response rates are higher with combination chemotherapy (in the range of 30-90%) compared with single-agent chemotherapy; 2 however, no randomized trials have been conducted to date. Over 50% of patients with locally advanced or metastatic thymoma or thymic carcinoma may fail initial therapy and therefore require second-line therapy. Active agents include cisplatin, vincristine, doxorubicin, etoposide, cyclophosphamide and ifosfamide. Widely used first line chemotherapy combinations include cisplatin/etoposide (EP), cisplatin/etoposide/ifosfamide (VIP), cisplatin/ doxorubicin/ cyclophosphamide (PAC) and Cisplatin/ doxorubicin/ cyclophosphamide/ vincristine (ADOC). Biological agents investigated thus far also have variable rates of response, ranging from 0 to 40%. Table 3 summarizes response rates to combination chemotherapy and biologic agents in patients with recurrent or metastatic thymic malignancies who failed prior chemotherapy. As discussed earlier, thymic carcinomas are associated with poorer response rates, more aggressive clinical course and shorter survival. Results of systemic therapy in patients with recurrent thymic carcinoma have been discouraging with most studies showing minimal to no objective responses and median PFS ranging between 1.4 and 6 months (Table 3B). In contrast, treatment with sunitinib was associated with a response rate of 23%, a disease control rate of 91% and median PFS of 6.7 months in patients with thymic carcinoma. These results were comparable to those seen in a recently reported clinical trial of carboplatin and amrubicin. It should be noted that almost 60% of patients with thymic carcinoma on this study had received no previous chemotherapy. However, treatment was poorly tolerated at the prescribed dose of 50 mg per day using a 4 weeks on and 2 weeks off schedule. More than half of the patients treated needed a dose reduction to 37.5 mg per day or 25 mg per day.  
| Table 3B. Systemic therapy in previously treated patients with Thymic Epithelial  Tumors              |                       |            |             |             |
|-------------------------------------------------------------------------------------------------------|-----------------------|------------|-------------|-------------|
| InterventionRef                                                                                       | Number of Patients    | Responses  | PFS/TTP     | OS          |
| Pemetrexed20                                                                                          | Thymoma = 16          | NR         | 45.4 weeks  | NR          |
| Thymic carcinoma = 11                                                                                 | NR                    | 5.1 weeks  |             |             |
| Capecitabine +                                                                                        | Thymoma = 12          | 5          | 11 months   | Not reached |
| Gemcitabine27                                                                                         | Thymic carcinoma = 3  | 1          | 6 months    |             |
| Octreotide +                                                                                          | Thymoma = 32          | 12         | 8.8 months  | Not reached |
| Prednisone22                                                                                          | Thymic Carcinoma = 6  | 0          | 4.5 months  | 23.4 months |
| Erlotinib +                                                                                           | Thymoma = 11          | 0          | NR          | Not reached |
| Bevacizumab28                                                                                         | Thymic carcinoma = 7  | 0          | NR          |             |
| Belinostat24                                                                                          | Thymoma = 25          | 2          | 11.4 months | Not reached |
| Thymic carcinoma = 16                                                                                 | 0                     | 2.7 months | 12.4 months |             |
| Amrubicin +                                                                                           | Thymoma = 18          | 3          | 7.6 months  | Not reached |
| Carboplatin*29                                                                                        | Thymic carcinoma = 33 | 10         | 7.6 months  | 27.3 months |
| Cixutumumab                                                                                           | Thymoma = 37          | 5          | 9.5 months  | 25 months   |
| (unpublished)                                                                                         | Thymic carcinoma = 12 | 0          | 1.4 months  | 8.3 months  |
| Sunitinib                                                                                             | Thymoma = 16          | 1          | 7.6 months  | Not reached |
| (unpublished)                                                                                         | Thymic carcinoma = 22 | 5          | 6.7 months  | 12.6 months |
| * Only 3 of 18 patients with thymoma and 14 of 33 thymic carcinoma had received previous chemotherapy |                       |            |             |             |
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2.2 sunitinib malate

Sunitinib malate (sunitinib; SU11248; SU011248; Sutent®) is an oral, multi-targeted, small molecule inhibitor of the receptor tyrosine kinases (RTKs) involved in tumor proliferation and angiogenesis, including vascular endothelial growth factor receptor-1 (VEGFR-1), -2, and -3, platelet-derived growth factor receptor (PDGFR) -α and -β, stem cell factor receptor (KIT), the tyrosine kinase (TK) receptor encoded by the ret proto-oncogene (RET; rearranged during transfection), fms-like tyrosine kinase 3 (Flt3), basic fibroblast growth factor (bFGF) and colonystimulating factor (CSF)-1R. 30-34 Sunitinib selectively and potently inhibits the class III and
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class v split-domain rtks.30

Sunitinib shows significant antitumor and anti-angiogenic activity in a number of human tumor xenograft and angiogenesis models in mice as well as in phase 1 and 2 studies in patients with a variety of tumor types.31,32 As of October 2009, a total of 9914 subjects with solid malignant tumors have received sunitinib, including patients with renal cell carcinoma (RCC) and those with gastrointestinal stromal tumors (GIST) (Investigator's Brochure, 2011). In phase 2 studies in cytokine-refractory metastatic RCC, sunitinib produced objective responses in 40% of patients with a median time-to-tumor- progression (TTP) of 8.7 months. 33 In phase 3 studies of patients with imatinib-resistant GIST, sunitinib was highly superior to placebo (p<0.0001) with respect to median TTP (27.3 weeks vs. 6.4 weeks), progression-free survival (PFS), and overall survival
(OS).34 Sunitinib was granted regular approval on January 26, 2006 by Food and Drug Administration (FDA) for the treatment of gastrointestinal stromal tumor (GIST) after disease progression on or intolerant to imatinib mesylate and accelerated approval for advanced RCC, which was changed to regular approval on February 2, 2007.35-37
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2.2.1 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 TK activity have been identified on human vascular endothelium; VEGFR-1/Flt-1 and VEGFR-2/kinase insert domain-containing receptor (KDR). Although the relative contributions of KDR and Flt-1 signaling in mediating tumor progression have not been 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.31,38 Sunitinib also exerts direct antitumor activity on cells that express target RTKs associated with tumor cell proliferation, such as KIT, PDGFR, and RET. The clinical activity of sunitinib in patients with advanced GIST is an example of this antitumor effect. 2.2.2 Nonclinical Specificity and Efficacy Studies In vitro studies have demonstrated the specificity of sunitinib for inhibition of the Class 3 and Class 5 RTKs, including receptors for VEGF (VEGFR), KIT, Flt-3, and PDGFR (Investigator's Brochure, 2011). 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*.  
39 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).30 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), nonsmall cell lung cancer (H460), breast cancer (MDA-MB-435), melanoma (A375), epidermoid cancer (A431), and glioma (SF763T).30 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).40 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.39 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.40 Moreover, the combination therapies each led to a significantly increased survival compared to either single agent alone. 40 Significantly delayed tumor growth has also been demonstrated in combination studies of sunitinib and cisplatin in NCI-H526 SCLC xenografts.39 2.2.3 Nonclinical Toxicology Studies Single- and multiple-dose toxicology studies were conducted in mice, rats, rabbits, dogs, and monkeys (Investigator's Brochure, 2011). 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 cTnI 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, noncompensated 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*. 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. 2.2.4 Nonclinical Pharmacokinetics Single-dose pharmacokinetics (PK) was evaluated in mice, rats, rabbits, dogs, and monkeys at oral doses of 20, 40, 80, and 160 mg/kg, respectively (Investigator's Brochure, 2011). At these doses, the respective Tmax values in mice were 3, 3, 0.5, and 6 hours, while maximum plasma concentration (Cmax) values were 420, 708, 877, and 1670 ng/mL, respectively. In monkeys, t1/2α, t1/2β, and t1/2γ were 4, 14.9, and 252 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. 2.2.5 Clinical Experience As of October 2009, 10186 subjects had received at least one dose of sunitinib in 84 completed or ongoing clinical studies, (Investigator's Brochure, 2011). In phase 1 studies, sunitinib demonstrated single-agent activity in patients with RCC, GIST, non-GIST sarcomas, non-small cell lung cancer (NSCLC), colorectal cancer, neuroendocrine tumors (NET), melanoma, prostate cancer, and thyroid cancer. Sunitinib has also been studied in the phase 1 setting in patients with acute myeloid leukemia (AML). Sunitinib is approved for use in previously untreated patients with advanced RCC, imatinib-refractory gastrointestinal stromal tumors GIST and unresectable, locally advanced, or metastatic progressive well-differentiated pancreatic neuroendocrine tumors (pNET).  
2.2.5.1 Phase 1 Experience 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).41 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.42 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.43,44 O'Farrell and colleagues 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,45 pemetrexed,46 docetaxel,47 gemcitabine,48 carboplatin/paclitaxel,49 and metronomic cyclophosphamide/ methotrexate50 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. Phase 1 trials evaluating the combination of sunitinib with other targeted agents like temsirolimus, 51 bevacizumab52 and IFN- α53 have shown problems with increased toxicity in patients with RCC.54 2.2.5.2 Phase 2 and 3 Experience Updated results have recently been published on 750 patients with MRCC treated on a phase 3 study of sunitinib at a daily dose of 50 mg on the 4/2 schedule compared to interferon (IFN)-α 9 MU subcutaneously thrice weekly.55 Median overall survival (OS) was greater in the sunitinib group than in the IFN-α group (26.4 vs. 21.8 months, respectively). Sunitinib treatment was associated with a higher objective response rate (RR) than IFN-α (47% vs. 12%, respectively). Eleven patients in the sunitinib group and four patients in the IFN-α group achieved a complete response per investigator assessment. Median progression-free survival (PFS) was 11 months for sunitinib compared with 5 months for IFN-α. The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and handfoot syndrome (9%). An exploratory analysis, which censored 25 patients from the IFN-α group who had crossed over to receive sunitinib on study, showed a median OS time of 26.4 months for sunitinib compared with 20 months for the IFN-α group. Results from a phase 1/2 dose-finding trial of sunitinib plus gefitinib, enrolling 42 patients, have been published.56 In phase 1, patients received sunitinib 37.5 or 50 mg on the 4/2 schedule plus gefitinib 250 mg, both once daily. The MTD was determined to be 37.5 mg. Two DLTs were observed with the 50 mg dose: grade 2 left ventricular ejection fraction decline and grade 3 fatigue. In phase 2, patients received sunitinib at the MTD plus gefitinib. Thirteen patients treated at the MTD achieved a partial response and 12 had stable disease. Median PFS was 11 months. The most commonly reported grade 3/4 adverse event was diarrhea. The promising results in phase 1 trials and the involvement of KIT and PDGFR-α, two of the sunitinib target RTKs in GIST led investigators to undertake a phase 1/2 trial in patients with GIST refractory or intolerant to imatinib to determine an appropriate dose and regimen for phase 2 development of sunitinib in this disease. Patients received up to 75 mg sunitinib daily on the 2/2, 4/2, or 2/1 schedule, with 50 mg daily on the 4/2 schedule being selected for continued study. In all, 75 patients were treated on the trial. Among 41 patients treated for at least 6 months, 6 had an objective response (OR; RECIST criteria) and an additional 16 had cessation of disease progression and minor responses for >6 months. Overall, 54% of the 41 patients had evidence of clinical benefit (OR or PFS). Determination of the GIST genotype in these 41 patients showed that clinical benefit had been achieved in several secondary mutational variants that conferred imatinib resistance.57 Fifty-three of the GIST patients treated on this trial subsequently underwent serial 18FDG-PET imaging where qualitative responses were graded as good in 33/53 patients, mixed in 15/53, and poor in 5/53.58 Correlation with clinical response (Fisher's exact p=0.03) showed that 22 of 33 patients graded as good by 18FDG-PET imaging had clinical benefit (OR or SD ≥ 6 months) after 6 months of therapy while 4 of 15 patients graded as mixed had benefit as did 2 of 5 patients graded as poor. Data from a pivotal multinational, randomized (2:1), double-blind, placebo-controlled phase 3 trial in over 300 patients with imatinib-resistant GIST has shown significant clinical effect with sunitinib compared with placebo.59 Patients on the active treatment arm received sunitinib at a dose of 50 mg daily on the 4/2 schedule. The median TTP for the treatment arm (n=207) was 27.3 weeks compared to a median of 6.4 weeks for placebo (n=105) (p<0.0001). Therapy was reasonably well tolerated; the most common adverse events were fatigue, diarrhea, skin discoloration and nausea.  
In addition to patients with RCC and GIST, sunitinib has been evaluated in breast cancer,60 NSCLC,61transitional cell carcinoma (TCC),62 NET 63, thyroid carcinoma,64 certain subtypes of sarcoma,65 gastro-eosophageal cancer,66 high-grade glioma ,67 squamous cell carcinoma of the head and neck (SCCHN),68 hepatocellular carcinoma (HCC) (Zhu *et al.*, 2008),69 colorectal carcinoma (CRC)70 and uveal melanoma .71
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2.2.5.3 safety profile

Sunitinib is reasonably well tolerated, with asthenia, hypertension, dermatitis, and mild myelosuppression as the most common AEs.72 Additionally, the inhibition of TK receptors by agents such as sunitinib can result in cutaneous AEs such as acral erythema, subungal splinter hemorrhages, modification of hair and skin pigmentation, mucositis, and (occasionally)
periocular edema.73,74 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) (Rosenbaum *et al*.,
2008).  
Cardiotoxicity, including congestive heart failure (3%-8%) and left ventricular dysfunction
(12%-14%), has been reported in patients undergoing treatment with sunitinib.75-78 More subjects treated with sunitinib experienced decline in left ventricular ejection fraction (LVEF) than subjects receiving either placebo or IFN-α (Investigator's Brochure, 2011). In a phase 3 GIST study in subjects with imatinib-resistant or -intolerant GIST, 22 of 209 (11%) subjects on sunitinib and 3 of 102 (3%) subjects on placebo had treatment-emergent LVEF values below the lower limit of normal (LLN). In a phase 3 study treatment-naive RCC patients, 27% and 15% of subjects on sunitinib and IFN-α, respectively, had an LVEF value below the LLN. Among 461 patients enrolled in CDUS-monitored trials with sunitinib alone, 2% of patients experienced left ventricular systolic dysfunction (CDUS data). It is unknown whether patients with concurrent cardiac conditions may be at a higher risk for developing drug-related LVEF. Baseline and periodic evaluations of LVEF should be considered while these patients are on sunitinib treatment. In patients without cardiac risk factors, a baseline evaluation of LVEF should be considered. Sunitinib has been shown to prolong the QT interval in a dose-dependent manner, which may lead to an increased risk for **ventricular arrhythmias,** including Torsade de Pointes. This condition has been reported in <0.1% of sunitinib-exposed patients. The DCTD, NCI, issued an IND AE Action Letter to all investigators using sunitinib describing the occurrence of QTc prolongation and Torsade de pointes (ventricular tachycardia) in patients on clinical trials utilizing sunitinib. As a result of this Action Letter, DCTD, NCI-sponsored sunitinib protocols were amended to include the requirement for a baseline EKG prior to study treatment, exclude patients with histories of serious ventricular arrhythmias or prolonged QTc, and exclude patients with certain cardiac conditions.  
Among 8832 solid tumor subjects treated with single-agent sunitinib, Grade 3 **hypertension** was reported in 6.8% of patients and was one of the most commonly reported Grade 3 AEs. Of subjects receiving sunitinib for treatment-naive MRCC, 34% receiving sunitinib experienced hypertension, compared with 4% on IFN-α. Grade 3 hypertension was reported in 13% of treatment-naive metastatic RCC subjects on sunitinib compared to <1% on IFN-α. Severe hypertension occurred in 4% GIST subjects on sunitinib, 1% GIST subjects on placebo, 9% RCC subjects on sunitinib and 1% RCC subjects on IFN-α (Investigator's Brochure, 2011). Among 516 patients enrolled in CDUS-monitored trials with sunitinib alone, 33.9% experienced hypertension (CDUS data).  
In subjects receiving sunitinib for treatment-naive MRCC, 37% had **bleeding events** compared with 8% receiving IFN-α (Investigator's Brochure, 2011). Bleeding events occurred in 18% of patients receiving sunitinib in the double-blind treatment phase of the GIST phase 3 study, compared with 17% receiving placebo. Among 516 patients enrolled in CDUS-monitored trials with sunitinib alone or in combination with other agents, there were 123 reported bleeding events
(CDUS data). Epistaxis was the most common hemorrhagic AE reported. Tumor-related hemorrhage can occur with sunitinib and in the case of pulmonary tumors, may present as severe and life-threatening hemoptysis or pulmonary hemorrhage.  
Hypothyroidism has been reported in 71% patients with RCC and in 36% of those with GIST
treated with sunitinib.79 Among 8832 subjects with solid tumors treated with single-agent sunitinib as of October 2009, 978 (11.1%) experienced treatment-emergent hypothyroidism. Among subjects treated with single-agent sunitinib, hyperthyroidism was reported in 0.7% and thyroiditis in 0.1% (Investigator's Brochure, 2011). Baseline measurement of thyroid function is recommended, and patients with thyroid dysfunction should be treated appropriately prior to starting sunitinib therapy.  
Nonclinical evidence of **adrenal toxicity** following sunitinib exposure led the company to perform specialized safety assessments in clinical studies, including computed tomography or MRI in 336 subjects to specifically identify any change in adrenal gland structure or the presence of adrenal gland hemorrhage (Investigator's Brochure, 2011). Neither event was observed. Adrenocorticotropic hormone (ACTH) stimulation testing was done in 400 patients across multiple sunitinib trials. One subject developed consistently abnormal test results during treatment that were unexplained and may be related to sunitinib treatment. Eleven additional subjects had abnormalities in the final test, with low peak cortisol levels. None of these patients had clinical evidence of adrenal insufficiency. However, based on the nonclinical findings, patients receiving sunitinib should be clinically followed for signs and symptoms of adrenal insufficiency, especially in (1) patients with comorbidities associated with adrenal dysfunction, (2) patients with preexisting adrenal insufficiency (primary or secondary), and (3) patients with concomitant stress (e.g., fever, infection, bleeding, serious accident, surgery) that may precipitate overt adrenal insufficiency in the presence of subclinical sunitinib-induced adrenal toxicity. Diarrhea, nausea, abdominal pain, vomiting, constipation and dyspepsia are some of the most frequent AEs reported with sunitinib (Investigator's Brochure, 2011). Serum chemistries including phosphate should be performed at the beginning of each treatment cycle. Supportive care may include anti-emetic premedication, supportive oral care products, and analgesics. Serious complications due to degeneration or shrinkage of tumors, including gastrointestinal perforation and tracheoesophageal fistula, have occurred rarely in patients with abdominal, head and neck, thyroid, and other malignancies treated with sunitinib, believed to be the result of the antitumor effect of sunitinib. Other serious effects include thromboembolic events, rare reversible posterior leukoencephalopathy syndrome (RPLS), proteinuria with rare nephrotic syndrome, and rare microangiopathic hemolytic anemia.
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alternative dosing schedules

Due to the toxicity associated with the standard dosing (50 mg per day for 4 weeks followed by a 2-week break) alternative dosing schedules have been explored. Superior tolerability has been demonstrated with a 2-weeks on and 1-week off schedule in patients with metastatic renal carcinoma. 80,81 2.2.5.4 Clinical Pharmacokinetics Orally-administered sunitinib is well absorbed in humans, with linear pharmacokinetics (PK) at doses of 50-150 mg/day. Metabolism of sunitinib occurs primarily through the cytochrome P450 3A4 (CYP3A4) to N-deethyl sunitinib to form the metabolite SU012662. SU012662 undergoes further metabolism to an inactive metabolite SU014335. SU012662 is also catalyzed primarily by CYP3A4, but at a much slower rate than the N-deethylation of sunitinib in human liver microsomes (Investigator's Brochure, 2011). There are no studies done to date that directly evaluate the effect of dexamethasone, a weak CYP3A4 inducer, on sunitinib. Studies done by Pfizer on the effects of coadministration of rifampin, a potent CYP3A4 inducer, resulted in a 23% and 46% reduction in Cmax and AUC0-∞ values, respectively (Investigator's Brochure, 2011). Metabolism of sunitinib administration with food does not significantly affect the bioavailability of sunitinib. The PK of sunitinib was studied in a variety of company-sponsored studies in both healthy volunteers (n=135) and in patients with solid tumors (n=266), including GIST and metastatic RCC; the PK was similar in the volunteers and in those with solid tumors. Terminal half-lives
(t1/2) of sunitinib and SU012662 are 40-60 hours and 80-110 hours, respectively, with a time to maximum concentration (Tmax) of 6-12 hours for sunitinib and its primary active metabolite, followed by a biexponential decline in concentrations. The PK of sunitinib and SU012662 were measured in a phase 1 dose-escalation study in patients with advanced solid malignancies.82 Twenty-eight patients received doses ranging from 15 mg/m2 to 59 mg/m2 (ranging from 50 mg every other day to 150 mg/day), on a 4 weeks on, 2 weeks off (4/2) schedule. Concentrationversus-time data were analyzed using a noncompartmental analytic technique. Overall, sunitinib displayed a long half-life and a large volume of distribution with moderate interpatient variability. Trough plasma concentrations of sunitinib and SU012662 increased with increasing doses. However, AUC values increased less than proportionally with dose. Accumulation ratios of sunitinib were >1, with detectable trough drug levels, suggesting drug accumulation over time.  
At the recommended dose, Cmax occurred approximately 5 hours after administration and t1/2 ranged from 41-86 hours. Doses of 50 mg daily led to plasma concentrations ranging from 50100 ng/mL. Most patients with DLTs had combined (sunitinib plus SU012662) trough plasma concentrations ≥100 ng/mL.82 PK values determined from body surface area (BSA)-based doses were adjusted to reflect fixed doses of 50, 75-100, and 100-150 mg doses to determine if there was a need for BSA-based dosing to be employed. AUC sum values obtained using BSA-normalized and fixed dosing were found to be comparable, suggesting that normalizing the dose based on BSA would not improve variability. Therefore, fixed dosing on a milligram basis was considered appropriate for phase 2 studies.82 To determine the effect of food on the PK of sunitinib and its active metabolite SU012662, 16 healthy subjects received a single dose of sunitinib 50 mg under fasting conditions and 14 subjects received a single dose of sunitinib 50 mg under fed conditions.83 Subjects were randomized to one of two treatment sequences each comprising two treatment periods (fasted and fed). In Sequence 1, the fasted treatment period was followed by the fed treatment period, and for Sequence 2, the fasted period followed the fed period. For the fasted period, a single oral
(PO) dose of sunitinib 50 mg was administered after a 10-hour fast. For the fed period, a single PO dose of sunitinib 50 mg was administered within 30 minutes of a high-fat, high-calorie meal. A washout period of at least 4 weeks separated sunitinib dosing between the two treatment periods. Two subjects in Sequence 1 discontinued prematurely due to grade 1 and 2 rash, but PK
information was collected and included in the analysis. Only a negligible difference in Tmax of sunitinib was observed between fed and fasted treatment periods; SU012662 Tmax was prolonged by 2 hours (median difference) in the fed compared with the fasted state. The 90% confidence intervals (CIs) for Cmax and AUC were within the 80-125% bioequivalence range, indicating the absence of food effect. Sunitinib exposure increased slightly in the fed compared with the fasted state (ratios of fed/fasted geometric least square means: Cmax 104%, AUC0-last and AUC0-∞ both 112%). There was a delay in the formation/absorption of the active metabolite SU012662 in the fed state (mean Cmax decreased 23%), but exposure remained unaffected (90% CIs for AUC 0-last and AUC0-∞ were within 80-125%). Sunitinib and SU012662 half-lives, and oral clearance of sunitinib, were not affected by food.83 A study of sunitinib PK in patients with AML indicated that a plasma concentration of 50-100 ng/mL of combined sunitinib and SU012662 could be achieved on the first cycle of a 50 mg/day 4/2 regimen, similar to that achieved in studies with patients having other tumor types.43 In a phase 1 trial of sunitinib given on the 4/2 schedule in pediatric patients with relapsed or refractory solid tumors, the median day 21 steady-state trough sunitinib plasma concentration was 24.6 ng/mL (range, 6.0-37.7 ng/mL) at the 15 mg/m2 dose and 37.4 (range, 24.2-62.9 ng/mL) at the 20 mg/m2 dose.84 Population PK methods indicated that the covariates of weight, gender, race, ethnicity, ECOG score, and tumor type had no clinically significant effects on drug exposure, and that adjustments of starting doses based on these covariates were not required (Investigator's Brochure, 2011). Concurrent administration of a single dose of sunitinib with ketoconazole (a CYP3A4 inhibitor) in healthy volunteers resulted in 49% and 51% increases in the combined (sunitinib +
SU012662) Cmax and AUC0-∞ values, respectively, compared with sunitinib alone.85 Concurrent administration of sunitinib and rifampin (a potent CYP3A4 inducer) in healthy subjects resulted in 23% and 46% reduction in combined Cmax and AUC0-∞, respectively, compared with sunitinib alone (Bello *et al*., 2005).86 Thus, dose adjustments for sunitinib should be considered when coadministered with CYP3A4 inhibitors and inducers.
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2.3 rationale

Molecular pathways and potential therapeutic targets in thymic malignancies are not well understood largely due to the rarity of the tumor, controversies about histopathologic classification, and the lack of established cell lines and animal models. Based on existing body of knowledge, some of the main targets of sunitinib including VEGFR-1, -2, and -3, KIT and PDGFR play key roles in the pathogenesis of thymic malignancies. Moreover, inhibition of these targets has led to clinical responses in anecdotal reports and case series. 2.3.1 Angiogenesis in thymic malignancies Neovascularization is crucial for tumor growth beyond 1–2 mm3 and for the switch from local vascular supply to novel microcapillary formation enabling progression and metastasis of cancer. It is also a crucial prognostic factor in many cancers, frequently correlating with tumour progression, disease severity and potential for metastasis.87,88 2.3.1.1 The role of VEGF/VEGFR family The VEGF receptor family includes VEGFR1 (Flt-1), VEGFR2 (Flk-1/KDR, Fetal liver kinase1/kinase domain-containing receptor), and VEGFR3 (Flt-4). VEGF, a mitogen specific for vascular endothelial cells, is one of the most potent pro-angiogenic molecules. VEGF-related angiogenic signal is mediated by intracellular tyrosine kinases and leads to angiogenesis, cell migration, proliferation, and survival. Angiogenesis plays an important role in the pathogenesis of thymic malignancies. Microvessel density and VEGF expression correlate with tumor invasion and clinical stage thymic epithelial tumors. Higher expression of angiogenesis markers is seen in invasive thymomas and thymic carcinomas as compared to non-invasive thymomas.89 Elevated serum VEGF and b-FGF levels are also seen in patients with thymic carcinoma.90 2.3.1.2 The role of PDGF/PDGFR family The PDGF/PDGFR family plays a supporting role in angiogenesis.91 The PDGFR family includes the colony stimulating factor-1 receptor (CSF-1R), Flt-3 (Fms-like tyrosyl kinase-3), Kit (the stem cell factor receptor), and the platelet-derived growth factor receptors (PDFGR-α and PDFGR-β). PDGF through PDGFR tyrosine kinases functions as a potent mitogen in mesenchymal and glial cells. During carcinogenesis, PDGF receptor is frequently activated through over-expression of the ligand and its receptor. KIT is a transmembrane receptor with tyrosine kinase activity encoded by the proto-oncogene *c-KIT*, which plays a major role in the development and maintenance of GISTs. KIT expression does not predict the presence and/or type of the *c-KIT* mutation, but its expression in GISTs has been associated with *c-KIT* activating mutations that mainly occur in exons 9 (extracellular domain), 11 (juxtamembrane domain), 13 (first kinase domain), and 17 (activation loop). These mutations lead to the constitutive activation of the KIT kinase. Imatinib mesylate, an oral KIT tyrosine kinase inhibitor, leads to rapid, substantial, and durable tumor responses in GIST, mainly in the form of stable disease or a partial response. Furthermore, the presence of the exon 11 *c-KIT* mutation seems to be the strongest predictor of a response in patients with GISTs. Imatinib resistance, which may result from secondary KIT mutations, may be overcome with sunitinib, which is approved for use in disease progression on imatinib. In thymic malignancies, KIT overexpression, as determined by immunohistochemistry has been reported in 23% of cases, with a higher frequency in thymic carcinomas (79%) especially of the squamous cell subtype (75-100%).92,93 However, KIT mutations are found only in 5% to 10% of thymic malignancies and have been found exclusively in thymic carcinoma.94-96 The known KIT
mutations in thymic carcinoma are listed in Table 4. The published mutations are located in exon 11, exon 14, and exon17.93 V560del and H697Y mutations were associated *in vitro* with imatinib sensitivity with H697Y mutant cells exhibiting greater sensitivity to sunitinib than imatinib.94 However, presence of KIT mutations may not be essential for sunitinib activity as demonstrated by responses of tumors with wild-type KIT.  
97 PDGF and PDGFR-α were also overexpressed in epithelial cells of thymoma, with increased intensity of staining in WHO types B2 and B3.98  
| Table 4: Known Kit mutations in thymic carcinoma Location Mutations Exon 11 V560, L576P, P577-D579del, Y533N Exon 14 H697Y Exon 17 D820E   |
|--------------------------------------------------------------------------------------------------------------------------------------------|  
2.3.2 Clinical studies Strobel and colleagues have described a series of 4 patients with refractory thymic carcinoma who were treated with variable schedules of sunitinib.97 Three patients achieved a partial response and one achieved disease stabilization. On phosphoprotein arrays, these tumors showed simultaneous activation of several receptor tyrosine kinases, including the EGFR, TYRO3, insulin receptor, and insulin-like growth factor-1 receptor (IGF1R). All three patients who responded had the squamous cell subtype of thymic carcinoma and none of them had c-*KIT*
mutations.97 SU14813 is a multi-kinase inhibitor with a profile very similar to sunitinib (blocks VEGFR 1, 2, and 3, PDGFR-A and -B, KIT and FLT3 at nanomolar concentrations).99 In a phase I, open-label, dose-escalation study, SU14813 was evaluated in 77 patients who received it either in a 4/1 (4 weeks of treatment followed by 1 week off) or continuous schedule. Two patients out of the 4 with malignant thymoma had partial responses (PFS 15.3 and 9.0 months).99 Unfortunately the development of this agent has been discontinued by the sponsor. Sunitinib and SU14813 differ in their pharmacokinetic properties: Sunitinib is more slowly absorbed, and eliminated, hence achieves steady state concentrations in 2 weeks while SU14813 attains steady state after 8 days of administration.99 As of Amendment E (version date 05/12/14): Group 1 results obtained from protocol 12-C-0118 so far in patients with recurrent thymic carcinoma have shown an objective response rate of 23% and disease control rate of 91% with sunitinib which is unprecedented for this histology. However, treatment at a dose of 50 mg once daily for four weeks followed by 2 weeks off was poorly tolerated. Twenty five out of 41 patients need dose reductions due to development of intolerable adverse events. Of the five partial responses seen in patients with thymic carcinoma (**Table 5**,
Thomas et al), two were seen at dose level one (50 mg daily) and three were seen despite dose reductions (37.5 mg and 25 mg daily for 4 weeks followed by two weeks off). Due to these promising results, we will evaluate the role of sunitinib further in patients with thymic carcinoma at an initial dose of 50 mg daily for 2 weeks followed by 1 week off to confirm the response rate and determine if the reduced dose of sunitinib is tolerated better (Group 2). Additionally, Group 1 results obtained from protocol 12-C-0118 have shown that among patients with thymoma only 1 partial response was observed in 16 treated patients (Table 5.) This is lower than the pre-specified statistical endpoint of 2 or more responses among the first 16 patients with thymoma. Hence, accrual for this cohort was stopped after the completion of the first stage and enrollment did not proceed to the accrual goal of 25 for the second stage in the thymoma cohort. In view of this lack of activity in patients with thymoma, we do not propose to evaluate further the activity of sunitinib for this histology. Hence, a thymoma cohort is not included in Group 2 of Amendment E. Table 5 summarizes the reports of clinical activity of anti-angiogenic agents in thymic malignancies.97,100-108 As noted by Girard N, despite the large tumor burden of thymic tumors and the frequent abutment of mediastinal vascular structures, no hemorrhagic side effects have been reported with the use of anti-angiogenic drugs in thymic malignancies.109  
| Table 5: Reports of clinical activity of anti-angiogenic agents in thymic malignancies Author   |                           |             |          |     |           |               |
|-------------------------------------------------------------------------------------------------|---------------------------|-------------|----------|-----|-----------|---------------|
| Drug                                                                                            | (year of                  |             |          |     |           |               |
| publication)                                                                                    | Number  of  patients      | Hist olog y |          |     |           |               |
| Dose/                                                                                           |                           |             |          |     |           |               |
| Schedule                                                                                        | Prior systemic  treatment | Response    | Comments |     |           |               |
| Azad A et al                                                                                    | 1                         | 75 mg BID/  | THY      | PAC | 28% tumor | PFS 12 months |
| 23                                                                                              |                           |             |          |     |           |               |  
| Version Date: 04/30/2020                                                                                                                                                   |                                                        |                            |                                |                            |                                |                                                                                          |                                       |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------|----------------------------|--------------------------------|----------------------------|--------------------------------|------------------------------------------------------------------------------------------|---------------------------------------|
| Motesanib                                                                                                                                                                  | (2009)                                                 | 2 weeks on  and 1week  off | ChlVPP                         | shrinkage after  17 cycles |                                |                                                                                          |                                       |
| Rosen LS et  al (2007)                                                                                                                                                     | 1                                                      | NR                         | THY                            | NR                         | SD for 8  months               |                                                                                          |                                       |
| Bedano PM  et al (2008)  [Abstract]                                                                                                                                        | 15 mg/kg IV  q 3 weeks+  150 mg q  day                 | THY  (11) TC  (7)          |                                |                            |                                |                                                                                          |                                       |
| Bevacizumab  + Erlotinib                                                                                                                                                   | NR                                                     | 11 patients had  SD        |                                |                            |                                |                                                                                          |                                       |
| 18                                                                                                                                                                         |                                                        |                            |                                |                            |                                |                                                                                          |                                       |
| Isambert N et  al (2008)  [Abstract]                                                                                                                                       |                                                        |                            |                                |                            |                                |                                                                                          |                                       |
| Aflibercept+  docetaxel                                                                                                                                                    | 1                                                      | NR                         | THY                            | NR                         | PR                             | Patient also had  CML and was in  lymphoid blast  crisis. Tumor c-Kit  staining negative |                                       |
| 1                                                                                                                                                                          | 140 mg                                                 | THY  B2                    | None                           | PR                         |                                |                                                                                          |                                       |
| daily                                                                                                                                                                      |                                                        |                            |                                |                            |                                |                                                                                          |                                       |
| Dasatinib                                                                                                                                                                  | Chuah C et al  (2006)                                  | 50 mg daily continuous     | TC                             | chemotherapy               | SD                             | OS 40 months                                                                             |                                       |
| 50 mg 4/2;  later 4/4,4/6  and 4/8  schedule                                                                                                                               | TC                                                     | chemotherapy               | PR                             | PFS 18 months              |                                |                                                                                          |                                       |
| 4                                                                                                                                                                          |                                                        |                            |                                |                            |                                |                                                                                          |                                       |
| Ströbel P et al  (2010)                                                                                                                                                    | 37.5 mg  daily                                         | TC                         | No                             |                            |                                |                                                                                          |                                       |
| chemotherapy                                                                                                                                                               | PR                                                     | PFS 14 months              |                                |                            |                                |                                                                                          |                                       |
| 50 mg daily 4/2 schedule                                                                                                                                                   | TC                                                     | chemotherapy               | PR                             | OS 4 months                |                                |                                                                                          |                                       |
| Sunitinib                                                                                                                                                                  | Chemotherapy                                           |                            |                                |                            |                                |                                                                                          |                                       |
| THY                                                                                                                                                                        | PR=1: SD=12                                            | PFS 7.6 mo; OS not         |                                |                            |                                |                                                                                          |                                       |
| (median prior                                                                                                                                                              |                                                        |                            |                                |                            |                                |                                                                                          |                                       |
| (16)                                                                                                                                                                       | reached                                                |                            |                                |                            |                                |                                                                                          |                                       |
| chemo = 2)                                                                                                                                                                 |                                                        |                            |                                |                            |                                |                                                                                          |                                       |
| Thomas A et al                                                                                                                                                             | 38                                                     | 50 mg daily                |                                |                            |                                |                                                                                          |                                       |
| (2013)                                                                                                                                                                     | 4/2 schedule                                           |                            |                                |                            |                                |                                                                                          |                                       |
| [Abstract]                                                                                                                                                                 | Chemotherapy                                           |                            |                                |                            |                                |                                                                                          |                                       |
| TC                                                                                                                                                                         | (median prior                                          | PR=5; SD=15                | PFS 6.7 mo; OS 12.6  mo        |                            |                                |                                                                                          |                                       |
| (22)                                                                                                                                                                       | chemo = 2)                                             |                            |                                |                            |                                |                                                                                          |                                       |
| SU14813                                                                                                                                                                    | W. Fiedler et  al (2010)                               | 2                          | 4/1 schedule                   | THY                        | NR                             | PR                                                                                       | PFS 15.3 and 9.0  months PFS 9 months |
| 1                                                                                                                                                                          | 400 mg  daily                                          | TC                         | ADOC                           | SD                         | c-KIT exon 11                  |                                                                                          |                                       |
| mutation (Y553N)                                                                                                                                                           |                                                        |                            |                                |                            |                                |                                                                                          |                                       |
| Imatinib                                                                                                                                                                   | Buti S et al (2011)                                    | Surgery PEI IA octreotide  | PR after 8  weeks;  maintained |                            |                                |                                                                                          |                                       |
| after 15 months                                                                                                                                                            | c-kit exon 17                                          |                            |                                |                            |                                |                                                                                          |                                       |
| (D820E) mutation                                                                                                                                                           |                                                        |                            |                                |                            |                                |                                                                                          |                                       |
| Bisagni G et                                                                                                                                                               | 1                                                      | 200 mg BID                 | TC                             |                            |                                |                                                                                          |                                       |
| al (2009)                                                                                                                                                                  | CDC CEIO CEP                                           |                            |                                |                            |                                |                                                                                          |                                       |
| Paclitaxel                                                                                                                                                                 | PFS 9 months; Tumor c-Kit and  VEGF staining  positive |                            |                                |                            |                                |                                                                                          |                                       |
| Sorafenib                                                                                                                                                                  | 1                                                      | Sorafenib                  | TC                             | SD                         |                                |                                                                                          |                                       |
| Li X et al  (2008)                                                                                                                                                         | PFS 6 months                                           |                            |                                |                            |                                |                                                                                          |                                       |
| 1                                                                                                                                                                          | Sorafenib                                              | TC                         | ADOC                           | PR                         | c-KIT exon 9  deletion present |                                                                                          |                                       |
| Abbreviations used: PAC: cisplatin, doxorubicin, cyclophosphamide; ChlVPP: chlorambucil, vinblastine, procarbazine and prednisolone; THY: Thymoma; Diel U et al  (2011) 24 |                                                        |                            |                                |                            |                                |                                                                                          |                                       |  
TC: Thymic carcinoma; NR: not reported; SD: stable disease; PR: partial response; EPI: cisplatin, etoposide, ifosfamide IA: ifosfamide, doxorubicin; CDC: cisplatin, doxorubicin, and cyclophosphamide; CEIO: cisplatin, ifosfamide, endostar, oxaliplatin; CEP: cisplatin, etoposide, pirarubicin; CML: chronic myeloid leukemia; ADOC: Cisplatin (CDDP), doxorubicin, vincristine, cyclophosphamide
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2.4 exploratory studies background

Cell-surface receptors and several pro- and anti-angiogenic factors mediate the complex process of angiogenesis, which results in the formation of new vasculature.110 As discussed earlier, there is considerable evidence associating angiogenesis with tumor growth and metastasis. However, the clinical development of antiangiogenic agents in many other malignancies has been hampered by the lack of objective measures of pharmacological response to these drugs. For example, in NSCLC, although several potential angiogenic biomarkers (e.g. microvessel density, vascular endothelial growth factor, vascular endothelial growth factor receptors) have been extensively studied, and several more are under investigation, no clinically validated predictive marker of antiangiogenic therapy has been identified to date.111 Translational research associated with clinical studies of sunitinib has led to the identification of three main types of potentially promising biomarkers: circulating proteins related to angiogenesis, circulating endothelial cells and/or their stem-cell progenitors, and vascular imaging.112 In this study we propose to evaluate in an exploratory fashion the first two:
angiogenesis-associated circulating proteins on pre-dose plasma samples on days 1 and 28 of cycles 1 and 2 as well as at progression; circulating endothelial cells (CEC)/ circulating endothelial progenitor cells (CEP) on days 1 and 14 of cycle 1. Where tumor samples are available, intra-tumoral immune infiltrate and tumor molecular profiling will be performed prior to study entry and at disease progression.
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2.4.1 serum vegfr2 plgf il-4

Utility of cytokine and angiogenic factors has been assessed for several different VEGF pathway inhibitors in various malignancies. A consistent pharmacodynamic effect for VEGF, placental growth factor (PlGF), soluble VEGFR3 (sVEGFR3) and soluble VEGFR2 (sVEGFR2) was observed in patients with RCC, refractory breast cancer, or unresectable GIST or (neuroendocrine tumors) NET. Significant increases in mean plasma levels of VEGF and PlGF, as well as dose-dependent decreases in sVEGFR2 and sVEGFR3 levels were observed during sunitinib treatment compared with baseline. These changes returned to baseline levels off drug, and greater magnitudes of changes were observed in patients showing an objective response to sunitinib.  
113-115 The effects of sunitinib on soluble forms of target receptors, including sVEGFR2 may be a result of a direct decrease in the number of receptor-secreting cancer and endothelial cells associated with tumor-growth inhibition and/or indirect transcriptional inhibiting effects on components of VEGFR-associated signaling pathways. By contrast, the slight elevation of VEGF observed in several patients may result from an autocrine survival feedback loop trying to compensate for the reduced receptor availability.115 However, baseline levels of these soluble factors have not been shown to correlate with outcome, limiting the predictive ability of these markers to affect clinical practice. Further, prospective work on a larger number of patients is needed to delineate whether these factors represent only a marker of pharmacodynamic drug effect or have predictive potential.114 A potential mechanism for sunitinib resistance is the upregulation of alternative proteins and/or pathways that could drive tumor angiogenesis and/or growth independent of VEGF. Preclinical studies, involving RCC and non-RCC models, have identified a variety of candidate proteins that may be involved in resistance to VEGF therapy. Among these proteins which stimulate angiogenesis directly or indirectly are fibroblast growth factor (FGF), HGF (hepatocyte growth factor) and PlGF.114 For example, HGF promotes angiogenesis through upregulation of VEGF
and also via downregulating thrombospondin-1 expression. HGF/c-Met activation has been suggested as a potential alternate mechanism of angiogenesis in sunitinib resistant tumors.116 Angiogenesis-associated circulating proteins have not been systematically studied previously in thymic malignancies. Whether the changes found in other tumors would be applicable to thymic malignancies is not known. We propose to explore the potential utility of these proteins as biomarkers of pharmacological and clinical activity of antiangiogenic agents in thymic malignancies. These assays will be performed using sandwich ELISA or an electrochemiluminescent multiplexed sandwich immunoassay (Meso-Scale Discovery), in the Trepel laboratory, DTB, NCI. 2.4.2 Regulatory T cells (Tregs), exhausted CD8 T cells, myeloid-derived suppressor cells
(MDSCs), and Th1/Th2 T cell populations (Group 2 only)
The immune system plays a critical role not only during oncogenesis, but also during tumor progression and as established neoplastic lesions respond to therapy. Sunitinib has been shown to decrease the frequency of regulatory T cells (Tregs) and myeloid-derived suppressor cells
(MDSCs) in metastatic renal cell carcinoma patients117,118. It has been shown that development of sunitinib resistance is partly mediated by the survival of MDSCs, thereby providing sustained immune suppression and angiogenesis 119. Sunitinib has also been shown to shift T-helper cells toward a T helper 1 (Th1)-polarized response and decrease the Th1 cell/ T helper 2 (Th2) cell ratio. A significant decrease in the Th1/Th2 ratio was seen after sunitinib treatment in the PFS-short group in mRCC 117,120. Exhausted CD8+ T cells, which express inhibitory receptors PD-1 and Tim3, were found in cancer patients117,121. Recent clinical trials have validated that blockade of PDL1/PD-1 signaling is a meaningful immune therapeutic regimen 122,123. In a phase I/II trial of belinostat in combination with cisplatin, doxorubicin and cyclophosphamide in the first-line treatment of advanced or recurrent thymic epithelial tumors (NCT01621568), decline in Tim-3+ CD8+T cells with treatment was larger in patients who responded to treatment compared with those who did not (p=0.049) (manuscript in preparation), suggesting that exhausted CD8+ T cells may play an important role in the prognosis of patients with thymic carcinoma. Therefore, monitoring immune subsets in thymic carcinoma pre- and post-sunitinib therapy will contribute to understanding of the mechanism of sunitinib activity in thymic carcinoma and the potential survival advantage of improved immune response, and inform future studies of combination regimens with immune modulatory agents. 2.4.3 Circulating Endothelial Cells and Endothelial Progenitor Cells (both groups) CECs have emerged as a potentially useful marker to assess anti-angiogenic therapy. At least two distinct populations of CECs have been identified, bone marrow-derived CEP cells and mature CECs. CEP cells bear antigens that identify them as endothelial cells, such as VEGFR-2
(Flk-1) and CD31 (platelet/endothelial cell adhesion molecule-1), as well as antigens for stem cells, such as CD117 (c-kit ligand receptor), CD133, and CD34. Upon appropriate stimulation, bone marrow-derived endothelial progenitor cells migrate to the circulation, where they are referred to as CEP cells. CEP cells have been shown to infiltrate human tumors and give rise to tumor neovasculature.124,125 Mature CECs derive from mature vasculature. They are thought to enter circulation as a result of vascular injury. Though the exact role that CECs play in tumor neovascularization is heavily debated, some evidence supports the observations discussed below. Firstly, levels of CECs are increased in patients with cancers and are correlated with disease progression.126,127 Secondly, VEGF and expression of VEGFR-2 mobilize CECs in human models.128-130 Thirdly, treatment with VEGF pathway inhibitors can have different effects on mature CECs and CEP cells. Inhibitors inhibit bone marrow-derived CEP cells mobilized by VEGF and trigger an increase in mature CECs, reflecting an increase in sloughing of fragile mature endothelium from tumor vasculature.131-133 Limited data is available on CEP/CEC in RCC patients treated with sunitinib. Available data thus far have yielded conflicting results with regard to baseline CEP/CEC numbers or change in these parameters and clinical outcome.  
134,135 To explore the effects of sunitinib on CECs and CEP cells in patients with thymic malignancies, these will be assayed on pre-dose peripheral blood samples on days 1 and 14 of cycle 1. Two lavender top tubes of whole blood will be collected for CEC/CEP analysis, which will be performed by multi-parameter flow cytometry, in the Trepel laboratory, DTB, NCI. Cells will be analyzed for forward and side scatter, and a dump channel will be created to exclude cells expressing hematopoietic markers, such as CD45. Endothelial cells will be identified using co-expression markers, such as CD31, and CD146 for mature endothelial cells and CD133 for CEP cells. The cell populations will also be analyzed for viability using scatter profiles and a vital stain (e.g., Hoechst 33258). Multi-parameter flow analysis will be performed with a flow cytometer equipped with FlowJo software, using a minimum of 500,000 events per analysis.136-139 2.4.4 Intra-tumoral immune infiltrate Sunitinib has been shown in preclinical models and in patients to favorably alter the immune cell environment through promotion of a T-helper 1 phenotype, reduction in T-regulatory cells and reduction in myeloid derived suppressor cells.117,118,140,141 The contribution of these observations to the antitumor mechanism of sunitinib is unclear at present. Where fresh tissue is available, we propose to analyze immune subsets including but not limited to CD8, CD4, CD56, CD68 by multiparameric flow cytometry in the Trepel laboratory, DTB, NCI.
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3 patient selection 3.1 eligibility

3.1.1 Histological confirmation of thymoma (Group 1 only) or thymic carcinoma by the pathology department/CCR/NCI or the pathology department of participating institutions.  
3.1.2 At least one prior line of platinum-based chemotherapy or patient must have refused  
cytotoxic chemotherapy. Progressive disease must be documented prior to study entry.  
3.1.3 Patients must not have received chemotherapy, radiation therapy, or undergone major surgery within 4 weeks prior to enrollment.  
3.1.4 Patients must have measurable disease, per RECIST 1.1. See Section 12 for the evaluation of measurable disease.
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3.1.5 age >=18 years

3.1.6 ECOG performance status ≤2 (Karnofsky >50%, see Appendix A). 3.1.7 Life expectancy of greater than 3 months  
3.1.8 Patients must have normal organ and marrow function as defined below:  
− hemoglobin >9 g/dL  
− leukocytes >3,000/mcL − absolute neutrophil count >1,200/mcL  
− platelets >100,000/mcL  
− total bilirubin within normal institutional limits − serum calcium <12.0 mg/dL  
− AST(SGOT)/ALT(SGPT) <2.5 × institutional upper limit of normal*  
− creatinine within normal institutional limits  
OR  
− creatinine clearance >60 mL/min/1.73 m2 for patients with  
creatinine levels above institutional normal.  
− * If subjects have liver metastases, both ALT and AST must be <5 ×  
ULN.  
− Patients must have QTc < 500 msec  
3.1.9 PT or INR, and APTT ≤ 1.5 x upper limit of normal (ULN), unless the abnormality can be explained by the presence of lupus anticoagulant or if these values are in the therapeutic range for a patient on low molecular weight heparin.  
3.1.10 The following groups of patients are eligible provided they have New York Heart Association Class II (NYHA; see Appendix B) cardiac function on baseline ECHO/MUGA:
- those with a history of Class II heart failure who are asymptomatic on treatment
- those with prior anthracycline exposure those who have received central thoracic radiation that included the heart in the radiotherapy port. 3.1.11 Patients must have blood pressure (BP) no greater than 140 mmHg (systolic) and 90 mmHg (diastolic) for eligibility. Initiation or adjustment of BP medication is permitted prior to study entry provided that the average of three BP readings at a visit prior to enrollment is less than 140/90 mmHg.  
3.1.12 Absence of brain metastases as confirmed by imaging of the brain by MRI or CT brain with contrast performed at baseline screening.  
3.1.13 The effects of sunitinib on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because anti-angiogenic agents are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. All women of childbearing potential must have a negative pregnancy test prior to receiving sunitinib. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of sunitinib administration.  
3.1.14 Ability to understand and willingness to sign a written informed consent document.
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3.2 exclusion criteria

3.2.1 Patients with tumor amenable to potentially curative therapy. 3.2.2 Prior treatment within the past 6 months with sunitinib, sorafenib, bevacizumab or other multikinase inhibitors targeting any of the following: vascular endothelial growth factors 1–3 (VEGF1–3), FMS-like tyrosine kinase 3 (FLT3), stem cell growth factor (c-KIT), platelet-derived growth factors-α and -β (PDGF-α,-β), colony-stimulating factor 1
(CSF1), and the 'RET' receptor for glial-derived neurotrophic factors.  
3.2.3 Patients with symptomatic brain metastases will be excluded from trial secondary to poor prognosis. However, patients who have had treatment for their brain metastasis and whose brain disease has remained stable for 3 months without steroid therapy may be enrolled. 3.2.4 Patients with evidence of severe or uncontrolled systemic disease, or any concurrent condition, which could compromise participation in the study, including, but not limited to, active or uncontrolled infection, immune deficiencies, uncontrolled HBV and/or HCV infection unless sustained virologic response to HCV therapy, uncontrolled diabetes, serious non-healing ulcer, wound or bone fracture, history of intra-abdominal abscess, abdominal fistula or gastrointestinal perforation within 28 days of treatment, history of pulmonary embolism in the past 12 months, uncontrolled hypertension, myocardial infarction, cardiac arrhythmia, stable/unstable angina, symptomatic congestive heart failure, or coronary/peripheral artery bypass graft or stenting within 12 months prior to study entry, Class III or IV heart failure as defined by the NYHA functional classification system (see Appendix B),stroke/cerebrovascular accident or transient ischemic attack within the past 12 months or psychiatric illness/social situations which would jeopardize compliance with the protocol.  
3.2.5 History of a previous invasive malignancy within the last 5 years, except adequately treated non-melanoma skin cancer, papillary carcinoma of the thyroid or carcinoma in situ of the uterine cervix.  
3.2.6 Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. 3.2.7 Patients who are receiving any other investigational agents. 3.2.8 History of allergic reactions attributed to compounds of similar chemical or biologic composition to sunitinib. Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible. (A list of potent CYP3A4 inducers or inhibitors can be found in Section 5.2) An exception will be made for patients who are on ritonavir-based highly active antiretroviral therapy, in which case the starting dose of sunitinib will be modified as indicated in Sections **5.2.11**. Every effort should be made to switch patients taking such agents or substances to other medications. A comprehensive list of medications and substances known or with the potential to alter the pharmacokinetics of sunitinib through CYP3A4 is provided in Appendix C.  
3.2.9 Pregnant women are excluded from this study because sunitinib angiogenesis inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with sunitinib breastfeeding should be discontinued if the mother is treated with sunitinib.  
3.2.10 Patients who require therapeutic doses of Coumadin derivative anticoagulants such as warfarin are excluded. Low molecular weight heparin is permitted, provided the patient's PT/INR is ≤ 1.5. Coumadin doses of up to 2 mg daily are permitted for prophylaxis of thrombosis.  
3.2.11 Patients with a pre-existing thyroid abnormality who are unable to maintain thyroid function in the normal range with medication are ineligible.  
3.2.12 Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow 30 and retain sunitinib tablets are excluded.  
3.2.13 Patients with QTc prolongation (defined as a QTc interval equal to or greater than 500 msec) or other significant ECG abnormalities are excluded.  
3.2.14 Patients with poorly controlled hypertension (systolic blood pressure of 140 mmHg or higher or diastolic blood pressure of 91 mmHg or higher) are ineligible.  
3.2.15 Patients who require use of therapeutic doses of coumarin-derivative anticoagulants such as warfarin are excluded, although doses of up to 2 mg daily are permitted for prophylaxis of thrombosis. Note: Low molecular weight heparin is permitted provided the patient's PT INR is ≤1.5.  
3.2.16 Patients with HIV infection are eligible provided their CD4 count is greater than or equal to the institutional LLN (≥ 334 cells/uL).
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3.3 inclusion of women and

| Accrual Targets                         |                                       |           |    |      |      |    |      |      |
|-----------------------------------------|---------------------------------------|-----------|----|------|------|----|------|------|
| Ethnic Category                         | Sex/Gender                            |           |    |      |      |    |      |      |
| Females                                 | Males                                 | Total     |    |      |      |    |      |      |
| Hispanic or Latino                      | 3                                     | +         | 3  | =    | 6    |    |      |      |
| Not Hispanic or Latino                  | 26                                    | +         | 26 | =    | 52   |    |      |      |
| Ethnic Category:  Total of all subjects | 29                                    | (A1) +    | 29 | (B1) | =    | 58 | (C1) |      |
| Racial Category                         |                                       |           |    |      |      |    |      |      |
| American Indian or Alaskan              | 2                                     | +         | 2  | =    | 4    |    |      |      |
| Native Asian                            | 5                                     | +         | 5  | =    | 10   |    |      |      |
| Black or African American               | 4                                     | +         | 4  | =    | 8    |    |      |      |
| Native Hawaiian or other                | 1                                     | +         | 1  | =    | 2    |    |      |      |
| Pacific Islander White                  | 17                                    | +         | 17 | =    | 34   |    |      |      |
| Racial Category:  Total of all subjects | 29                                    | (A2)      | +  | 29   | (B2) | =  | 58   | (C2) |
| (A1 = A2)                               | (B1 = B2)                             | (C1 = C2) |    |      |      |    |      |      |
| Accrual Rate: 3 patients/month          | Total Expected Accrual: 41 Min 58 Max |           |    |      |      |    |      |      |
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4 registration procedures 4.1 coordinating

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.
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4.2 participating site

All patients must be registered through the NCI Central Registration Office (CRO). The CRO is open from 8:30am to 5:30pm EST Monday through Friday, excluding federal holidays. A protocol registration form will be supplied by the CCR study coordinator and updates will be provided as needed. Subject eligibility and demographic information is required for registration. To initially register a subject after the participant has signed consent, complete the top portion of the form and send to CCR study coordinator. Once eligibility is confirmed, complete the remainder of the form which is the eligibility checklist and send to CCR study coordinator. In addition, source documents supporting the eligibility criteria must be sent to the CCR study coordinator. The CCR study coordinator will notify you either by e-mail or fax that the protocol registration form has been received which will include the unique patient/subject ID number. Questions about eligibility should be directed to the CCR study coordinator or PI. Questions related to registration should be directed to the CCR study coordinator. Technical questions about the form should be directed to the Central Registration: Office (301402-1732).
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4.3 treatment initiation timeline

Following registration, patients should begin protocol treatment within 5 days. Issues that would cause treatment delays should be discussed with the Principal Investigator. If a patient does not receive protocol therapy within 5 days following registration, the patient may have to be removed from study. The Lead Associate Investigator should be notified of treatment initiation delays as soon as possible.
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5 treatment plan 5.1 agent

Sunitinib will be administered on an outpatient basis. Reported adverse events and potential risks are described in Section 7. Appropriate dose modifications are described in Section 6. No investigational or commercial agents or therapies other than sunitinib may be administered with the intent to treat the patient's malignancy. 5.1.1 For Group 1, sunitinib will be administered orally at a dose of 50 mg daily for 4 consecutive weeks followed by 2 weeks of rest with no sunitinib, every 6 weeks (4/2 schedule). For Group 2, sunitinib will be administered orally at a dose of 50 mg daily for 2 consecutive weeks followed by 1 week of rest with no sunitinib, every 3 weeks (2/1 schedule). Patients should be instructed to store sunitinib at room temperature. Patients will take sunitinib once daily, 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.  
5.1.2 Because hypertension is a known and potentially serious but rare adverse event associated with sunitinib maleate treatment, patients will have their blood pressure monitored and recorded at baseline and weekly during treatment including the weeks off the investigational drug either at the doctor's office or using any calibrated electronic device (such as those found at a local drug store or pharmacy). Appendix D and Appendix F detail the collection and recording of blood pressure related information.  
5.1.3 Baseline assessment of cardiac function (ECHO/MUGA) is required for all patients.  
Routine monitoring for cardiac function (ECHO/MUGA) should be performed at baseline and then every other cycle of treatment in the following groups of patients: (1) those entering the trial with NYHA Class II cardiac dysfunction (see Appendix B), (2) those with a history of Class II heart failure who are asymptomatic on treatment, and (3) in those previously exposed to anthracyclines or thoracic irradiation if the heart was included in the radiotherapy port.  
5.1.4 Although adrenal gland insufficiency is rarely seen with sunitinib treatment, patients should be clinically followed for the signs and symptoms of this complication, especially (1) patients with co-morbidities associated with adrenal dysfunction, (2) patients with pre-existing adrenal insufficiency (primary or secondary), and (3) patients with concomitant stress (e.g., fever, infection, bleeding, serious accident, surgery) that may precipitate overt adrenal insufficiency in the presence of subclinical sunitinib-induced adrenal toxicity. If clinically indicated, objective testing for adrenal gland function should be conducted.  
5.1.5 Patients with bulky solid tumors should be monitored closely for pneumothorax, intestinal fistulae, or intestinal perforation in the event of rapid tumor destruction.  
5.1.6 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.  
5.1.7 Patients will be requested to maintain a medication diary of each dose of medication.  
The medication diary will be returned to clinic staff at the end of each course.  
5.1.8 Thyroid function (free T4 and TSH) will be monitored at baseline and subsequently every 6 weeks (2 cycles).
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5.2 general concomitant medication and

5.2.1 Concomitant medications A concomitant medication is any medication a patient entering the trial is using and is expected to continue using for some portion of the trial as well as any medication the patient uses during the course of the trial. Study drugs are not considered concomitant medication. 5.2.2 All concomitant medications recorded at trial entry must have a related, ongoing concomitant illness listed under the medical history at the time of patient entry into the trial unless the medication is used for prophylaxis. Patients may continue to use any ongoing medications not prohibited by the protocol.  
5.2.3 All prescription and over-the-counter medications at trial entry as well as any new medications started during the trial must be documented. The documentation should continue until 30 days from the end of the last study drug treatment.  
5.2.4 No other anti-cancer therapy including chemotherapy, radiation therapy, hormonal cancer therapy and immunotherapy, or experimental medications are permitted while the patient is on this trial.  
5.2.5 Any disease progression that requires other specific anti-tumor therapy will be cause for discontinuation from study medication.  
5.2.6 Steroid use is not recommended during sunitinib treatment unless absolutely necessary
(e.g., for treatment of adverse events or protocol-required premedication) because many steroids (e.g., prednisone, prednisolone, dexamethasone, etc.) effectively lower sunitinib exposure through CYP3A4 interactions. Also steroids are known to have anti-tumor activity in thymic malignancies.  
5.2.7 The case report form (CRF) must capture the concurrent use of all other drugs, over-thecounter medications, or alternative therapies.  
5.2.8 The Principal Investigator should be alerted if the patient is taking any agent known to affect or with the potential to affect selected CYP450 isoenzymes. A comprehensive list of CYP3A4 inhibitors, inducers, and substrates is provided (see Appendix C).  
5.2.9 In addition, patients and their caregivers should be provided the patient information sheet
(see Appendix H) describing potential interactions of the study agents with other drugs, remedies, and medications.  
5.2.10 Use of agents with proarrhythmic potential (terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide, and flecainide) is not permitted during treatment with sunitinib. A comprehensive list of agents with proarrhythmic potential can be found at http://torsade.org.
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5.2.11 cytochrome p450-3a4 (cyp3a4) inhibitors

Sunitinib is primarily metabolized by liver enzymes, in particular CYP3A4. There was a mean 1.8-fold increase in exposure of SU011248 when co-administered with ketoconazole, a strong inhibitor of CYP3A4 and a mean 4-fold decreased in exposure of SU011248 when coadministered with rifampin, a strong inducer of CYP3A4.  
Therefore, co-administration with strong inhibitors (grapefruit/grapefruit juice, ketoconazole, itraconazole, clarithromycin, indinavir, saquinavir, ritonavir, atazanavir, nelfinavir, nefazodone, voriconazole, telithromycin) and strong inducers (dexamethasone, rifampin, rifabutin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John's wort) of CYP3A4 may result in significant increases/decreases in exposure of SU011248 and may alter the safety/efficacy of the drug. However for patients who are on ritonavir, sunitinib may be administered at a starting dose of 37.5 mg q day.142 Strong CYP3A4 inhibitors and inducers are not permitted 7 and 12 days before dosing, respectively. During the study, strong CYP3A4 inhibitors and inducers are not recommended. Alternative therapies should be used when available. If usage of a strong CYP3A4 inhibitor or inducer is necessary, this must be in agreement with the Sponsor. The following drugs should not be used before or during the study:  
| azole antifungals (ketoconazole,   | diltiazem   |
|------------------------------------|-------------|
| itraconazole) clarithromycin       | verapamil   |
| erythromycin                       |             |  
Inducers - prohibited **12 days** before dosing and during study.  
| rifampin      | phenobarbital   |
|---------------|-----------------|
| rifabutin     | phenytoin       |
| carbamazepine | St. John's wort |  
Aprepitant, fluconazole and voriconazole are clinically relevant moderate CYP3A4 inhibitors that should be avoided, if possible, or used with great caution.  
35 Additional inducers or inhibitors of CYP3A4 can be found at http://medicine.iupui.edu/clinpharm/ddis. Interacting drugs with sunitinib should be avoided or used with great caution. A comprehensive list of CYP3A4 inhibitors, inducers, and substrates is provided in Appendix C. In addition, patients and their caregivers should be provided the patient information sheet (see Appendix E) describing potential interactions of sunitinib with other drugs, remedies, and medications. 5.2.12 The use of coumarin-derivative anticoagulants such as warfarin (Coumadin®) is not recommended, although doses of up to 2 mg daily are permitted for prophylaxis of thrombosis.  
5.2.13 Supportive care guidelines
- **Nausea/vomiting** - Patients with treatment-related nausea should be treated initially with a phenothiazine (prochlorperazine - 10 mg every 8 hours orally as needed or promethazine - 12.5-25 mg IV every 6 hours as needed). If this is inadequate, a benzodiazepine should be added until acute nausea is controlled or toxicity is limiting. Should this prove inadequate acutely, a steroid may be added (e.g., dexamethasone 4 mg every 6 hours as needed). After acute nausea has resolved, consideration should be given to initiation of prophylactic anti-emetic therapy. If nausea recurs despite reasonable medical intervention (as outlined above), dose reduction will be needed as described in Section 6.  
- **Diarrhea** should be managed with loperamide: 4 mg at first onset, then 2 mg every 2-4 hours until diarrhea is controlled (maximum = 16 mg loperamide per day).  
- **Hand-foot syndrome** may be treated with topical emollients (such as Aquaphor), topical/systemic steroids, and/or antihistamine agents. Vitamin B6 (pyridoxine; 50-150 mg orally each day) may also be used. Avoid exposure to heat, hot water, pressure, or friction. Use of soft, well-fitting shoes may help, as may use of acetaminophen if needed for analgesia.  
- Patients with **neutropenic fever** or infection should be evaluated promptly and treated with IV antibiotic therapy or therapeutic colony-stimulating factors as appropriate following the ASCO guidelines [*J Clin Oncol* 18(20):3558-85, 2000]. Packed red blood cell and platelet transfusion should be administered as clinically indicated. Erythropoietic agents may be used at the discretion of the treating physician.
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5.3 duration of therapy

In the absence of treatment delays due to adverse event(s), treatment may continue until one of the following criteria (off treatment criteria) applies:
- Disease progression, - Intercurrent illness that prevents further administration of treatment, - Unacceptable adverse event(s), - Delay of treatment of ≥ 3 weeks, - Positive pregnancy test - Patient decides to withdraw from the study, or - General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.
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5.4 duration of follow up

Prior to documenting removal from the study, effort must be made to have all subjects complete a safety visit approximately 30 days following the last dose of study therapy; then patients will be followed either with clinic visits or phone interviews yearly until death. Patients removed from treatment for unacceptable adverse event(s) will be followed clinically until resolution or stabilization of the adverse event, and then via clinic visits or phone interviews yearly until death. The following information will be collected:
- Date of follow up
- Is patient dead or alive?  
- If dead, document exact date of death. - Further treatment(s), if any
- Document date of disease progression
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5.5 criteria for removal from

5.5.1 Once a patient has been removed from study, no further data can be collected; therefore, with completion of the duration of follow-up described in Section 5.4, the criteria for removal from study are:
- Lost to follow-up - Death, or
- The patient decides to withdraw from the study.  
The reason for study removal and the date the patient was removed must be documented in the database. 5.5.2 Off Protocol Therapy and Off Study Procedure Authorized staff must notify the NCI Central Registration Office (CRO) when a patient is taken off protocol therapy and when a subject is taken off study. The CRO is open from 8:30am to 5:30pm EST Monday through Friday, excluding federal holidays. A Participant Status Update Form from the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and sent via encrypted email to: NCI Central Registration Office ncicentralregistration-l@mail.nih.gov. The Participant Status Update Form will be supplied by the CCR study coordinator. Send the completed form to the CCR study coordinator.
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6 dosing delays/dose modifications 6.1

6.1.1 Patients may continue to receive therapy provided the following criteria are met on day 1 of each cycle:
- ANC ≥ 1,000/mcL
- Platelets ≥ 75,000/mcL
- Non-hematologic toxicity recovered to < grade 2 (or tolerable grade 2 or baseline) - No evidence of progressive disease 6.1.2 In the event of an adverse event at least possibly related to the agent, the doses of such agent should be adjusted according to the guidelines shown in the Dose Delays / Dose Modifications tables shown below. If a patient experiences several adverse events and there are conflicting recommendations, the investigator should use the recommended dose adjustment that reduces the dose to the lowest level. If an adverse event is not covered in such tables, doses may be reduced or held at the discretion of the investigator for the subject's safety. Subjects with adverse events that are manageable with supportive therapy may not require dose reductions (e.g., nausea/vomiting may be treated with antiemetics, diarrhea may be treated with loperamide, and electrolyte abnormalities may be corrected with supplements rather than by dose reduction).  
6.1.3 Subjects will be withdrawn from the study if they fail to recover to CTC Grade 0-1 or tolerable grade 2 (or within 1 grade of starting values for pre-existing laboratory abnormalities) from a treatment-related adverse event within 21 days OR they experience agent related adverse events requiring dose modification despite two previous dose reductions (i.e. would require a 3rd dose reduction) unless the investigator and CTEP monitor agree that the subject should remain in the study arm because of evidence that the patient is/may continue deriving benefit from continuing study treatment (i.e. patient has PR, CR, SD > 3 months). The appropriate reduced dose will be determined after discussion between the principal investigator and CTEP monitor.
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6.2 treatment delays and modifications

Brief interruptions and delays may occasionally be required due to travel delays, airport closure, 38 inclement weather, family responsibilities, security alerts, and government holidays, etc. Delays of up to 1 week will not be considered protocol deviations and will not be separately reported. If a patient takes 75% or more of scheduled doses during a cycle, missed doses will not be reported as deviations. If the study team instructs a patient to hold the investigational drug, it will not be considered a protocol deviation. A patient that interrupts therapy for more than 3 weeks will be taken off treatment.
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6.3 treatment delays and modifications

Patients experiencing complications of their disease or other medical illness not attributable to disease progression, or protocol therapy may also require brief interruptions and delays that will not be considered protocol deviations, and will not be separately reported. A patient that interrupts therapy for more than 21 days will be taken off treatment.
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6.4 sunitinib monotherapy dose level

| Dose Level            | Sunitinib Dose     |
|-----------------------|--------------------|
| Starting Dose         | 50 mg once a day   |
| First Dose Reduction  | 37.5 mg once a day |
| Second Dose Reduction | 25 mg once a day   |
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6.5 management of treatment-emergent hypertension

Increases in blood pressure (BP) and cases of hypertension have been associated with many drugs acting on the VEGF pathway. The proposed mechanism for this increase is through inhibition of VEGF-induced peripheral vasodilation. Hypertension following sunitinib treatment has rarely been seen in animal studies or clinical trials. Specific guidelines for management of this adverse event and a table of various antihypertensive medications are provided in Appendix G. In addition, guidance on the collection and recording of BP information is provided in Appendix F.
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6.6 dosage modification criteria for

| Event        | AE Grade  or  Observation   | Dose modification   |
|--------------|-----------------------------|---------------------|
| Grades 1 and |                             |                     |
| Neutropenia  | Grade 2 ≥  1200             | Maintain dose       |  
| Event                                                         | AE Grade  or  Observation                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Dose modification            |
|---------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|
| Grade 2 < 1200 and  Grade 3*                                  | Hold sunitinib until ANC > 1000, then  reduce 1 dose level and resume treatment                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                              |
| Grade 4                                                       | Hold sunitinib until ANC > 1000, then  reduce 1 dose level and resume treatment                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                              |
| Grade 1                                                       | Maintain dose                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                              |
| Grades 2 and                                                  | Hold sunitinib until platelets > 75, 000,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                              |
| 3*                                                            | then reduce 1 dose level and resume  treatment                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                              |
| Grade 4                                                       | Hold sunitinib until platelets > 75, 000,  then reduce 1 dose level and resume  treatment                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                              |
| Fever or flu-like                                             | Grades 1-4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Maintain dose                |
| symptoms                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                              |
| Thrombocytopenia                                              | Grades 1 and                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Maintain dose                |
| 2 Grade 3* and  severe grade  2, at  investigator  discretion | Hold sunitinib until ≤ grade 2, then  reduce 1 dose level and resume treatment                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                              |
| Fatigue (lethargy,  malaise, asthenia)                        | >450 but                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Review patient's concomitant |
| < 550 msec                                                    | medications for QT interval-prolonging  agents. Correct any electrolyte  abnormalities. Continue sunitinib at current dose level.                                                                                                                                                                                                                                                                                                                                                                                                         |                              |
| > 550 msec                                                    | Stop sunitinib and any other QT-interval  prolonging agents immediately. Correct  any electrolyte abnormalities, then:  If there is a plausible explanation for AE  other than sunitinib treatment, resume  sunitinib at current dose level.  If sunitinib may have contributed to the  AE: Reduce 2 dose levels and restart  sunitinib.  If QTc remains <500 msec after 14 days  at reduced dose, increase one dose level  and continue sunitinib.  If QTc remains <500 msec after 14 days,  original dose of sunitinib may be  resumed. |                              |
| QTc prolongation  Do not use CTCAE  v5 grades                 | 40                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                              |  
| Event                                   | AE Grade  or  Observation                                                                                                                                                                                                                                                                            | Dose modification                                                                           |
|-----------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|
| Grades 1 and                            | Maintain dose                                                                                                                                                                                                                                                                                        |                                                                                             |
| 2                                       |                                                                                                                                                                                                                                                                                                      |                                                                                             |
| Hand-foot syndrome                      | Grade 3*                                                                                                                                                                                                                                                                                             | Hold sunitinib until ≤ grade 1, then  resume treatment at same dose or reduce  1 dose level |
| Grades 1 and                            | Maintain dose                                                                                                                                                                                                                                                                                        |                                                                                             |
| 2 Grades 3 and                          | Sunitinib should be dose delayed if                                                                                                                                                                                                                                                                  |                                                                                             |
| 4                                       | elevation of ALT is >5 × ULN, AST is  >5 × ULN, and/or bilirubin is >3 × ULN.  Sunitinib may be re-administered when  levels of ALT and AST are ≤5 × ULN  and bilirubin is ≤3 × ULN. Sunitinib  should NOT be re-administered if  subjects develop ≥ grade 3 hepatic failure  (CTCAE v5 definition). |                                                                                             |
| AST and/or ALT  elevation  (SGOT, SGPT) | Patients must have LFTs checked at  baseline and during each treatment cycle.  LFTs should be obtained at any time  when they are clinically indicated.                                                                                                                                              |                                                                                             |
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6.7 management of other clinically

| Observation                                                                                                                                                                                                                                                                                     | Action                                  |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------|
| AE resolves promptly with supportive care                                                                                                                                                                                                                                                       | Maintain dose level                     |
| 1. Grade 3 or higher (non-hematologic or grade 4 (hematologic) AE related to sunitinib and lasting >5 days that does not resolve to grade 2 or below despite maximum supportive care for < 48 hours.                                                                                            | Reduce one dose level                   |
| AE does not resolve to grade 2 or below after treating patient at the lowest (i.e., 25* mg or 12.5* daily) reduced dose level.                                                                                                                                                                  | In general, remove patient from study** |
| * 25 mg if the patients start dosing at 50 mg on a 4/2 schedule (solid tumors) or 12.5 mg if patients start dosing at 37.5 mg ** After consultation with study sponsor (DCTD, NCI), a dose of 25 mg daily may be considered for patients on study > 3 months who are benefiting from the agent. |                                         |  
(not specifically addressed above)
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7 nih reporting requirements/data and

Please refer to definitions provided in Policy 801: Reporting Research Events found here.
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7.2 ohsrp office of compliance

7.2.1 Expedited Reporting Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported per these policies. 7.2.2 NIH Intramural IRB Requirements for PI Reporting at Continuing Review Please refer to the reporting requirements in Policy 801: Reporting Research Events found here. 7.2.3 NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials Report events to the Reviewing IRB as per its policy. Please also notify the coordinating center PI and study coordinator of your submission at the time you make it.
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7.3 nci clinical director reporting

Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical Director. In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death.
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7.4 ind sponsor reporting criteria

7.4.1 Adverse Events: List and Reporting Requirements Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of AEs (Section **7.3.1.1**) and the characteristics of an observed AE (Section 7.3.1.2) will determine whether the event requires expedited reporting (via CTEP-AERS) in addition to routine reporting.  
7.4.1.1 Comprehensive Adverse Events and Potential Risks list (CAEPR) For Sunitinib Malate
(SU011248 L-malate, NSC 736511)