Clinical trial NCT01621568
Conditions: Thymoma Thymus Neoplasms
Keywords: VEGF Anti-Angiogenesis Targeted Agent
Sponsor: National Cancer Institute (NCI)
Start date: 2012-05-15; Completion date: 2024-07-31
Enrollment: 56 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Background:

\- Sunitinib is drug that is approved for treating various types of cancers, including kidney cancers. However, it has not been approved to treat cancers of the thymus. Sunitinib works by blocking proteins that are responsible for cell division and growth. Some of these proteins can be found on thymus cancer cells. Researchers want to see if sunitinib can be used to treat advanced thymus cancer. It will be given to people who have had at least one earlier chemotherapy treatment containing platinum.

Objectives:

\- To see if sunitinib is a safe and effective treatment for advanced thymus cancer that has not responded to earlier treatments.

Eligibility:

* Individuals at least 18 years of age who have advanced thymus cancer that has not responded to earlier treatments.
* At least one previous cancer treatment must have been chemotherapy treatment containing platinum.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies and tumor biopsies will be used to check the severity of the cancer.
* Participants will take sunitinib tablets once a day, in the morning. They will take the tablets daily for 4 weeks, followed by 2 weeks of rest with no sunitinib. This 6-week period is called a cycle.
* Treatment will be monitored with frequent blood tests and imaging studies.
* Treatment cycles may be repeated as long as the tumor does not continue to grow and there are no severe side effects....

Detailed description:
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.

OBJECTIVES:

Primary objective:

\- To evaluate the objective response rate (Partial Response (PR)+Complete Response (CR) for sunitinib in patients with relapsed or refractory thymoma or thymic carcinoma

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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
* Adequate renal, hepatic and hematopoietic function
* No major surgery, radiotherapy, chemotherapy or biologic therapy within 28 days of sunitinib

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 Common Terminology Criteria for Adverse Events (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 vascular endothelial growth factor (VEGF), placental growth factor (PlGF), interleukin 4 (IL-4), interleukin 12 (IL-12), hepatocyte growth factor (HGF), and basic fibroblast growth factor (bFGF) (Group 1 only); and circulating tumor cells, endothelial progenitors, and mature apoptotic endothelial cells (both groups). In Group 2, regulatory T cells (Tregs), exhausted cluster of differentiation 8 (CD8) T cells, myeloid-derived suppressor cells (MDSCs), and Type 1 T helper (Th1)/Type 2 T helper (Th1) 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 National Cancer Institute (NCI) only.

Arms: arm 1: Group 1 (Thymoma and thymic carcinoma) treated with sunitinib 50 mg/day, 4 weeks on, 2-weeks off (6 week cycle). arm 2: Group 2 (Thymic carcinoma only) treated with sunitinib 50 mg/day, 2 weeks on, 1 week off (3 week cycle).
Interventions: intervention 1: Sunitinib intervention 2: Sunitinib
Intervention descriptions: intervention 1: 50mg/day for 4 weeks daily, by mouth with 2 weeks off (6 week cycle) intervention 2: 50mg/day for 2 weeks daily, by mouth with 1 week off (3 week cycle)

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
1 
 
Abbreviated Title: Ph2Sunitinib-Thymoma/Thymic Ca 
CTEP Protocol #:  9174 
 
CC Protocol #: 
 12-C-0118 
NCT Number: 
 NCT01621568 
 
 
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  
 
 
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 
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 
 


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
2 
 
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 
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  
 
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 
 
 


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
3 
 
 
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 
 
 
 
 
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  


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
4 
 
PRÉCIS  
 
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.  
 
Objectives:  
Primary objective:  
• To evaluate the objective response rate (PR+CR) for sunitinib in patients with relapsed or 
refractory thymoma or thymic carcinoma 
 
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 
 
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. 
 


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
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TABLE OF CONTENTS 
SUMMARY OF PROTOCOL CHANGES ................................... Error! Bookmark not defined. 
Précis 4 
TABLE OF CONTENTS .................................................................................................................5 
1 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objectives...................................................................................................8 
1.2 
Secondary Objectives...............................................................................................8 
1.3 
Exploratory Objectives ............................................................................................8 
2 
BACKGROUND AND RATIONALE ................................................................................8 
2.1 
Thymoma and Thymic Carcinoma ..........................................................................8 
2.2 
Sunitinib Malate .....................................................................................................11 
2.3 
Rationale ................................................................................................................21 
2.4 
Exploratory Studies Background ...........................................................................25 
3 
PATIENT SELECTION ....................................................................................................27 
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 ...............................................................................................32 
4.2 
Participating Site ....................................................................................................32 
4.3 
Treatment Initiation Timeline ................................................................................32 
5 
TREATMENT PLAN ........................................................................................................32 
5.1 
Agent Administration.............................................................................................32 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................34 
5.3 
Duration of Therapy ...............................................................................................37 
5.4 
Duration of Follow Up ...........................................................................................37 
5.5 
Criteria for Removal from Study ...........................................................................37 
6 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................38 
6.1 
General Guidance...................................................................................................38 
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) ........................39 
6.5 
Management of Treatment-Emergent Hypertension .............................................39 
6.6 
Dosage Modification Criteria for Other Hematologic and Non-
Hematologic Adverse Events .................................................................................39 
6.7 
Management of Other Clinically Significant Sunitinib-related AEs .....................41 
7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN .................................................................................................................................42 


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
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Version Date: 04/30/2020 
 
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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 


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
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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 


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
 
8 
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  
 
1.2 
SECONDARY OBJECTIVES 
 
• 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 
 
1.3 
EXPLORATORY OBJECTIVES  
 
Peripheral blood will be collected to evaluate serum VEGFR2, PLGF, IL-4, IL-12, HGF, and b-
FGF (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. 
 
2 BACKGROUND AND RATIONALE 
2.1 
THYMOMA AND THYMIC CARCINOMA 
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 


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
 
9 
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 
Stage description 
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 


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
 
10 
 
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% 
Loehrer (1994)16 
29 
PAC 
50% 
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% 
Giaccone (2009)23 
7 
Imatinib 
0 
Giaccone (2011)24 
41 
Belinostat 
8% 
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.  
 


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
 
11 
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 
Thymic carcinoma = 11 
NR 
NR 
45.4 weeks 
5.1 weeks 
NR 
Capecitabine + 
Gemcitabine27 
Thymoma = 12 
Thymic carcinoma = 3 
5 
1 
11 months 
6 months 
Not reached 
Octreotide + 
Prednisone22 
Thymoma = 32 
Thymic Carcinoma = 6 
12 
0 
8.8 months 
4.5 months 
Not reached 
23.4 months 
Erlotinib + 
Bevacizumab28 
Thymoma = 11 
Thymic carcinoma = 7 
0 
0 
NR 
NR 
Not reached 
Belinostat24 
Thymoma = 25 
Thymic carcinoma = 16 
2 
0 
11.4 months 
2.7 months 
Not reached 
12.4 months 
Amrubicin + 
Carboplatin*29 
Thymoma = 18 
Thymic carcinoma = 33 
3 
10 
7.6 months 
7.6 months 
Not reached 
27.3 months 
Cixutumumab 
(unpublished) 
Thymoma = 37 
Thymic carcinoma = 12 
5 
0 
9.5 months 
1.4 months 
25 months 
8.3 months 
Sunitinib 
(unpublished) 
Thymoma = 16 
Thymic carcinoma = 22 
1 
5 
7.6 months 
6.7 months 
Not reached 
12.6 months 
* Only 3 of 18 patients with thymoma and 14 of 33 thymic carcinoma had received previous chemotherapy 
 
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 colony-
stimulating 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 
 
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 proto-
oncogene activation and hypoxia, with the hypoxic state frequently arising in solid tumors 
because of inadequate perfusion.  In addition to its angiogenic role, VEGF also profoundly 
increases the permeability of the vasculature thereby, potentially contributing to tumor 
progression.  A leaky tumor endothelium enhances nutrient and catabolite exchange and 
represents less of a barrier to tumor cell migration and intravasation during metastasis.  Two 
high-affinity receptors for VEGF with associated 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. 


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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), non-
small 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 


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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 


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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. 
 


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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 hand-
foot 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 


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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   
 
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 


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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 


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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.  
 
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 


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(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.  Concentration-
versus-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 50-
100 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 


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21 
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. 
 
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 kinase-
1/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 


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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 


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23 
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 
Drug 
Author 
(year of 
publication) 
Number 
of 
patients 
Dose/ 
Schedule 
Hist
olog
y 
Prior systemic 
treatment 
Response 
Comments 
 
Azad A et al 
1 
75 mg BID/ 
THY 
PAC 
28% tumor 
PFS 12 months 


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24 
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 
 
Bevacizumab 
+ Erlotinib 
Bedano PM 
et al 
(2008) 
[Abstract] 
18 
15 mg/kg IV 
q 3 weeks+ 
150 mg q 
day 
THY 
(11) 
TC 
(7) 
NR 
11 patients had 
SD 
 
Aflibercept+ 
docetaxel 
Isambert N et 
al 
(2008) 
[Abstract] 
1 
NR 
THY 
NR 
PR 
 
Dasatinib 
 
 
 
Chuah C et al 
(2006) 
1 
140 mg 
daily 
THY 
B2 
None 
PR 
Patient also had 
CML and was in 
lymphoid blast 
crisis. Tumor c-Kit 
staining negative 
 
 
Sunitinib 
 
 
 
Ströbel P et al 
(2010) 
4 
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 
37.5 mg 
daily 
TC 
No 
chemotherapy 
PR 
PFS 14 months 
50 mg daily 
4/2 schedule 
TC 
chemotherapy 
PR 
OS 4 months 
Thomas A et al 
(2013) 
[Abstract] 
38 
50 mg daily 
4/2 schedule 
THY  
(16) 
Chemotherapy 
(median prior 
chemo = 2) 
PR=1: SD=12 
 
PFS 7.6 mo; OS not 
reached 
TC 
(22) 
Chemotherapy 
(median prior 
chemo = 2) 
PR=5; SD=15 
PFS 6.7 mo; OS 12.6 
mo 
SU14813 
W. Fiedler et 
al (2010) 
2 
4/1 schedule 
THY 
NR  
PR  
PFS 15.3 and 9.0 
months 
Imatinib 
 
 
Buti S et al 
(2011) 
1 
400 mg 
daily 
TC 
ADOC 
SD 
PFS 9 months 
c-KIT exon 11 
mutation (Y553N) 
Sorafenib 
 
 
Bisagni G et 
al (2009) 
1 
200 mg BID 
TC 
Surgery 
PEI 
IA 
octreotide 
PR after 8 
weeks; 
maintained 
after 15 months 
c-kit exon 17 
(D820E) mutation 
 
 
Li X et al 
(2008) 
1 
Sorafenib 
TC 
CDC 
CEIO 
CEP 
Paclitaxel 
SD 
PFS 9 months; 
Tumor c-Kit and 
VEGF staining 
positive 
 
 
Diel U et al 
(2011) 
1 
Sorafenib 
TC  
ADOC 
PR 
PFS 6 months 
c-KIT exon 9 
deletion present  
Abbreviations used: PAC: cisplatin, doxorubicin, cyclophosphamide; ChlVPP: chlorambucil, vinblastine, procarbazine and prednisolone; THY: Thymoma; 


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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.   
 
2.4.1 Serum VEGFR2, PlGF, IL-4, IL-12, HGF, b-FGF (Group 1 only) 
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 
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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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 Tim-
3, were found in cancer patients117,121. Recent clinical trials have validated that blockade of PD-
L1/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 


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(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. 
 
3 PATIENT SELECTION 
3.1 
 ELIGIBILITY CRITERIA  
 
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 


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28 
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. 
 
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 


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29 
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. 
 
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 


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30 
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 


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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). 
 
3.3 
INCLUSION OF WOMEN AND MINORITIES 
Both men and women of all races and ethnic groups are eligible for this trial.   
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 
Native 
2 
+ 
2 
= 
4 
Asian 
5 
+ 
5 
= 
10 
Black or African American 
4 
+ 
4 
= 
8 
Native Hawaiian or other 
Pacific Islander 
1 
+ 
1 
= 
2 
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 CENTER 
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.  
 
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 (301-
402-1732). 
 
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. 
 
5 TREATMENT PLAN 
5.1 
AGENT ADMINISTRATION 
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 


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33 
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.  
 


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34 
5.1.8 Thyroid function (free T4 and TSH) will be monitored at baseline and subsequently every 
6 weeks (2 cycles). 
 
5.2 
 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
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-the-
counter 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.  
 


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35 
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. 
 
5.2.11 Cytochrome P450-3A4 (CYP3A4) inhibitors and/or inducers:  Patients must not have 
received potent inhibitors within 7 days and potent inducers within 12 days prior to drug 
administration. 
 
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 co-
administered 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: 
 
Inhibitors – prohibited 7 days before dosing and during study. 
azole antifungals (ketoconazole, 
itraconazole) 
diltiazem 
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. 


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36 
 
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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37 
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. 
 
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 
 
5.5 
CRITERIA FOR REMOVAL FROM STUDY 
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. 


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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. 
 
6 DOSING DELAYS/DOSE MODIFICATIONS 
6.1 
GENERAL GUIDANCE 
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. 
 
6.2 
TREATMENT DELAYS AND MODIFICATIONS FOR ADMINISTRATIVE NEEDS 
Brief interruptions and delays may occasionally be required due to travel delays, airport closure, 


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39 
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. 
 
6.3 
TREATMENT DELAYS AND MODIFICATIONS FOR MEDICAL NEEDS 
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. 
 
6.4 
 SUNITINIB MONOTHERAPY DOSE LEVEL REDUCTIONS (GROUPS 1 AND 2) 
 
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 
          
 
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. 
 
6.6 
DOSAGE MODIFICATION CRITERIA FOR OTHER HEMATOLOGIC AND NON-
HEMATOLOGIC ADVERSE EVENTS  
 
 
Event 
AE Grade 
or 
Observation 
Dose modification 
Neutropenia 
Grades 1 and 
Grade 2 ≥ 
1200 
Maintain dose 


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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 
Thrombocytopenia 
Grade 1 
Maintain dose 
Grades 2 and 
3* 
Hold sunitinib until platelets > 75, 000, 
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 
symptoms 
Grades 1-4 
Maintain dose 
Fatigue (lethargy, 
malaise, asthenia) 
Grades 1 and 
2 
Maintain dose 
Grade 3* and 
severe grade 
2, at 
investigator 
discretion 
Hold sunitinib until ≤ grade 2, then 
reduce 1 dose level and resume treatment 
 
 
 
 
 
 
 
QTc prolongation 
Do not use CTCAE 
v5 grades 
>450 but 
 < 550 msec 
Review patient’s concomitant 
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. 


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Event 
AE Grade 
or 
Observation 
Dose modification 
Hand-foot syndrome 
Grades 1 and 
2 
Maintain dose 
Grade 3* 
Hold sunitinib until ≤ grade 1, then 
resume treatment at same dose or reduce 
1 dose level 
AST and/or ALT 
elevation 
(SGOT, SGPT) 
 
Grades 1 and 
2 
Maintain dose 
Grades 3 and 
4 
Sunitinib should be dose delayed if 
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).  
 
Patients must have LFTs checked at 
baseline and during each treatment cycle.  
LFTs should be obtained at any time 
when they are clinically indicated. 
 
 
6.7 
MANAGEMENT OF OTHER CLINICALLY SIGNIFICANT SUNITINIB-RELATED AES 
(not specifically addressed above) 
 
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. 


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42 
7 NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING  / IRB REPORTING  
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. 
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. 
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) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Sunitinib malate (SU011248 L-malate, NSC 736511) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 


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43 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for 
further clarification. Frequency is provided based on 7115 patients. Below is the CAEPR for 
Sunitinib malate (SU011248 L-malate). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
   Version 2.14, February 15, 20191 
 
 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 5.0 Term) 
[n= 7115] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
 
Hemolytic uremic syndrome 
  
 
 
Thrombotic thrombocytopenic 
purpura 
  
CARDIAC DISORDERS 
  
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction 
  
ENDOCRINE DISORDERS 
  
 
 
Endocrine disorders - Other 
(thyroiditis) 
  
 
 
Hyperthyroidism 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
EYE DISORDERS 
  
 
 
Eye disorders - Other (macular 
edema) 
 Eye disorders - Other (macular edema) (Gr 
2) 
 
 Papilledema 
  
 Papilledema (Gr 2) 
 
 
 Vision decreased 
 Vision decreased (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
 Abdominal distension (Gr 2) 
Abdominal pain 
 
 
 Abdominal pain (Gr 3) 
Anal mucositis 
 
 
 Anal mucositis (Gr 2) 
Constipation 
 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 


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 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 5.0 Term) 
[n= 7115] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
Dyspepsia 
 
 
 Dyspepsia (Gr 2) 
 
 
Esophagitis 
  
 
Flatulence 
 
 Flatulence (Gr 2) 
 
 Gastritis 
 
 Gastritis (Gr 2) 
 
 Gastroesophageal reflux disease 
  
  
 
 
 Gastrointestinal perforation143   
Mucositis oral 
 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Oral pain 
 
 Oral pain (Gr 2) 
 
 
Pancreatitis 
  
Rectal mucositis 
 
 
 Rectal mucositis (Gr 2) 
Small intestinal mucositis 
 
 
 Small intestinal mucositis (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2)  
 
Flu like symptoms 
 
  
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Cholecystitis 
  
 
 
Hepatic failure 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction144 
  
INFECTIONS AND INFESTATIONS 
  
 
 
Infections and infestations - 
Other (necrotizing fasciitis) 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine aminotransferase increased (Gr 3) 
 
Alkaline phosphatase increased 
 
 Alkaline phosphatase increased (Gr 2) 
 
Aspartate aminotransferase increased  
 Aspartate aminotransferase increased (Gr 
3) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
CPK increased 
 
  
 
Creatinine increased 
 
 Creatinine increased (Gr 3) 
 
 
Electrocardiogram QT 
corrected interval prolonged 
  
 
Lipase increased 
 
 Lipase increased (Gr 4) 
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 2) 


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45 
 
 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 5.0 Term) 
[n= 7115] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 4) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 4) 
 
Serum amylase increased 
 
 Serum amylase increased (Gr 2) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hyperuricemia 
 
 Hyperuricemia (Gr 2) 
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 2) 
 
Hypocalcemia 
 
  
 
 
Hypoglycemia 
  
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 2) 
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
 
Musculoskeletal and 
connective tissue disorder - 
Other (fistula formation) 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
 
 
Osteonecrosis of jaw 
  
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
 
 
Rhabdomyolysis 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
  
 
 
Leukemia secondary to 
oncology chemotherapy 
  
 
 
Myelodysplastic syndrome 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
Dysgeusia 
 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
 
Leukoencephalopathy 
  
 
 
Nervous system disorders - 
Other (cerebral infarction) 
  
 
Paresthesia 
 
  
 
 
Reversible posterior 
leukoencephalopathy syndrome 
  
 
 
Transient ischemic attacks 
  
PSYCHIATRIC DISORDERS 
  
 
Depression 
 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
RENAL AND URINARY DISORDERS 
  


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46 
 
 Adverse Events with Possible  
 Relationship to Sunitinib malate (SU011248 L-malate) 
 (CTCAE 5.0 Term) 
[n= 7115] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
 
Acute kidney injury 
  
 
 
Nephrotic syndrome 
  
 
 
Proteinuria 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
 Epistaxis (Gr 2) 
Laryngeal mucositis 
 
 
 Laryngeal mucositis (Gr 2) 
Pharyngeal mucositis 
 
 
 Pharyngeal mucositis (Gr 2) 
Tracheal mucositis 
 
 
 Tracheal mucositis (Gr 2)  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Erythema multiforme 
  
 
 Hair color changes 
 
 Hair color changes (Gr 2) 
Palmar-plantar 
erythrodysesthesia syndrome 
 
 
 Palmar-plantar erythrodysesthesia 
syndrome (Gr 3) 
 
Pruritus 
 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
 
 
Skin and subcutaneous tissue 
disorders - Other (pyoderma 
gangrenosum) 
  
 
Skin hypopigmentation 
 
 Skin hypopigmentation (Gr 2) 
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
 
Thromboembolic event 
  
 
Vascular disorders - Other 
(hemorrhage)5 
 
  
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric 
perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the 
GASTROINTESTINAL DISORDERS SOC. 
 
3Allergic reactions observed include anaphylaxis and angioedema. 
 
4The majority of hemorrhage events were mild.  Major events, defined as symptomatic bleeding in a critical area or organ 
(e.g., eye, GI tract, GU system, respiratory tract, nervous system [including fatal intracranial hemorrhage, and 
cerebrovascular accident], and tumor site) have been reported. 
 
 


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Adverse events reported on Sunitinib malate (SU011248 L-malate) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that Sunitinib malate (SU011248 L-malate) caused the adverse 
event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Pericardial effusion 
GASTROINTESTINAL DISORDERS - Ascites; Dysphagia; Gastrointestinal disorders - Other (enteritis); Hemorrhoids; 
Ileus; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Pain 
INVESTIGATIONS - GGT increased; INR increased 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperglycemia; Hyperkalemia; Hypokalemia; 
Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain 
NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Peripheral sensory neuropathy; Seizure; Spinal cord 
compression; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion 
RENAL AND URINARY DISORDERS - Hematuria; Urinary retention 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Hematosalpinx 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Pharyngolaryngeal pain; Pleural effusion; 
Pneumothorax 
VASCULAR DISORDERS - Flushing; Hypotension 
 
Note: Sunitinib malate (SU011248 L-malate) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never previously associated 
with either agent. 
 
7.4.1.2 Adverse Event Characteristics  
• CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized until March 31, 2018 for AE reporting. 
CTCAE version 5.0 will be utilized for AE reporting beginning April 1, 2018. All 
appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
• 
For expedited reporting purposes only:   
o AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed 
in the SPEER column, Section 7.3.1.1) should be reported through CTEP-
AERS only if the grade is above the grade provided in the SPEER. 
o Other AEs for the protocol that do not require expedited reporting are outlined 
in section 7.3.2.4. 
 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 


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7.4.2 Expedited Adverse Event Reporting 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP Web site (http://ctep.cancer.gov).  The reporting procedures to 
be followed are presented in the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded 
from the CTEP Web site (http://ctep.cancer.gov).  These requirements are briefly outlined in the 
tables below (Sections 7.3.2.3 and 7.3.2.4). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
 
7.4.2.1 CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Study Coordinator of the Lead Organization, Principal Investigator, and the local 
treating physician.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
7.4.2.2  Expedited Reporting Guidelines  
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.”  Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
7.4.2.3 Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 


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ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
7.4.2.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
For this protocol only, the AEs/grades listed below do not require expedited reporting via CTEP-
AERS.  However, they still must be reported through the routine reporting mechanism (Section 
7.4): 
 
CTCAE SOC 
Adverse Event Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 
GI disorders 
Nausea  
2 to 3 
 
 
 
 
Diarrhea 
2 to 3 
 
 
 
Constipation 
2 to 3 
 
 
 
Vomiting  
2 to 3 
 
 
 
Metabolism 
and 
Electrolyte 
abnormalities 
2 to 4 
 
 
 


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50 
nutrition 
disorders 
Nervous 
system 
disorders 
 
 
Disguesia  
 
2 
 
 
 
Dermatology/
Skin 
Rash 
Acne/Acneifo
rm 
2 to 3 
 
 
 
 
Events that are clearly consequences of the “main” event (e.g., hypokalemia associated with 
diarrhea or the arrhythmias, hypotension, hypoxia, etc. that are known to occur concurrently with 
sepsis) may be noted in the Description of Event in the CTEP-AERS report and do not require 
separate CTEP-AERS reports. 
 
The possibility of the contribution of comorbid conditions to the event should be considered 
when reporting adverse events. Examples include hyperglycemia in patients with diabetes or 
headaches and seizures in patients with brain tumors. 
 
 
7.5 
ROUTINE ADVERSE EVENT REPORTING 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 
 
7.5.1 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.5.2 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified.  
 


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7.6 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
All clinical research requires monitoring to ensure the quality data and human subjects protection 
(HSP).  The following plan will be used for this study.    
 
7.6.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis (at least weekly) when patients are being 
actively treated on the trial to discuss each patient. All data will be collected in a timely manner 
and reviewed by the principal investigator or the lead associate investigator. Events meeting 
requirements for expedited reporting as described in section 7.2.1 will be submitted within the 
appropriate timelines.  
 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
 
8 PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.3. 
 
8.1 
SUNITINIB [SUNITINIB MALATE (NSC 736511)] 
 
 
Chemical Name 
N-[2-(Diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-
ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, compound with (S)-2-
hydroxybutanedioic acid  
 
 
 
Other Names 
 
 
 SU011248 L-malate; Sutent 
 
 
 
Classification 
 
 
Multi-kinase inhibitor 
 
 
 
Molecular Formula:  C22H27FN4O2•C4H6O5  M.W.: 532.57 Daltons 
 
 
 
Description:  Sunitinib malate is the L-malate salt of SU011248 free base. 
 
 
 
CAS Registry Number 
 
 
341031-54-7 
 
 
 
Aqueous Solubility 
Solvent 
Solubility (mg/mL) 
0.1 M HCl 
59.1 


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Solubility in Various Solvents 
 
Mode of Action:  Sunitinib is a 
small molecule that inhibits 
multiple receptor tyrosine 
kinases (RTKs), some of which 
are implicated in tumor growth, 
pathologic angiogenesis, and 
metastatic progression of 
cancer. Sunitinib is an inhibitor 
of platelet-derived growth 
factor receptors (PDGFRα and 
PDGFRβ), vascular endothelial 
growth factor receptors 
(VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like 
tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), 
and the glial cell-line derived neurotrophic factor receptor (RET). 
 
How Supplied: Sunitinib malate capsules are supplied by Pfizer, Inc. and 
distributed by the Pharmaceutical Management Branch, CTEP/DCTD/NCI.  
Capsules are packaged in 28-count bottles with mannitol, croscarmellose sodium, 
povidone (K-25) and magnesium stearate as inactive ingredients in the following 
strengths: 
• 12.5 mg hard gelatin capsule (size 4) with orange cap and orange body, 
printed with white ink "Pfizer" on the cap and "STN 12.5 mg" on the body.  
• 25 mg hard gelatin capsule (size 3) with caramel cap and orange body, 
printed with white ink "Pfizer" on the cap and "STN 25 mg" on the body.  
• 50 mg hard gelatin capsule (size 2) with caramel top and caramel body, 
printed with white ink "Pfizer" on the cap and "STN 50 mg" on the body.  
Orange gelatin capsule shells contain titanium dioxide, and red iron oxide.  Caramel 
gelatin capsule shells contain titanium dioxide, red iron oxide, yellow iron oxide 
and black iron oxide.  White printing ink contains shellac, propylene glycol, sodium 
hydroxide, povidone and titanium dioxide. 
 
Storage:  Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). 
 
pH 4.5 buffer 25.4 
pH 6.8 buffer 37.8 
pH 7.5 buffer  0.05 
in water  
1.6 
Solvent  
Solubility (mg/mL) 
Acetonitrile  
0.1 
Dimethyl sulfoxide  
92.9 
Tetrahydrofuran  
0.2 
Methanol  
1.5 
Ethanol  
0.3 
1-Butanol  
0.1 
1-Butano:Water (80/20 
v/v)  
6.2 
N,N-Dimethylacetamide  37 
N,N-
Dimethylformamide  
18.4 


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53 
Stability:  Refer to the package label for expiration. 
 
Route of Administration:  Oral administration, take with or without food. 
 
Potential Drug Interaction 
Sunitinib is metabolized primarily by CYP3A4.  Avoid co-administration of 
strong CYP3A4 inducers/inhibitors. 
 
Patient Care Implications: 
A yellow discoloration of the skin area may result following direct contact with 
the capsules. Wash the exposed area with soap and water immediately. 
 
Availability:  
Sunitinib is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. Sunitinib is provided to the NCI 
under a Collaborative Agreement between the Pharmaceutical Collaborator and 
the DCTD, NCI (see Section 16). 
 
8.2 
AGENT ORDERING AND AGENT ACCOUNTABILITY 
8.2.1 NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
8.2.2 Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call 240-276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
8.2.3 Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form (DARF).  (See 


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54 
the NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage.) 
 
 
9 BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
As soon as possible after the patient is scheduled please send an email notification to the Trepel 
lab (trepel@helix.nih.gov), Sunmin Lee (leesun@pop.nci.nih.gov), and Min-Jung Lee 
(leemin@mail.nih.gov) that the sample is scheduled. After the sample is drawn please call the 
Trepel lab at 240-760-6330 to communicate that the sample is ready. Keep the sample on the 
unit at room temperature and the sample will be picked up by the lab. Correlative studies will be 
performed on all patients who enroll in the protocol (including those with HIV infection).  
 
9.1 
SERUM VEGFR2, PLGF, IL-4, IL-12, HGF, B-FGF – GROUP 1 ONLY 
a. Collection of Specimen(s): one 10-cc redtop serum tube 
b. Handling of Specimens(s): keep at room temp.  The sample will be picked up by the 
Trepel lab. 
c. Shipping of Specimen(s):  There is no shipping; these studies apply to NCI only. 
d. Methods; Isolate serum from redtop serum tube, freeze, thaw, run sandwich ELISA 
or an electrochemiluminescent multiplexed sandwich immunoassay (Meso-Scale 
Discovery). 
e. Site(s) Performing Correlative Study: Trepel Lab, DTB, Building 10, Room 12N218. 
 
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*   
a. Collection of Specimen(s): four 10-ml lavender top tubes 
b. Handling of Specimens(s): Keep at room temp.  The sample will be picked up by the 
Trepel lab. 
c. Shipping of Specimen(s): There is no shipping; these studies apply to NCI only. 
d. Methods:  Cell-based analyses will be performed by multiparametic flow cytometry. 
e. Site(s) Performing Correlative Study: Trepel Lab, DTB, Building 10, Room 12N218. 
 
Note: Subsets marked with an asterisk (*) will be applicable to Group 2 only. 
 
9.3 
INTRA-TUMORAL IMMUNE INFILTRATE, WHERE TUMOR SAMPLES ARE AVAILABLE 
a. Collection of Specimen(s): Tissue will be placed in media provided by the lab.  The 
Trepel lab will go to the OR or IR to be present at the time of the procedure. 
b. Handling of Specimens(s): On ice.  Tumor will be immediately dissociated into 
single viable cells and viably frozen until thawing for multiparameter flow 
cytometric analysis. 
c. Shipping of Specimen(s): No shipping. 
d. Methods: Thaw and stain for immune subsets including but not limited to CD8, 


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55 
CD4, CD56, CD68 and analyze by multiparameric flow cytometry. 
e. Site(s) Performing Correlative Study; Trepel Lab, DTB, Building 10, Room 12N218. 
 
9.4 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required.  
 
Any specimens that are remaining at the completion of the protocol will be stored in the 
conditions described below. The study will remain open so long as sample or data analysis 
continues.  Samples from consenting subjects will be stored until they are no longer of scientific 
value or if a subject withdraws consent for their continued use, at which time they will be 
destroyed.  
 
If the patient withdraws consent the participant’s data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved. 
 
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of section 7.2. 
 
10 DATA COLLECTION AND EVALUATION  
10.1 DATA COLLECTION 
The PI will be responsible for overseeing entry of data into C3D, an in-house password protected 
electronic system; and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts.  All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for a minimum of 30 days after removal from study treatment 
or until off-study, whichever comes first. 
 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  


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56 
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.3.2.  
 
11 STUDY CALENDAR 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. 
 
 


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57 
Group 1 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3j 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13m 
Off- Treatment 
Follow-up 
Evaluationsi 
Sunitinib 
 
A 
A 
A 
A 
 
 
A 
A 
A 
A 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
 
 
 
Physical exam 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
Vital signs 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
Blood Pressure h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
Performance status 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
X 
CBC w/diff, pltsl 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
Serum chemistrya 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram/MUGA 
scan k 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------X 
 
X 
 
Tumor measurements 
X 
Tumor measurements are repeated every 6 weeks for patients on treatment < 1 year; every 
12 weeks for patients on treatment ≥ 1 year.  Documentation (radiologic) must be provided 
for patients removed from study for progressive disease. 
 
X 
 
Radiologic evaluation 
X 
Radiologic measurements should be performed every 6 weeks for patients on treatment < 1 
year; every 12 weeks for patients on treatment ≥ 1 year. 
 
X 
 


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Group 1 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3j 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13m 
Off- Treatment 
Follow-up 
Evaluationsi 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH and Free T4 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Circulating angiogenic 
proteins d  
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
CEP/CEC/CTC e 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Tumor molecular profiling f 
and intra-tumoral immune 
infiltrate g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Follow-up Evaluations per 
Section 5.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
A: Sunitinib:  Dose as assigned; administration schedule 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, 
SGOT [AST], SGPT [ALT], sodium; at baseline; on weeks 1 and 3 for Cycle 1; and then on Weeks 1 and 7 only for subsequent cycles, unless 
clinically indicated. 
b: 
Serum pregnancy test (women of childbearing potential). 
c: 
Off-study evaluation.   
d:      Serum VEGFR2, PlGF, IL-4, IL-12, HGF, b-FGF will be collected at baseline; on Week 7 (= Cycle 2, Week 1), and Week 13 (= Cycle 3, Week 1) 
at NCI only 
e:    Circulating endothelial cells, circulating endothelial progenitor cells, and circulating tumor cells will be collected at baseline; on Week 7 (= Cycle 2, 
Week 1), and Week 13 (= Cycle 3, Week 1) at NCI only 
f:      only in patients who also enroll in pilot study 11-C-0096 
g:     only in patients who donate fresh tissue 
h:     BP will be measured at baseline, and then weekly thereafter; i.e., at every clinic visit, and at home on weeks when there is no clinic visit.  See Appendix 
F. 
i:    Follow-up evaluations will be conducted by clinic visits or phone interviews yearly until death, in accordance with Section 5.4. 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. 
j:      Cycle 1 only 
k:      Echo will be done at baseline, on Cycle 1 Week 1, and then every other cycle; i.e., Cycles 3, 5, 7, etc., according to Section 5.1.3  
l:     CBC w/diff, plts: at baseline; on weeks 1 and 3 for Cycle 1; and then on Weeks 1 and 7 only for subsequent cycles, unless clinically indicated. 
m:   Week 13 refers to Cycle 3 Week 1 only 
 
 


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Group 2 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Off- Treatment 
Follow-up 
Evaluationsh 
Sunitinib 
 
A 
A 
 
A 
A 
 
A 
A 
 
A 
A 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
 
 
 
Physical exam 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
Vital signs 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
Blood Pressure g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Performance status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
CBC w/diff, plts 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Serum chemistrya 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brain imaging (MRI or CT 
w/contrast) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram/MUGA 
scan i 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------X 
 
X 
 
Tumor measurements 
X 
Tumor measurements are repeated every 6 weeks for patients on treatment < 1 year; every 
12 weeks for patients on treatment ≥ 1 year.  Documentation (radiologic) must be provided 
for patients removed from study for progressive disease. 
 
X 
 


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Group 2 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Off- Treatment 
Follow-up 
Evaluationsh 
Radiologic evaluation 
X 
Radiologic measurements should be performed every 6 weeks for patients on treatment < 1 
year; every 12 weeks for patients on treatment ≥ 1 year. 
 
X 
 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH and Free T4 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Immune subsets d  
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
CEP/CEC/CTC e 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
intra-tumoral immune 
infiltrate f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Follow-up Evaluations per 
Section 5.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
A: Sunitinib:  Dose as assigned; administration schedule 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, 
SGOT [AST], SGPT [ALT], sodium; at baseline, and every 3 weeks, unless clinically indicated. 
b: 
Serum pregnancy test (women of childbearing potential). 
c: 
Off-study evaluation.   
d:      Samples for Tregs, MDSCs, Th1/Th2, and exhausted T cell analysis will be collected at baseline; on Week 4 and 7 (= Cycle 2, Week 1 and Cycle 3, 
Week 1), and Week 13 (= Cycle 5, Week 1) at NCI only 
e:    Circulating endothelial cells, circulating endothelial progenitor cells, and circulating tumor cells will be collected at baseline; on Week 7 (= Cycle 2, 
Week 1), and Week 13 (= Cycle 3, Week 1) at NCI only 
 
f:     only in patients who donate fresh tissue 
g:     BP will be measured at baseline, and then weekly thereafter; i.e., at every clinic visit, and at home on weeks when there is no clinic visit.  See Appendix 
F. 
h:    Follow-up evaluations will be conducted by clinic visits or phone interviews yearly until death, in accordance with Section 5.4. 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. 
i:      Echo will be done at baseline, on Cycle 1 Week 1, and then every other cycle; i.e., Cycles 3, 5, 7, etc., according to Section 5.1.3 for patients on 
treatment < 1 year; then every 12 weeks for patients on treatment ≥ 1 year. 
 


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61 
12 MEASUREMENT OF EFFECT 
12.1 ANTITUMOR EFFECT – SOLID TUMORS 
 
For the purposes of this study, patients should be re-evaluated for response every 6 weeks for 
patients on treatment < 1 year; every 12 weeks for patients on treatment ≥ 1 year.  In addition to 
a baseline scan, confirmatory scans should also be obtained 4 weeks following initial 
documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) 145.Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
 
12.1.1 Definitions 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with sunitinib.  
 
Evaluable for objective response:  Only those patients who have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for response.  
These patients will have their response classified according to the definitions stated below.  
(Note:  Patients who exhibit objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.) 
 
12.1.2 Disease Parameters 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as: 
• By chest x-ray: ≥20 mm; 
• By CT scan: 
o Scan slice thickness 5mm or under: as ≥10 mm 
o Scan slice thickness >5 mm: double the slice thickness  
o With calipers on clinical exam ≥10 mm  
 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.   
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
 


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62 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
12.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 


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63 
ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 


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64 
12.1.4 Response Criteria 
12.1.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
 
Partial Response (PR): 
 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of 
one or more new lesions is also considered 
progressions). 
 
Stable Disease (SD):  
 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference 
the smallest sum diameters while on study. 
 
12.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes 
must be non-pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
 
 
Non-CR/Non-PD:  
 
 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  
Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 


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65 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
12.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-
Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-
CR/Non-
PD 
No 
PR 
>4 wks. 
Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or 
CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is 
evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary 
endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-
target lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 


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“symptomatic deterioration.”  Every effort should be made to 
document the objective progression even after discontinuation 
of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
12.1.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
12.1.6 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
13 DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
 
13.1 DATA REPORTING 
13.1.1 Method 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis, either by FTP burst of data or via the CDS web application.  Reports are due 


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January 31, April 30, July 31, and October 31.  Instructions for submitting data using the CDUS 
can be found on the CTEP Web site: (http://ctep.cancer.gov/reporting/cdus.html).  
 
13.1.2 Responsibility for Data Submission 
Participating sites will enter data into C3D. The coordinating center is responsible for quarterly 
CDUS submissions for all sites. 
14 CTEP MULTICENTER GUIDELINES 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix E. 
• The Principal Investigator/Coordinating Center is responsible for distributing all 
IND Action Letters or Safety Reports received from CTEP to all participating 
institutions for submission to their individual IRBs for action as required. 
 
• Except in very unusual circumstances, each participating institution will order 
DCTD-supplied agents directly from CTEP.  Agents may be ordered by a 
participating site only after the initial IRB approval for the site has been 
forwarded by the Coordinating Center to the CTEP PIO (PIO@ctep.nci.nih.gov) 
except for Group studies. 
 
15 CCR MULTI-INSTITUTIONAL GUIDELINES 
15.1 IRB APPROVALS  
The PI will provide the NIH Intramural IRB with a copy of the participating institution’s 
approved yearly continuing review.  Registration will be halted at any participating institution in 
which a current continuing approval is not on file at the NIH Intramural IRB. 
 
15.2 AMENDMENTS AND CONSENTS 
The CCR PI will provide the NIH Intramural IRB with copies of all amendments, consents and 
approvals from each participating institution. 
 
16 COLLABORATIVE AGREEMENTS  
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 


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1.   Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the 
clinical study.  Collaborator(s) data for Agent(s) are confidential and proprietary 
to Collaborator(s) and shall be maintained as such by the investigators.  The 
protocol documents for studies utilizing Agents contain confidential information 
and should not be shared or distributed without the permission of the NCI.  If a 
copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement.  
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2.   For a clinical protocol where there is an investigational Agent used in 
combination with (an)other Agent(s), each the subject of different Collaborative 
Agreements, the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as "Multi-
Party Data”): 
 
a.  NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NCI, the design of the proposed combination protocol, and the existence of 
any obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b.  Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow 
said other Collaborator to develop, obtain regulatory approval or 
commercialize its own Agent. 
 
c.  Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use 
the Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
 
3.   Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4.   When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 


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contact them. 
 
5.   Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6.   Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least 
three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings.  Press releases and other media 
presentations must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
17 STATISTICAL CONSIDERATIONS 
17.1  STUDY DESIGN/ENDPOINTS 
 
The primary endpoint of the study is objective response rate (CR+PR) according to RECIST 1.1 
criteria for sunitinib monotherapy in patients with advanced thymic malignancies.  The cohorts 
will separately be evaluated in this regard as the primary endpoint for each. All sample size 
estimates are based on the objective response rate.  
 
Group 1 
Based on available results of systemic treatments of thymic carcinoma in the literature it is 
concluded that an objective response rate consistent with 25% and greater than 5% could be 
considered better, or at least similar, to what has been shown for chemotherapy in this setting. 
For thymomas, a target of 30% is being proposed. For each cohort, this study will use a Simon 2-
stage design, optimal for thymic carcinomas and MinMax for thymomas, and set the probability 
for accepting a poor drug to 10% (alpha=0.10) and the probability of rejecting a good drug at 
10% (beta=0.10).  
 


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For thymic carcinomas, the study will try to rule out a 5% objective response rate (p0=0.05) and 
target a modest response rate of 25% (p1=0.25). The study will initially enroll 9 evaluable 
patients with thymic carcinoma; if 0 of the 9 patients demonstrate a partial response then no 
further patients will be accrued. If 1 or more of the first 9 patients have a response, then accrual 
would continue until a total of 24 evaluable patients have been treated. A temporary pause in the 
accrual to the trial may be necessary to ensure that enrollment to the second stage is warranted. If 
there are 1 to 2 patients with a response in the total of 24 evaluable patients, then this would be 
an uninterestingly low rate, while if there were 3or more patients of the 24 who have a response, 
this would be sufficiently interesting to warrant further study of this agent in later trials. Under 
the null hypothesis (5% response rate), the probability of early termination in this cohort is 63%.  
For thymomas, the study will try to rule out a 10% objective response rate (p0=0.10) and target a 
modest response rate of 30% (p1=0.30).  The study will initially enroll 16 evaluable patients with 
thymoma; if 0 to 1 of the 16 patients demonstrate a partial response then no further patients will 
be accrued. If 2 or more of the first 16 patients have a response, then accrual would continue 
until a total of 25 evaluable patients have been treated. A temporary pause in the accrual to the 
trial may be necessary to ensure that enrollment to the second stage is warranted. If there are 2 to 
4 patients with a response in the total of 25 evaluable patients, then this would be an 
uninterestingly low rate, while if there were 5 or more patients of the 25 who have a response, 
this would be sufficiently interesting to warrant further study of this agent in later trials. Under 
the null hypothesis (10% response rate), the probability of early termination in this cohort is 
51%. 
  
Group 2 
To gain further information about the use of this agent in this specific disease, we would like to 
treat 15 additional subjects with thymic carcinoma.  Effective with Amendment E (version date 
05/12/14), up to 15 patients will be enrolled as a small, pilot cohort to obtain preliminary data on 
efficacy as well as on a small number of exploratory parameters. The prior overall response rate 
using the original dose and schedule was approximately 26%. This portion of the study would 
aim to demonstrate if the response rate were similar to that rate in a limited number of patients 
treated using a modified dosing schedule (50 mg per day for 2 weeks with 1 week off) in order to 
determine if further, more definitive study would be warranted. With 15 patients, the two-tailed 
90% confidence interval about 26% extends approximately +/- 18.6% and the two-tailed 80% 
confidence interval about 26% extends approximately +/- 14.5%. Thus, the response rate 
obtained would be able to only approximately estimate the true response rate, but would be 
sufficient to be used as a basis for determining if a more definitive study is warranted, and to 
estimate parameters to consider for the subsequent study.  Similarly, with 15 patients, only an 
approximate estimate of the PFS probabilities can be obtained, but these results could be 
informally compared to those resulting from the original dose and schedule. A cohort of 15 
subjects would also provide adequate patients for exploratory analyses of a variety of 
pharmacodynamic studies and to study the effect of sunitinib therapy on regulatory T cells 
(Tregs), exhausted CD8 T cells, myeloid-derived suppressor cells (MDSCs), and Th1/Th2 T cell 
populations, as well as the exploratory studies of circulating tumor cells, endothelial progenitors, 
and mature apoptotic endothelial cells applicable to both groups. 
 


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17.2  SAMPLE SIZE/ACCRUAL RATE 
12-C-0118 used a Simon 2-stage design with an accrual ceiling of 52 (Group 1) based on the 
assumption that the individual cohorts for thymoma and thymic carcinoma would proceed to the 
second stage with accrual ceilings of 25 and 24 evaluable patients respectively (plus an 
additional 3 patients to allow for a small number of inevaluable patients.) However, the results 
from the study demonstrated only 1 PR in the thymoma cohort among the first 16 evaluable 
patients, and hence accrual was halted at 16 patients as previously specified and did not proceed 
to the accrual ceiling of 25 patients for this cohort (2 or more responses needed to be observed to 
proceed to 25 patients.) However, in the thymic carcinoma cohort more than 1 PR was observed 
in the first 9 evaluable patients. Hence, accrual proceeded to the second stage with an accrual 
ceiling of 24 patients in this cohort. The total accrual in study 12-C-0118 was therefore 16+25 
=41 patients. Therefore, a total of 11 slots remained unfilled in the original study due to the 
inability of the thymoma cohort to proceed to the second-stage of accrual.  
 
In Amendment E, (version date 05/12/14), we provide a justification to evaluate sunitinib in 
patients with thymic carcinoma while discontinuing evaluation of this drug in patients with 
thymoma. Further, we would like to evaluate sunitinib in thymic carcinoma using a modified 
dosing schedule in an additional 15 patients (Group 2). Hence, we would like to utilize the 9 
unfilled thymoma slots from the original study, add 6 new slots (to obtain 15 slots for the new 
thymic carcinoma cohort, Group 2) and retain 2 slots for inevaluable patients for an accrual 
ceiling of 52+6=58 patients. 
 
It is anticipated that approximately 3 patients per month overall may enroll on this trial. Group 1 
accrual was completed in less than two years.  Thus, Group 2 accrual should be completed with 
approximately one additional year, thereby completing overall trial accrual in a total of three 
years. Progression free and overall survival will also be determined for each group separately, 
using Kaplan-Meier curves, and reported as a secondary endpoint.  
 
17.3  STRATIFICATION FACTORS 
 
 
 
N/A   
 
17.4  ANALYSIS OF SECONDARY ENDPOINTS 
We will follow all patients from the time that they are enrolled in the trial until the time of death. 
Demographic information such as age, gender and race will be tabulated. Durations of response, 
progression free survival, and overall survival will be determined actuarially using the Kaplan-
Meier method. The results of this analysis may be compared in an informal manner to any 
similarly defined curves available from other published studies in comparable patients with the 
same disease. Correlative studies are exploratory, hence statistical power calculations will not be 
provided. Expression levels of various proteins from pre- and post-treatment samples will be 
compared using an appropriate nonparametric test and pre-post differences between responders 
and non-responders using a Wilcoxon rank sum test. These latter evaluations will be considered 
exploratory and the resulting p-values will be presented as being exploratory and without 


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adjustment for multiple comparisons. 
 
17.5 REPORTING AND EXCLUSIONS 
17.5.1 Evaluation of toxicity  
All patients will be evaluable for toxicity from the time of their first treatment with sunitinib. 
 
17.5.2 Evaluation of response  
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a 
clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate.  Precise definitions for categories 4-9 will be 
protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol deviations, etc.).  However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  The 95% confidence intervals should also be provided.  
 
18 HUMAN SUBJECTS PROTECTIONS  
18.1  RATIONALE FOR SUBJECT SELECTION 
This study will be open to all individual with relapsed or refractory thymoma (Group 1 only) or 
thymic carcinoma regardless of gender, ethnicity, or race provided that the aforementioned 
inclusion and exclusion criteria are met. To date, there is no information that suggests that 
differences in drug metabolism or disease response would be expected in one sex, racial or ethnic 
group compared to another. Efforts will be made to extend accrual to each representative 
population, but in this preliminary study, a balance must be struck between patient safety 
considerations and limitations on the number of individuals exposed to potentially toxic and/or 
ineffective treatments on the one hand and the need to explore racial/ethnic aspects of clinical 
research on the other hand. If differences in outcome that correlate to ethnic identity are noted, 
accrual may be expanded or a follow-up study may be written to investigate those differences 
more fully. 
 


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This study will be recruited through internal referral, our local physician referral base, and 
through various cancer information hotlines (i.e., Clinical Studies Support Center, 1-800-
4Cancer). 
 
For safety reasons, only pregnant women and children are excluded from this study. Pregnant 
women are excluded from this study because sunitinib angiogenesis inhibitor with the potential 
for teratogenic or abortifacient effects. Patients with HIV and immunosuppression [CD4 count < 
institutional LLN (334 cells/uL)] are excluded from the study due to potential for sunitinib 
induced myelosuppression which could place these patients at increased risk of lethal infections. 
Sunitinib metabolism is predominantly mediated by CYP3A4 and concurrent treatment with 
CYP3A4 inducers and inhibitors may affect sunitinib metabolism. Hence patients with HIV who 
are being treated with drugs which are inhibitors or inducers of CYP3A4 are also excluded from 
the study.  
 
Patients with evidence of severe or uncontrolled systemic disease, including active or 
uncontrolled infection, immune deficiencies, Hepatitis B, Hepatitis C, uncontrolled diabetes, 
uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, 
myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, 
stroke/cerebrovascular accident within the past 6 months, or psychiatric illness/social situations 
that would limit compliance with study requirements) are excluded due to the possibility that 
sunitinib may worsen their condition and the likelihood that the underlying condition may 
obscure the attribution of adverse events with respect to sunitinib. Patients with symptomatic 
brain metastases will be excluded from trial secondary to poor prognosis.   
 
18.2  PARTICIPATION OF CHILDREN 
Patients under the age of 18 will be excluded from study due to the low occurrence of these 
oncologic histologies in the pediatric population. In addition, the risk of exposure to an 
investigational agent without proven benefit in the targeted histologies supports excluding 
children until additional safety and efficacy data is available. 
 
18.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 18.5), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation as needed for the following: an independent 
assessment of whether an individual has the capacity to provide consent; assistance in identifying 
and assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to 
appoint a surrogate.  For those subjects that become incapacitated and do not have a pre-
determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for 


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appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and 
(b) who do not have a legal guardian or durable power of attorney, will be followed. 
 
18.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
Patients should realize that we are hopeful that they may gain benefit from this study, but there is 
no objective evidence to support our optimism at this time. The potential benefit to a patient who 
enters study is a reduction in the bulk of his/her tumor, which may or may not have a favorable 
impact on symptoms and/or survival. Potential risks include the possible occurrence of any of a 
range of side effects that are listed in the pharmaceutical section and the consent document. The 
procedure for protecting against or minimizing risks will be to medically evaluate patients on a 
regular basis as described earlier. 
 
18.5  RISKS/BENEFITS ANALYSIS 
Sunitinib has been extensively studied and approved for use in several other malignancies. 
Previous studies and in clinical experience have demonstrated that sunitinib has an acceptable 
toxicity profile. For adults and adults unable to consent, there is more than minimal risk 
associated with the treatment offered in this study with the prospect for direct benefit.  The 
potential benefit of disease stabilization, tumor shrinkage or reduction of symptoms provided by 
sunitinib justifies the risk in this high risk patient population of advanced thymic malignancies. 
 
18.6  CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
An associate or principal investigator on the trial will inform patients of the purpose, alternatives, 
treatment plan, research objectives and follow-up of this trial. The patient will be provided an 
IRB-approved consent for review and signature and his/her questions will be answered. After a 
decision is made to enroll into the study, a signature will be obtained from the patient at a 
subsequent visit. The original of the signed informed consent will be placed in the patient's 
medical record. All patients must have a signed informed consent form and an on-study 
(confirmation of eligibility) form filled out and signed by a participating investigator before 
entering on study. 
 
Telephone Consent: 
When re-consent is required due to an amendment, the patient can be consented via telephone if 
needed for logistical reasons. Telephone consent will be obtained and documented per 
OHSRP/IRBO and CCR policies and procedures.  


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reversal of immune suppression and modulation of tumor microenvironment for immune-
based cancer therapies. Cancer Res. 2009;69(6):2514-2522. 
142. 
Deeken J, Rudek M, Moore P. A Phase I/PK study of Sunitinib With Highly Active 
Antiretroviral Therapy (HAART) HIV+ Patients with Solid Tumors: AIDS Malignancy 
Consortium Study 061. 13th International Conference on Malignancies in AIDS and 
Other Acquired Immunodeficiencies, Bethesda, MD. 2011. 
143. 
Rieker RJ, Hoegel J, Morresi-Hauf A, et al. Histologic classification of thymic epithelial 
tumors: comparison of established classification schemes. Int J Cancer. 2002;98(6):900-
906. 
144. 
Kuo TT. Tumours of the thymus. In: Travis WD, Brambilla E, Muller-Hermelink HK, et 
al., editors. World Health Organization Classification of Tumors: Pathology and Genetics 
of Tumors of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press; pp. 146–
248, 2004. 
145. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
 
 
 


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


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21 APPENDIX B: NEW YORK HEART ASSOCIATION CLASSIFICATION OF 
CARDIAC DISEASE 
 
 
 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure 
or the anginal syndrome may be present even at rest.  If any 
physical activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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22 APPENDIX C: DRUGS KNOWN TO BE METABOLIZED BY SELECTED CYP450 
ISOENZYMES 
 
Cytochrome P450 (CYP) Enzyme 
 
CYP3A4 Substrates, Inhibitors, and Inducers 
 
 
 
 
 
 
 
3A4 Substrates 
Albuterol 
Alfentanil 
Alprazolam 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Buprenorphine 
Buspirone 
Busulfan 
Carbamazapine 
Cerivastatin 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Cisapride 
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Colchicine 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Delavirdine 
Diazepam 
Digitoxin 
Dihydroergotamine 
Diltiazem 
Disopyramide 
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Efavirenz 
Eletriptan 
Enalapril 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, conj., synthetic 
Estrogens, conj., equine 
Estrogens, conj., esterified 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Felbamate 
Felodipine 
Fentanyl 
Flurazepam 
Flutamide 
Fosamprenavir 
Fulvestrant 
Gefitinib 
Halofantrine 
Haloperidol 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide dinitrate 
Isosorbide mononitrate 
Isradipine 
Itraconazole 
Ketamine 
Ketoconazole 
Lansoprazole 
Letrozole 
Levomethadyl acetate 
hydrochloride 
Levonorgestrel 
Lidocaine 
Losartan 
Lovastatin 
Medroxyprogesterone 
Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methysergide 
Miconazole 
Midazolam 
Miglustat 
Mirtazapine 
Modafinil 
Montelukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Norethindrone 
Norgestrel 
Ondansetron 
Paclitaxel 
Pergolide 
Phencyclidine 
Pimozide 
Pioglitazone 
Primaquine 
Progesterone 
Quetiapine 
Quinidine 
Rabeprazole 
Repaglinide 
Rifabutin 
Rifampin 
Ritonavir 
Saquinavir 
Sertraline 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Tamsulosin 
Telithromycin 
Teniposide 
Terbinafine 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tolterodine 
Toremifene 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zolpidem 
Zonisamide 
Zopiclone 


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87 
 
3A4 Inhibitors 
Acetominophen 
Acetazolamide 
Amioderone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffiene 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetadine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Cyclophosphamide 
Cyclosporine 
Danazol 
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit juice 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Isoniazid 
Isradapine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan 
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nitrendipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarpine 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapimil 
Vinblastine 
Vincristine 
Vinorelbine 
Zafirlukast 
Ziprasidone 
 
 
 
 3A4 Inducers 
Aminoglutethimide 
Carbamazapine 
Efavirenz  
Etravirine 
Fosphenytoin 
St. John’s wort 
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin 
Rifampin 
Rifapentine 
 
 
When Study Agent is co-administered with drugs classified as “substrates,” the plasma concentration of the substrate is high. 
When Study Agent is co-administered with drugs classified as ‘inhibitors,’ plasma concentrations of the Study Agent will be 
high.  When Study Agent is co-administered with drugs classified as “inducers,” the plasma concentration of the Study Agent 
will be low.   
In general, drug interactions occur significantly between substrates and either inhibitors or inducers of the same enzymes 
usually classified as “strong” substrates, inhibitors, or inducers. 
These lists are not all-inclusive.  Check additional references or sources. 
 
 (Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In: Lacy CF, Armstrong LL, Goldman MP, Lance LL eds. 
Drug Information Handbook 12TH ed. Hudson, OH; LexiComp Inc. 2004: 1619-1631.) 
 
(1)  Malhorta et al. (2000). Clin Pharmacol Ther. 69:14-23 
 
(2)  Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249 
      Frye et al. (2004). Clin Pharmacol Ther. 76:323-329 
 


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23 APPENDIX D: PATIENT’S MEDICATION DIARY  
 
Today’s date: 
Patient’s name: 
Patient’s study ID:  
 
Patient’s Medication Diary - Group 1 
 
 INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each 6 week-period while you take sunitinib. 
2. You will take your dose of sunitinib by mouth each day in the morning. You will 
take ____12.5 mg capsules and/or  ____ 25 mg capsules or ___50 mg capsule. You 
may take the capsules with or without food as you wish. 
3. Record the date, the number of capsules of each size you took, and when you took 
them. 
4. Record the daily dose onto the diary, including missed, skipped, or vomited doses. If 
you vomit after taking the tablets, the dose is replaced only if the tablets can actually be 
seen and counted. If you miss a dose, you should resume with the next scheduled dose. 
5. If you have any comments or notice any side effects, please record them in the 
Comments column. 
6. Wash your hands with soap and water after touching the capsule(s). Do not share 
this medication with anyone. 
7. Please return unused sunitinib capsules (or empty bottles) and this form to your 
physician when you go for your next appointment. 
Day 
 
Date 
 
Time 
of 
daily 
dose 
 
# of capsules 
taken 
 
BP 
readings 
Comments 
12.5 
mg  
25 mg 
 
50 mg 
1 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 


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16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
29-42   
 
 
Drug holiday  
 Physician’s Office will complete this section: 
1. Date patient started protocol treatment 
__________________________________________ 
2. Date patient was removed from study 
________________________________________ 
3. Patient’s planned total daily dose 
____________________________________________ 
4. Total number of tablets taken this month  
___________________________________ 
5. Physician/Nurse/Data Manager’s Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Today’s date: 
Patient’s name: 
Patient’s study ID:  
 
Patient’s Medication Diary - Group 2 
 
 INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each 3 week-period while you take sunitinib. 
2. You will take your dose of sunitinib by mouth each day in the morning. You will 
take ____12.5 mg capsules and/or  ____ 25 mg capsules or ___50 mg capsule. You 
may take the capsules with or without food as you wish. 
3. Record the date, the number of capsules of each size you took, and when you took 
them. 
4. Record the daily dose onto the diary, including missed, skipped, or vomited doses. If 
you vomit after taking the tablets, the dose is replaced only if the tablets can actually be 
seen and counted. If you miss a dose, you should resume with the next scheduled dose. 
5. If you have any comments or notice any side effects, please record them in the 
Comments column. 
6. Wash your hands with soap and water after touching the capsule(s). Do not share 
this medication with anyone. 
7. Please return unused sunitinib capsules (or empty bottles) and this form to your 
physician when you go for your next appointment. 
Day 
 
Date 
 
Time 
of 
daily 
dose 
 
# of capsules 
taken 
 
BP 
readings 
Comments 
12.5 
mg  
25 mg 
 
50 mg 
1 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
15-21 
 
 
 
Drug holiday  
 Physician’s Office will complete this section: 
1. Date patient started protocol treatment 
__________________________________________ 


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2. Date patient was removed from study 
________________________________________ 
3. Patient’s planned total daily dose 
____________________________________________ 
4. Total number of tablets taken this month  
___________________________________ 
5. Physician/Nurse/Data Manager’s Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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24 APPENDIX E: CTEP MULTICENTER GUIDELINES 
 
If an institution wishes to collaborate with other participating institutions in performing a 
CTEP sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
•  Prior to the activation of the protocol at each participating institution, an OHRP form 
310 (documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports.  There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the 
Coordinating Center who in turn report to CTEP.  The Coordinating Center will submit 
AE reports to the Protocol Chair for timely review. 
 
 
 
Audits may be accomplished in one of two ways: (1) source documents and research records 
for selected patients are brought from participating sites to the Coordinating Center for audit, 


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or (2) selected patient records may be audited on-site at participating sites.  If the NCI 
chooses to have an audit at the Coordinating Center, then the Coordinating Center is 
responsible for having all source documents, research records, all IRB approval documents, 
NCI Drug Accountability Record forms, patient registration lists, response assessments 
scans, x-rays, etc. available for the audit. 
 
Agent Ordering 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP.  Investigational agents may be 
ordered by a participating site only after the initial IRB approval for the site has been 
forwarded by the Coordinating Center to the CTEP PIO.  
 
 
 
 
 
 
 
 


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25 APPENDIX F: COLLECTION/RECORDING OF BLOOD PRESSURE 
INFORMATION 
 
1.0 
General Guidelines 
1.1          Frequency of monitoring.  Blood pressure (BP) should be monitored at baseline, and then weekly 
thereafter; i.e., at every clinic visit, and at home on weeks when there is no clinic visit.   
1.2          Data recording.  All required data should be recorded in the appropriate CRF or on the patient’s blood 
pressure monitoring diary, as appropriate.  The following data are required at baseline and at each 
subsequent assessment: 
• 
Assessment date and time 
• 
Pulse 
• 
Systolic and diastolic BP  
 
1.3         Risk factors for hypertension (assess and record data in baseline history/physical CRF) 
• 
Diabetes (type 1 or type 2) 
• 
Renal disease (specify on CRF) 
• 
Endocrine condition associated with HTN (specify on CRF) 
• 
Use of steroids or NSAIDs (specify all concomitant meds) 
• 
Underlying cardiovascular condition – specify (i.e., ischemic heart disease) 
 
 
2.0         Baseline data collection (at study entry) 
       2.1      All patients 
• 
Current BP 
• 
Proteinuria, if present 
 
      2.2 Patients with preexisting hypertension (i.e., those for whom “hypertension” is entered as a concomitant 
condition at study entry, or those who are currently receiving therapy with antihypertensive medication) – 
also record: 
• 
Date of HTN diagnosis (original) 
• 
Type HTN (essential or secondary) 
• 
CTCAE grade of HTN (at time of study entry) 
• 
Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of the following: 
- 
Antihypertensive agents taken at study entry 
- 
Antihypertensive agents taken in past (e.g., discontinued for toxicity, lack of efficacy) 
 
3.0       Follow up BP data collection (during study) 
      3.1 All patients (at each clinic visit) 
• 
Current BP 
• 
Proteinuria, if present 
 
     3.2 
Patients with treatment-emergent hypertension [defined as BP increase of >20 mmHg (diastolic) OR 
systolic BP >139 OR diastolic BP > 90  (if previously normal or grade 1 per CTCAE v5) – record at time 
of hypertension diagnosis and at all subsequent clinic visits: 
• 
BP changes from baseline (or from previous assessment) (specify CTCAE grade changes) 
• 
Hypertension-related symptoms as reported by patient (e.g., headache) 
• 
Other relevant changes associated with development of hypertension (e.g., ECG 
abnormalities) 
• 
Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of currently 
prescribed antihypertensive agents 
 
     3.3 
Patients with pre-existing hypertension at study entry – record at each clinic visit 
• 
BP changes from previous clinic visit (specify CTCAE grade changes) 


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• 
Hypertension-related symptoms reported by patient (e.g., headache) 
• 
Other relevant changes associated with development of hypertension (e.g., ECG 
abnormalities) 
• 
Changes in antihypertensive medications since last assessment (e.g., dose change, 
add/discontinue drug) 
 
*Classes of antihypertensive drugs include ACE inhibitors, calcium channel blockers, alpha blockers, beta blockers, 
diuretics, angiotension II receptor antagonists. 
 
 


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26 APPENDIX G: MANAGEMENT OF SUNITINIB-INDUCED HYPERTENSION 
 
Recommended Hypertension Monitoring and Management 
(BP in mmHg) 
 
 
Grade 
(CTCAE v5) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Sunitinib 
Dose Modification 
Persistent Grade 1 
Pre-hypertension 
Systolic 120-139 
Diastolic 80-90 
 
 
Standard       
 
No change 
Persistent Grade 2- 
Moderate 
Systolic 140-159  
Diastolic 90-99  
   
Protocol-specific 
guidance supersedes 
any other management 
guidelines, including 
CTCAE v5  
Step 1) Initiate LA DHP 
CCB treatment and if 
needed, after 24-48 hr Rx,  
increase dose in stepwise  
fashion every 24-48 hours  
until BP is controlled or at 
max dose of Rx 
 
Step 2) If BP still not 
controlled, add another 
antihypertensive Rx, a 
BB, ACE1, ARB, or 
ABB; increase dose of this 
drug as described in step 1   
 
Step 3) If BP still not 
controlled, add 3rd drug 
from the list of 
antihypertensives in step 
2; increase dose of this 
drug as described in step 1 
 
Step 4) If BP still not 
controlled, consider either 
1 dose reduction of 
sunitinib or stopping 
sunitinib  
 
NOTE: Stopping or 
reducing the dose of 
sunitinib is expected to 
cause a decrease in BP 
The treating physician 
should monitor the patient 
for hypotension and adjust 
the number and dose of 
antihypertensive 
medication(s) accordingly. 
 
BP should be 
monitored as 
recommended by the 
treating physician  
No change except as 
described in step 4 


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Persistent Grade 3 
Severe  
Systolic >160 
Diastolic >100  
 
Protocol-specific 
guidance supersedes 
any other management 
guidelines, including 
CTCAE v5 
HOLD sunitinib until 
systolic BP <159 and 
diastolic BP <99.  
 
 
BP management is 
identical to that for Grade 
2 (see steps 1-4 above) 
with 2 major exceptions:  
1)  If systolic BP >180 or 
diastolic BP >110 and 
the patient is 
symptomatic: optimal 
management with 
intensive IV support in 
ICU; STOP sunitinib 
and notify hospital staff 
that stopping sunitinib 
may result in a decrease 
in BP 
 and  
2) If systolic BP >180 or 
diastolic BP >110 and 
the patient is 
asymptomatic, 
2 new anti-hypertensives 
must be given together 
in step 1 (and dose 
escalated appropriately 
as in step 1). 
 
NOTE: Stopping or 
reducing the dose of 
sunitinib is expected to 
cause a decrease in BP 
The treating physician 
should monitor the patient 
for hypotension and adjust 
the number and dose of 
antihypertensive 
medication(s) accordingly 
BP should be 
monitored as 
recommended by the 
treating physician 
unless the patient is 
symptomatic with  
systolic BP >180 or 
diastolic BP >110 in 
which case, 
monitoring should 
be intensive. 
 
 
HOLD sunitinib until 
systolic BP <159 and 
diastolic BP  
<99. 
 
In most 
circumstances, if   
BP cannot be 
controlled after an 
optimal trial of anti-
hypertensive 
medications, 
consider either 1 
dose reduction of 
sunitinib or stopping 
sunitinib. 
HOWEVER, 
if the patient 
requires 
hospitalization for 
management of 
symptomatic 
systolic BP >180 or 
diastolic BP >110,  
permanently 
discontinue sunitinib 
or if BP is controlled, 
re-start sunitinib at 1 
lower dose level after 
consultation with the 
study Principal 
Investigator 
 
 
 
 
 
Grade 4 
Life-threatening 
consequences of 
hypertension 
 
Optimal management 
with intensive IV 
support in ICU; STOP 
sunitinib and notify 
hospital staff that 
stopping sunitinib may 
result in a decrease in 
BP 
Intensive 
Permanently 
discontinue sunitinib 
or if BP is controlled, 
re-start sunitinib at 1 
lower dose level after 
consultation with the 
study Principal 
Investigator 
 
Abbreviations: dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers (BB), angiotensin 
converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), alpha beta blocker (ABB) 
• *See table below for suggested antihypertensive medications by class 
• If patients require a delay of >2 weeks for management of hypertension, discontinue protocol therapy 
• If patients require >2 dose reductions, discontinue protocol therapy 


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
 
98 
• Patients may have up to 2 drugs for management of hypertension prior to any dose reduction in sunitinib 
• 24-48 hours should elapse between modifications of anti-hypertensive therapy 
• Hypertension should be graded using CTCAE v5. 
 
Oral Antihypertensive Medications 
 
Agents in bold characters are suggested as optimal choices to avoid or minimize potential drug-
interactions with sunitinib through CYP450. 
Agent 
class 
 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine XL 
30 mg daily 
60 mg daily 
90 mg daily 
CYP 3A4 
substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate 
felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
and inhibitor 
Selective 
β Blockers 
(BB) 
metoprolol 
25 mg 
twice daily 
50 mg 
twice daily 
100 mg 
twice daily 
CYP 2D6 substrate 
atenolol 
25 mg daily 
50 mg daily 
100 mg daily 
No 
acebutolol 
100 mg 
twice daily 
200-300 mg 
twice daily 
400 mg 
twice daily 
Yes (CYP450 
unknown) 
bisoprolol 
2.5 mg daily 
5-10 mg daily 
20 mg daily 
Yes (CYP450 
unknown) 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
 
captopril 
12.5 mg 3x 
daily 
25 mg 3x daily 
50 mg 3x daily 
CYP 2D6 substrate 
enalapril 
5 mg daily 
10-20 mg daily 
40 mg daily 
CYP 3A4 substrate 
ramipril 
2.5 mg daily 
5 mg daily 
10 mg daily 
Yes (CYP450 
unknown) 
lisinopril 
5 mg daily 
10-20 mg daily 
40 mg daily 
No 
fosinopril 
10 mg daily 
20 mg daily 
40 mg daily 
Yes (CYP450 
unknown) 
Rarely used: 
perindopril 
 
4 mg daily 
 
none 
 
8 mg daily 
 
Yes, but not 
CYP450 
Rarely used: 
quinapril 
10 mg daily 
20 mg daily 
40 mg daily 
No 
Angiotensin II 
Receptor 
Blockers 
(ARBs) 
losartan 
25 mg daily 
50 mg daily 
100 mg daily 
CYP 3A4 substrate 
candesartan 
4 mg daily 
8-16 mg daily 
32 mg daily 
CYP 2C9 substrate 
irbesartan 
75 mg daily 
150 mg daily 
300 mg daily 
CYP 2C9 substrate 
telmisartan 
40 mg daily 
none 
80 mg daily 
Yes, but not 


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
 
99 
Agent 
class 
 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
CYP450 
valsartan 
80 mg daily 
none 
160 mg daily 
Yes, but not 
CYP450 
α and β 
Blocker 
labetolol 
100 mg twice 
daily 
200 mg twice 
daily 
400 mg twice 
daily 
CYP 2D6 substrate 
and inhibitor 
 


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
 
100 
27 APPENDIX H 
 
Instructions to site investigators:  Photocopy the following two pages back-to-back and provide 
the sheet to your patients at the time of enrollment.  The third page following contains a wallet-
sized information card for the patient to carry at all times. 
 
 


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
 
101 
 
INFORMATION ON POSSIBLE INTERACTIONS WITH OTHER AGENTS FOR 
PATIENTS AND THEIR CAREGIVERS AND NON-STUDY HEALTH CARE TEAM 
 
The patient _________________ is enrolled on a clinical trial using the experimental agent 
sunitinib. This clinical trial is sponsored by the National Cancer Institute. This form is addressed 
to the patient, but includes important information for others who care for this patient.  
 
Sunitinib interacts with many drugs that are processed by your liver. Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study. It is 
also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study. When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the counter 
remedy), or anything that you buy from the health food store or grocery store (herbal 
supplement).  
 
Many health care prescribers can write prescriptions. You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you. These are the things that you and they need to know:  
 
• 
Sunitinib is metabolized (converted in the body) by a liver enzyme called CYP3A4. 
Sunitinib must be used very carefully with other medicines that need this liver enzyme to be 
effective or to be cleared from your system.  
• 
You and healthcare providers who prescribe drugs for you must be careful about adding 
or removing any drug in this category.  
• 
Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors or substrates of 
CYP3A4.” 
• 
Your regular prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/table.asp to see if any medicine they want to 
prescribe is on a list of drugs to avoid.   
• 
Please be very careful! Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye. They also have a generic name—it’s usually small 
and printed on the ingredient list. Find the generic name (your pharmacist can help) and 
look at the table on the back of this page. Be careful. 
 
• 
You should not take St. John’s wort or grapefruit juice with sunitinib.  
 
• 
You should not receive steroids unless they are absolutely necessary; tell your study 
doctor if you are taking, have a prescription for, or have been given steroids. 
 
• 
You should not take drugs that affect your heart rhythm.  Tell your study doctor if you 
are taking, have a prescription for, or have been given such heart medications. 
 
Other medicines can be a problem with your study drugs.  


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
 
102 
• 
You should check with your doctor or pharmacist whenever you need to use an over-the-
counter medicine or herbal supplement.  
 
• 
Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you. Your study doctor’s name is  
 
________________________________ and he or she can be contacted at  
 
________________________________.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
 
103 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
sunitinib.  This clinical trial is sponsored by the NCI.  Sunitinib 
interacts with drugs that are processed by your liver.  Because of this, 
it is very important to: 
 Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
 Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
Sunitinib interacts with a specific liver enzyme called CYP3A4, and 
must be used very carefully with other medicines that interact with 
this enzyme.  
 Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP3A4.” 
 Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/table.asp for a list 
of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is ______________ and can be 
contacted at ______________.  


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
 
104 
28 APPENDIX I: LIST OF PRESCRIPTION AND OVER THE COUNTER 
MEDICATIONS THAT MAY INTERACT WITH SUNITINIB (SUTENT®) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acetaminophen    
Acetazolamide 
Albuterol 
Alfentanil 
Alprazolam 
Aminoglutethimide 
Amioderone 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Benzphetamine 
Betamethasone 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Buprenorphine 
Buspirone 
Busulfan 
Caffeine 
Carbamazapine 
Cerivastatin 
Chloramphenicol 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Chlorzoxazone 
Cimetadine 
Ciprofloxacin 
Cisapride 
Citalopram 
Clarithromycin 
Clemastine 
Clobazam 
Clofazimine 
Clonazepam 
Clorazepate 
Clotrimazole 
Clozapine 
Cocaine 
Colchicine 
Cyclophosphamide 
Cyclosporine 
Danazol 
Dantrolene 
Dapsone 
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Digitoxin 
Dihydroergotamine 
Diltiazem 
Disopyramide 
Disulfiram 
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Eletriptan 
Enalapril 
Enoxacin 
Entacapone 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, conj., synthetic 
Estrogens, conj., equine 
Estrogens, conj., esterified 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Felbamate 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Flurazepam 
Flutamide 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Fosphenytoin 
Fulvestrant 
Gefitinib 
Glyburide 
Grapefruit juice 
Halofantrine 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Irinotecan 
Isoniazid 
Isosorbide dinitrate 
Isosorbide mononitrate 
Isradipine 
Itraconazole 
Ketamine 
Ketoconazole 
Lansoprazole 
Letrozole 
Levomethadyl acetate 
hydrochloride 
Levonorgestrel 
Lidocaine 
Lomustine 
Losartan 
Lovastatin 
Medroxyprogesterone Mefloquine 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylergonovine 
Methylprednisolone 
Methysergide 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Miglustat 
Mirtazapine 
Mitoxantrone 
Modafinil 
Montelukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Nizatidine 
Norethindrone 
Norfloxacin 
Norgestrel 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxcarbazepine 
Oxybutynin 
Ondansetron 
Paclitaxel 
Paroxetine 
Pentobarbital 
Pergolide 
Phencyclidine 
Phenobarbital  
Phenytoin 
Pilocarpine 
Pimozide 
Pioglitazone 
Pravastatin 
Prednisolone 
Primaquine 
Primidone 
Progesterone 
Propofol 
Propoxyphene 
Quetiapine 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Repaglinide 
Rifabutin 
Rifampin 


Abbreviated Title: Ph2Sunitinib Thymoma/Thymic Ca 
CTEP Protocol #: 9174 
Version Date: 04/30/2020 
 
 
105 
 
 
 
Rifapentine  
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
St. John’s wort  
Sufentanil 
Sulconazole 
Tacrolimus 
Tamoxifen 
Tamsulosin 
Telithromycin 
Teniposide 
Terbinafine 
Testosterone 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tolterodine 
Toremifene 
Tranylcypromine 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Valproic acid 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zafirlukast 
Ziprasidone 
Zolpidem 
Zonisamide 
Zopiclone 
 

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/30/2020
Page 1 of 14
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:
Arun Rajan, MD
STUDY 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
STUDY SITE:
NIH Clinical Center
Cohort: 
Standard – Group 1 
Consent Version:
April 30, 2020 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator:
Arun Rajan, MD 
Phone: 240-760-6236
Email: rajana@mail.nih.gov 
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document. 
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to evaluate the safety, tolerability and effectiveness of the drug 
sunitinib malate (referred to as sunitinib) in cancers of the thymus. Sunitinib is a Food and Drug 
Administration (FDA) approved drug for use in at least three other types of cancers including 
IRB NUMBER: 12C0118
IRB APPROVAL DATE: 05/12/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/30/2020
Page 2 of 14
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
cancers of the kidney, but it is not FDA approved for treatment of thymomas or thymic carcinomas 
and is experimental in this setting. Sunitinib acts by blocking several proteins involved in control 
of cell division and growth. In tumor cells such controls are altered and lead to abnormal and 
uncontrolled cell growth.  Some of the proteins which are blocked by sunitinib are known to be 
abnormal in a few patients with cancers of the thymus. There have also been isolated reports of 
effectiveness of sunitinib in cancers of thymus. 
This study will evaluate the amount of tumor reduction, if any, and the length of time the tumor 
growth is controlled, as well as the safety and tolerability of sunitinib in advanced cancers of 
thymus, which have progressed despite at least one prior chemotherapy regimen containing 
platinum. Some patients may not have any tumor reduction or control of tumor growth with 
sunitinib. 
Why are you being asked to take part in this study?
You are being asked to take part in this study because you have an advanced thymoma or thymic 
carcinoma which has progressed despite prior treatment with at least one platinum-based 
chemotherapy regimen.
How many people will take part in this study? 
This study is being conducted at the National Cancer Institute and affiliated institutions, and it 
consists of two groups.  You are participating in Group 1, and enrollment has now been completed 
for that group.  A total of 41 people with thymoma or thymic carcinoma enrolled in Group 1.  In 
Group 2, approximately 15 patients with thymic carcinoma will take part in the study.
DESCRIPTION OF RESEARCH STUDY
This study is being conducted on an outpatient basis.  Sunitinib is taken orally once a day, in the 
morning, with or without food.  Sunitinib is stored at room temperature.  The dose regimen for this 
study is 50 mg of sunitinib daily for 4 weeks, followed by 2 weeks of rest with no sunitinib.  This 
6-week period is called a cycle.  The cycles may be repeated as long as you are receiving benefit 
from the drug and any side effects which you may experience are tolerable.
Clinic visits will take place every three weeks in order to monitor your progress on this trial and 
manage any side effects which you may be having.  Every cycle (6 weeks) we will perform a CT 
scan, MRI and/or chest x-ray to see if you are getting any benefit from the study drug. As long as 
you are receiving benefits from the treatment and you do not have unacceptable side effects, then 
we will continue to provide you with the treatment. Once you have completed one year of the study 
drug, we will perform a CT scan, MRI and/or chest x-ray every 2 cycles (12 weeks) to see if you 
continue to receive benefits from the study drug.  Once you stop getting any benefit from the study 
drug, or the side effects are no longer tolerable, we will stop the treatment. 
What will happen if you take part in this research study?
Before you begin the study
Before any study-related procedures are performed, you will be asked to read and sign this 
informed consent form. If you wish to participate, you agree to return to this clinic for all study-
related appointments and tests mentioned below. Additional visits may be required to treat side 
IRB NUMBER: 12C0118
IRB APPROVAL DATE: 05/12/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/30/2020
Page 3 of 14
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
effects. No overnight hospital or clinic stays are required; however, if serious side effects occur, 
overnight hospital stays may be required to treat the side effects.
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to your study doctor.

Routine physical exam (includes an examination of major body systems, height, weight, 
blood pressure, and pulse rate) 

Documentation of all prescription and over-the-counter medications which you are taking 

Blood tests including blood cell counts, chemistries, tests to see how well your blood 
clots and thyroid functions

Computed tomography (CT) or MRI and/or chest x-ray (CT- a series of x-rays will be 
passed through your body while you lie inside a machine) or other imaging tests to locate 
and measure your tumors

Tissue block of the cancer to submit to the study doctor or a member of the research team

An electrocardiogram (ECG), a recording of the electrical activity of your heart

An echocardiogram or MUGA scan, an ultrasound study which shows the structure and 
function of your heart

Serum pregnancy test for women of childbearing age
During the study
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will need the following tests and procedures that are part of regular cancer care:

Clinic visits to discuss any symptoms you may have and to undergo a physical examination. 
During the first cycle, clinic visits are scheduled for Weeks 1 and 3.  After the first cycle, 
clinic visits may be changed to once every 6 weeks, on Week 1 of each cycle, at the 
discretion of your study doctor.

Blood tests

Computed tomography or other imaging test approximately every 6 weeks for the first year 
you receive the study medication, and approximately every 12 weeks thereafter, as long as 
you continue to receive the study medication.

Tests to monitor your heart function, as needed
You will need these tests and procedures that are either being tested in this study or being done 
to see how the study is affecting your body and your cancer: 

Blood test to study different biological markers that we anticipate may be affected after 
treatment with sunitinib 

Blood test to evaluate the effect of the study drug on cells involved in specialized functions 
such as blood vessel formation. 
IRB NUMBER: 12C0118
IRB APPROVAL DATE: 05/12/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/30/2020
Page 4 of 14
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
You will be asked to maintain a medication diary and a blood pressure (BP) chart.
When you are finished taking the study drug (sunitinib malate)
As explained in the paragraphs above, if you do not experience benefit from the sunitinib, or 
the side effects are no longer tolerable, then we will stop giving you the sunitinib.  We will 
continue to monitor you, either by clinic visit or telephone interview, until all of the side 
effects have been resolved or stabilized, and then annually until death.
Study Chart
Day
What you do
Before 
starting 
study

Check-in to the Outpatient Clinic

Physical examination by a Health Care Provider

Blood Pressure (BP) measurement

Routine blood tests

Research blood tests

Tissue block of the cancer to confirm the diagnosis

CT or other imaging studies

ECG

Echocardiogram

Serum pregnancy test for women of childbearing age 
During 
treatment

Sunitinib 50 mg daily for 4 weeks, then 2 weeks of rest with no sunitinib

Clinic visits during Cycle 1 on Weeks 1 and 3, including physical 
examination by a Health Care Provider, and other tests as determined by your 
study doctor.  After the first cycle, clinic visits may be changed to once every 
6 weeks, on Week 1 of each cycle, at the discretion of your study doctor.

Research blood tests on Week 1 of Cycles 2 and 3

CT or other imaging studies every 6 weeks for the first year you receive the 
study medication, and every 12 weeks thereafter, as long as you continue to 
receive the study medication.

Routine blood tests on Weeks 1 and 3 for Cycle 1; then on Week 1 for Cycle 
2 and after

Maintain a medication diary

Maintain a BP diary with weekly BP recordings.  CT or other imaging 
studies every 6 weeks for the first year you receive the study medication, and 
every 12 weeks thereafter, as long as you continue to receive the study 
medication.

Routine blood tests on Weeks 1 and 3 for Cycle 1; then on Week 1 for Cycle 
2 and after

Maintain a medication diary

Maintain a BP diary with weekly BP recordings.  
After 
treatment

Follow-up clinic visits or telephone interviews until side effects are resolved 
or stabilized, and then annually until death.
IRB NUMBER: 12C0118
IRB APPROVAL DATE: 05/12/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/30/2020
Page 5 of 14
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Study Drug Administration 
Sunitinib is taken orally once a day, in the morning, with or without food.  Sunitinib is stored at 
room temperature. The dose regimen for this study is 50 mg of sunitinib daily for 4 weeks, 
followed by 2 weeks of no sunitinib.  This 6-week period is called a cycle.  After 12 weeks of 
treatment, we will perform a CT scan to see if you are getting any benefit from the treatment. If 
you do not experience benefit from sunitinib, we will stop it. If you experience benefit from 
sunitinib, we will continue it until you stop benefiting from it and do not have unacceptable side 
effects. We would like to follow up with you even after you stop taking sunitinib; for your entire 
life with the intention of knowing more about how the genetic characteristics of your cancer have 
an impact on how your cancer behaves.
Study Restrictions/Subject Responsibilities 

Store sunitinib at controlled room temperature (15to 30o C), and protect from light.

Sunitinib may be taken without regard to meals in the morning. 

A yellow discoloration of the skin area may result following direct contact with the capsules. 
Wash the exposed area with soap and water immediately.

Blood pressure (BP) should be monitored before you begin the study, and then weekly for the 
duration of treatment.  Blood pressure may be monitored either at the doctor’s office or using 
any calibrated electronic device (such as those found at a local drug store or pharmacy).
Sunitinib may interact with many other medications and remedies. We would like to know all the 
medications that you take before starting sunitinib as well as any new medications and over the 
counter drugs. We will provide you information sheet describing drugs, remedies, and medications 
with potential interactions with sunitinib.
BIRTH CONTROL
If you are a woman who is breast feeding or pregnant, you may not take part in the study 
because we don’t know how these medicines used in this study would affect your baby or your 
unborn child. If you are a woman who can become pregnant, or are the partner of a woman 
who can become pregnant, you will need to practice an effective form of birth control before 
starting study treatment and while receiving study treatment. If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse at once.  It is also important to 
note that some of the drugs used in the study may make you unable to have children in the 
future.
Effective forms of birth control include: 
•
Abstinence 

intrauterine device (IUD)
•
hormonal [birth control pills, injections, or implants]
•
tubal ligation
•
vasectomy
IRB NUMBER: 12C0118
IRB APPROVAL DATE: 05/12/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/30/2020
Page 6 of 14
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
RISKS OR DISCOMFORTS OF PARTICIPATION
What side effects or risks can I expect from being in this study? 
If you choose to take part in this study, there is a risk that sunitinib malate (SU011248 L-
malate) may not be as good as the usual approach for your cancer or condition at shrinking or 
stabilizing your cancer.
You also may have the following discomforts:

Spend more time in the hospital or doctor’s office.

Be asked sensitive or private questions about things you normally do not discuss.

May not be able to take part in future studies.
The sunitinib malate (SU011248 L-malate) used in this study may affect how different parts of 
your body work such as your liver, kidneys, heart, and blood. The study doctor will test your 
blood and will let you know if changes occur that may affect your health.
There is also a risk that you could have side effects from the study drug(s)/study approach.
Here are important points about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, or some may never go 
away.

Some side effects may make it hard for you to have children.

Some side effects may be mild.  Other side effects may be very serious and even result in 
death.
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem:

If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect.

Your study doctor will work with you to treat your side effects.

Your study doctor may adjust the study drugs to try to reduce side effects.
The table below shows the most common and the most serious side effects doctors know about. 
Keep in mind that there might be other side effects doctors do not yet know about. If important 
new side effects are found, the study doctor will discuss these with you.
IRB NUMBER: 12C0118
IRB APPROVAL DATE: 05/12/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/30/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Sunitinib Risks
COMMON, SOME MAY BE SERIOUS  
In 100 people receiving sunitinib malate (SU011248 L-malate), more than 20 and up to 100 may 
have:

Pain

Constipation, diarrhea, heartburn, nausea, vomiting

Sores in the mouth

Tiredness

Loss of appetite

Changes in taste

Sore throat

Redness, pain or peeling of palms and soles
OCCASIONAL, SOME MAY BE SERIOUS  
In 100 people receiving sunitinib malate (SU011248 L-malate), from 4 to 20 may have:

Anemia which may require blood transfusion

Blurred vision with chance of blindness

Bloating, passing gas

Dry mouth, skin

Chills, fever

Swelling of arms, legs

Flu-like symptoms including body aches

Bruising, bleeding

Weight loss

Infection, especially when white blood cell count is low

Dehydration

Dizziness, headache

Feeling of "pins and needles" in arms and legs

Depression

Difficulty sleeping

Cough, shortness of breath

Nose bleed

Hair loss, rash, itching, skin changes

Change in hair color

High blood pressure which may cause headaches, dizziness, blurred vision
IRB NUMBER: 12C0118
IRB APPROVAL DATE: 05/12/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/30/2020
Page 8 of 14
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
RARE, AND SERIOUS
In 100 people receiving sunitinib malate (SU011248 L-malate), 3 or fewer may have:

Anemia, kidney problems which may cause tiredness, bruising, swelling, or may require 
dialysis

Blood clot which may cause confusion, paralysis, seizures or swelling, pain, shortness of 
breath

Damage to organs (heart, brain, others) which may cause shortness of breath, swelling of 
ankles, and tiredness, changes in thinking

Heart failure, heart attack which may cause shortness of breath, swelling of ankles, and 
tiredness

Pain and swelling of thyroid

Visual loss

Difficulty swallowing

A tear or hole in or between internal organs which may cause drainage and may require 
surgery

Swelling of the gallbladder

Liver damage which may cause yellowing of eyes and skin, swelling

Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat

Flesh-eating bacteria syndrome

Non-healing surgical site

Change in the heart rhythm

Kidney damage which may require dialysis 

Damage to the jawbone which may cause loss of teeth

Damage to muscle which may cause muscle pain, dark red urine

Cancer of bone marrow caused by chemotherapy

Damage to the bone marrow (irreversible) which may cause infection, bleeding, may 
require transfusions

Stroke

Brain damage which may cause headache, seizure, blindness (also known as Reversible 
Posterior Leukoencephalopathy Syndrome)

Sores on the skin

Severe skin rash with blisters and peeling which can involve mouth and other parts of the 
body
Test and Procedure Risks
In addition to the side effects for the drugs in this protocol there may be side effects associated 
with the tests and procedures that occur during this study. These include:

Drawing blood: Risks associated include pain at the needle site, bruising, possible 
dizziness if you stand up quickly and possible inflammation of the vein or infection at 
the needle site. Care will be taken to avoid these complications.

Scans, x-rays, and heart tests: There is a small risk of developing a reaction to the 
agents used during the test. Otherwise risk factors are similar to those associated with 
taking a blood sample which includes pain at the needle site, bruising, possible 
IRB NUMBER: 12C0118
IRB APPROVAL DATE: 05/12/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/30/2020
Page 9 of 14
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
dizziness if you stand up quickly and possible inflammation of the vein or infection at 
the needle site. Care will be taken to avoid these complications.

An intravenous line will be used in some cases. There may be a risk of infection, blood 
clot or bleeding at the site of the line. There is also a risk of some of the drug leaking 
out, referred to as extravasation. If that occurs there may be some damage to skin tissue 
in a limited area. Patients are urged to alert the study physicians at the first sign of any 
skin changes, for example redness or tenderness around the infusion site or any 
discomfort near that area as well. If there is any evidence of toxicity from leaking, the 
infusion will be held until a central line can be placed for the infusion of drug. In 
addition, any toxic effects to the skin will be treated to the fullest extent possible. 
Development of air in the chest is a risk of a central line catheter. However, this 
complication is rare. Air in the chest outside the lung would require temporary 
placement of a chest tube by the surgeon.
For more information about risks and side effects, ask your study doctor.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study? 
Taking part in this study may or may not make your health better.  The aim of this study is to see 
if the drug sunitinib malate will cause your tumor to shrink.  We hope that you will get personal 
medical benefit from taking part in this study, but we cannot be certain.  These potential benefits 
could include shrinking of your tumor or lessening of your symptoms, such as pain, that are caused 
by the tumor. We do know that the information gained from this study will help doctors learn more 
about sunitinib as a treatment for cancer.  This information could help future cancer patients.
ALTERNATIVE APPROACHES OR TREATMENTS
What other choices do I have if I do not take part in this study? 
Instead of being in this study, you have these options:

Getting treatment or care for your cancer, without being in a study, with standard of care 
chemotherapy regimens 

Taking part in another study

Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible.
Please talk to your doctor about these and other options
STOPPING THERAPY 
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease gets worse during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you
IRB NUMBER: 12C0118
IRB APPROVAL DATE: 05/12/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/30/2020
Page 10 of 14
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you.  However, according to FDA guidelines, 
information collected on you up until that point may still be provided to the NCI or Pfizer, or 
designated representatives. If you withdraw from the study early, you may be asked if you will 
allow further medical information to be collected for study purposes. In that case, we would ask 
you to enroll on a separate protocol.
CONFLICT OF INTEREST
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research team 
for a copy of the Protocol Review Guide or for more information.  Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH 
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.  
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses.  These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for research 
purposes. Your specimens and data will be used for research purposes only and will not benefit 
you.  It is also possible that the stored specimens and data may never be used.  Results of research 
done on your specimens and data will not be available to you or your doctor.  It might help people 
who have cancer and other diseases in the future.  
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
IRB NUMBER: 12C0118
IRB APPROVAL DATE: 05/12/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/30/2020
Page 11 of 14
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines. 
On this study, the NCI will cover the cost for some of your expenses. Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid. The amount and form 
of these payments are determined by the NCI Travel and Lodging Reimbursement Policy. You 
will be given a summary of the policy which provides more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center.

If some tests and procedures are performed outside the NIH Clinical Center, you may have 
to pay for these costs if they are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be provided 
by the NIH Clinical Center.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor (CTEP) or their agent(s) 

Qualified representatives from Pfizer, the pharmaceutical company who produces sunitinib 
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
IRB NUMBER: 12C0118
IRB APPROVAL DATE: 05/12/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/30/2020
Page 12 of 14
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
information about your research involvement without your written permission.  However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
IRB NUMBER: 12C0118
IRB APPROVAL DATE: 05/12/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/30/2020
Page 13 of 14
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Arun Rajan, 
MD (rajana@mail.nih.gov or 240-760-6236). You may also call the NIH Clinical Center Patient 
Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you 
have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 12C0118
IRB APPROVAL DATE: 05/12/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/30/2020
Page 14 of 14
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation.
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 12C0118
IRB APPROVAL DATE: 05/12/2020

ICF_003.pdf: 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
   MEDICAL RECORD
              •  Adult Patient or     •  Parent, for Minor Patient
INSTITUTE:National Cancer Institute
STUDY NUMBER:
12-C-0118
PRINCIPAL INVESTIGATOR:  Arun Rajan, MD
STUDY 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
Continuing Review Approved by the IRB on 07/22/19
Amendment Approved by the IRB 05/08/19 (N)
Date Posted to Web: 07/26/19
Standard – Group 2
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL
RESEARCH STUDY
•   Adult Patient or    •   Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.: 09-25-0099
File in Section 4:  Protocol Consent (2)
INTRODUCTION
We invite you to take part in a research study at the National Institutes of Health (NIH).
First, we want you to know that:
Taking part in NIH research is entirely voluntary.
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation.
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future.
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study.
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.
Why is this study being done? 
The purpose of this study is to evaluate the safety, tolerability and effectiveness of the drug 
sunitinib malate (referred to as sunitinib) in cancers of the thymus. Sunitinib is a Food and Drug 
Administration (FDA) approved drug for use in at least three other types of cancers including 
cancers of the kidney, but it is not FDA approved for treatment of thymic carcinomas and is 
experimental in this setting. Sunitinib acts by blocking several proteins involved in control of 
cell division and growth. In tumor cells such controls are altered and lead to abnormal and 
uncontrolled cell growth.  Some of the proteins which are blocked by sunitinib are known to be 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
12-C-0118
CONTINUATION: page 2 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
abnormal in a few patients with cancers of the thymus. There have also been isolated reports of 
effectiveness of sunitinib in cancers of thymus. 
This study will evaluate the amount of tumor reduction, if any, and the length of time the tumor 
growth is controlled, as well as the safety and tolerability of sunitinib in advanced cancers of 
thymus, which have progressed despite at least one prior chemotherapy regimen containing 
platinum. Some patients may not have any tumor reduction or control of tumor growth with 
sunitinib. 
Why are you being asked to take part in this study?
You are being asked to take part in this study because you have an advanced thymic carcinoma 
which has progressed despite prior treatment with at least one platinum-based chemotherapy 
regimen.
How many people will take part in this study? 
This study consists of two groups.  A total of 41 people participated in Group 1, and enrollment 
has now been completed for that group.  In Group 2, approximately 15 patients with thymic 
carcinoma will take part in the study, which is being conducted at the National Cancer Institute 
and affiliated institutions.  You are being invited to participate in Group 2.
Description of Research Study
This study is being conducted on an outpatient basis.  Sunitinib is taken orally once a day, with 
or without food.  Sunitinib is stored at room temperature.  The dose regimen for this study is 50 
mg of sunitinib daily for 2 weeks, followed by 1 week of rest with no sunitinib.  This 3-week 
period is called a cycle.  The cycles may be repeated as long as you are receiving benefit from 
the drug and any side effects which you may experience are tolerable.
Clinic visits will take place every three weeks in order to monitor your progress on this trial and 
manage any side effects which you may be having.  Every 2 cycles (every 6 weeks) we will 
perform a CT scan, MRI and/or chest x-ray to see if you are getting any benefit from the study 
drug. As long as you are receiving benefits from the treatment and you do not have unacceptable 
side effects, then we will continue to provide you with the treatment. Once you have completed 
one year of the study drug, we will perform a CT scan, MRI and/or chest x-ray every 4 cycles 
(every 12 weeks) to see if you continue to receive benefits from the study drug.  Once you stop 
getting any benefit from the study drug, or the side effects are no longer tolerable, we will stop 
the treatment. 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
12-C-0118
CONTINUATION: page 3 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
What will happen if you take part in this research study?
Before you begin the study
Before any study-related procedures are performed, you will be asked to read and sign this 
informed consent form. If you wish to participate, you agree to return to this clinic for all study-
related appointments and tests mentioned below. Additional visits may be required to treat side 
effects. No overnight hospital or clinic stays are required; however, if serious side effects occur, 
overnight hospital stays may be required to treat the side effects.
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to your study doctor.

Routine physical exam (includes an examination of major body systems, height, weight, 
blood pressure, and pulse rate) 

Documentation of all prescription and over-the-counter medications which you are taking 

Blood tests including blood cell counts, chemistries, tests to see how well your blood 
clots and thyroid functions

Computed tomography (CT) or MRI and/or chest x-ray (CT- a series of x-rays will be 
passed through your body while you lie inside a machine) or other imaging tests to locate 
and measure your tumors

Brain MRI

Tissue block of the cancer to submit to the study doctor or a member of the research team

An electrocardiogram (ECG), a recording of the electrical activity of your heart

An echocardiogram or MUGA scan, an ultrasound study which shows the structure and 
function of your heart

Serum pregnancy test for women of childbearing age
During the study
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will need the following tests and procedures that are part of regular cancer care:

Clinic visits once every three weeks, on Week 1 of each cycle, to discuss any symptoms you 
may have and to undergo a physical examination.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
12-C-0118
CONTINUATION: page 4 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

Blood tests

Computed tomography or other imaging test approximately every 6 weeks for the first year 
you receive the study medication, and approximately every 12 weeks thereafter, as long as 
you continue to receive the study medication.

Tests to monitor your heart function, as needed
You will need these tests and procedures that are either being tested in this study or being done 
to see how the study is affecting your body and your cancer: 

Blood test to study different biological markers that we anticipate may be affected after 
treatment with sunitinib 

Blood test to evaluate the effect of the study drug on cells involved in specialized 
functions such as blood vessel formation. 
You will be asked to maintain a medication diary and a blood pressure (BP) chart.
When you are finished taking the study drug (sunitinib malate)
As explained in the paragraphs above, if you do not experience benefit from the sunitinib, or 
the side effects are no longer tolerable, then we will stop giving you the sunitinib.  We will 
continue to monitor you, either by clinic visit or telephone interview, until all of the side 
effects have been resolved or stabilized, and then annually until death.
Study Chart
Day
What you do
Before 
starting 
study

Check-in to the Outpatient Clinic

Physical examination by a Health Care Provider

Blood Pressure (BP) measurement

Routine blood tests

Research blood tests

Tissue block of the cancer to confirm the diagnosis

CT or other imaging studies

Brain MRI

ECG

Echocardiogram

Serum pregnancy test for women of childbearing age 
During 
treatment

Sunitinib 50 mg daily for 2 weeks, then 1 week of rest with no sunitinib

Clinic visits on Week 1 of each cycle, including physical examination by a Health Care 
Provider, and other tests as determined by your study doctor.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
12-C-0118
CONTINUATION: page 5 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

Research blood tests on Week 1 of Cycles 2, 3, and 5

CT or other imaging studies every 6 weeks for the first year you receive the study 
medication, and every 12 weeks thereafter, as long as you continue to receive the study 
medication.

Routine blood tests on Week 1 of each cycle

Maintain a medication diary

Maintain a BP diary with weekly BP recordings.  
After 
treatment

Follow-up clinic visits or telephone interviews until side effects are resolved or 
stabilized, and then annually until death.
Study Drug Administration 
Sunitinib is taken orally once a day, with or without food.  Sunitinib is stored at room 
temperature. The dose regimen for this study is 50 mg of sunitinib daily for 2 weeks, followed by 
1 week of no sunitinib.  This 3-week period is called a cycle.  After 12 weeks of treatment, we 
will perform a CT scan to see if you are getting any benefit from the treatment. If you do not 
experience benefit from sunitinib, we will stop it. If you experience benefit from sunitinib, we 
will continue it until you stop benefiting from it and do not have unacceptable side effects.  We 
would like to follow up with you even after you stop taking sunitinib; for your entire life with the 
intention of knowing more about how the genetic characteristics of your cancer have an impact 
on how your cancer behaves. 
Study Restrictions/Subject Responsibilities 

Store sunitinib at controlled room temperature (15to 30o C), and protect from light.

Sunitinib may be taken without regard to meals. 

A yellow discoloration of the skin area may result following direct contact with the capsules. 
Wash the exposed area with soap and water immediately.

Blood pressure (BP) should be monitored before you begin the study, and then weekly for the 
duration of treatment.  Blood pressure may be monitored either at the doctor’s office or using 
any calibrated electronic device (such as those found at a local drug store or pharmacy).

Sunitinib may interact with many other medications and remedies. We would like to know all 
the medications that you take before starting sunitinib as well as any new medications and 
over the counter drugs. We will provide you information sheet describing drugs, remedies, 
and medications with potential interactions with sunitinib.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
12-C-0118
CONTINUATION: page 6 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
Birth Control
If you are a woman who is breast feeding or pregnant, you may not take part in the study 
because we don’t know how these medicines used in this study would affect your baby or your 
unborn child. If you are a woman who can become pregnant, or are the partner of a woman 
who can become pregnant, you will need to practice an effective form of birth control before 
starting study treatment and while receiving study treatment. If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse at once.  It is also important to 
note that some of the drugs used in the study may make you unable to have children in the 
future.
Effective forms of birth control include: 
•
Abstinence 

intrauterine device (IUD)
•
hormonal [birth control pills, injections, or implants]
•
tubal ligation
•
vasectomy
Risks or Discomforts of Participation
What side effects or risks can I expect from being in this study? 
If you choose to take part in this study, there is a risk that sunitinib malate (SU011248 L-
malate) may not be as good as the usual approach for your cancer or condition at shrinking or 
stabilizing your cancer.

Spend more time in the hospital or doctor’s office.

Be asked sensitive or private questions about things you normally do not discuss.

May not be able to take part in future studies.
The sunitinib malate (SU011248 L-malate) used in this study may affect how different parts of 
your body work such as your liver, kidneys, heart, and blood. The study doctor will test your 
blood and will let you know if changes occur that may affect your health.
There is also a risk that you could have side effects from the study drug(s)/study approach.
Here are important points about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, or some may never go 
away.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
12-C-0118
CONTINUATION: page 7 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

Some side effects may make it hard for you to have children.

Some side effects may be mild.  Other side effects may be very serious and  even result 
in death.
You can ask your study doctor questions about side effects at any time.  Here are important 
ways to make side effects less of a problem:

If you notice or feel anything different, tell your study doctor.  He or she can check to 
see if it is a side effect.

Your study doctor will work with you to treat your side effects.

Your study doctor may adjust the study drugs to try to reduce side effects.
The table below shows the most common and the most serious side effects that doctors know 
about.  Keep in mind that there might be other side effects that doctors do not yet know about. 
If important new side effects are found, the study doctor will discuss these with you.
Sunitinib Risks
COMMON, SOME MAY BE SERIOUS  
In 100 people receiving sunitinib malate (SU011248 L-malate), more than 20 and up to 100 may 
have:

Pain

Constipation, diarrhea, heartburn, nausea, vomiting

Sores in the mouth

Tiredness

Loss of appetite

Changes in taste

Sore throat

Redness, pain or peeling of palms and soles


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
12-C-0118
CONTINUATION: page 8 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
OCCASIONAL, SOME MAY BE SERIOUS  
In 100 people receiving sunitinib malate (SU011248 L-malate), from 4 to 20 may have:

Anemia which may require blood transfusion

Blurred vision with chance of blindness

Bloating, passing gas

Dry mouth, skin

Chills, fever

Swelling of arms, legs

Flu-like symptoms including body aches

Bruising, bleeding

Weight loss

Infection, especially when white blood cell count is low

Dehydration

Dizziness, headache

Feeling of "pins and needles" in arms and legs

Depression

Difficulty sleeping

Cough, shortness of breath

Nose bleed

Hair loss, rash, itching, skin changes

Change in hair color

High blood pressure which may cause headaches, dizziness, blurred vision


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
12-C-0118
CONTINUATION: page 9 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
RARE, AND SERIOUS
In 100 people receiving sunitinib malate (SU011248 L-malate), 3 or fewer may have:

Anemia, kidney problems which may cause tiredness, bruising, swelling, or may require 
dialysis

Blood clot which may cause confusion, paralysis, seizures or swelling, pain, shortness of 
breath

Damage to organs (heart, brain, others) which may cause shortness of breath, swelling of 
ankles, and tiredness, changes in thinking

Heart failure, heart attack which may cause shortness of breath, swelling of ankles, and 
tiredness

Pain and swelling of thyroid

Visual loss

Difficulty swallowing

A tear or hole in or between internal organs which may cause drainage and may require 
surgery

Swelling of the gallbladder

Liver damage which may cause yellowing of eyes and skin, swelling

Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat

Flesh-eating bacteria syndrome

Non-healing surgical site

Change in the heart rhythm

Kidney damage which may require dialysis 

Damage to the jawbone which may cause loss of teeth

Damage to muscle which may cause muscle pain, dark red urine

Cancer of bone marrow caused by chemotherapy

Damage to the bone marrow (irreversible) which may cause infection, bleeding, may 
require transfusions

Stroke

Brain damage which may cause headache, seizure, blindness (also known as Reversible 
Posterior Leukoencephalopathy Syndrome)

Sores on the skin

Severe skin rash with blisters and peeling which can involve mouth and other parts of the 
body
Test and Procedure Risks
In addition to the side effects for the drugs in this protocol there may be side effects associated 
with the tests and procedures that occur during this study. These include:

Drawing blood: Risks associated include pain at the needle site, bruising, possible 
dizziness if you stand up quickly and possible inflammation of the vein or infection at 
the needle site. Care will be taken to avoid these complications.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
12-C-0118
CONTINUATION: page 10 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

Scans, x-rays, and heart tests: There is a small risk of developing a reaction to the 
agents used during the test. Otherwise risk factors are similar to those associated with 
taking a blood sample which includes pain at the needle site, bruising, possible 
dizziness if you stand up quickly and possible inflammation of the vein or infection at 
the needle site. Care will be taken to avoid these complications.

An intravenous line will be used in some cases. There may be a risk of infection, blood 
clot or bleeding at the site of the line. There is also a risk of some of the drug leaking 
out, referred to as extravasation. If that occurs there may be some damage to skin tissue 
in a limited area. Patients are urged to alert the study physicians at the first sign of any 
skin changes, for example redness or tenderness around the infusion site or any 
discomfort near that area as well. If there is any evidence of toxicity from leaking, the 
infusion will be held until a central line can be placed for the infusion of drug. In 
addition, any toxic effects to the skin will be treated to the fullest extent possible. 
Development of air in the chest is a risk of a central line catheter. However, this 
complication is rare. Air in the chest outside the lung would require temporary 
placement of a chest tube by the surgeon.
For more information about risks and side effects, ask your study doctor.
Potential Benefits of Participation
Are there benefits to taking part in this study? 
Taking part in this study may or may not make your health better.  The aim of this study is to see 
if the drug sunitinib malate will cause your tumor to shrink.  We hope that you will get personal 
medical benefit from taking part in this study, but we cannot be certain.  These potential benefits 
could include shrinking of your tumor or lessening of your symptoms, such as pain, that are 
caused by the tumor. We do know that the information gained from this study will help doctors 
learn more about sunitinib as a treatment for cancer.  This information could help future cancer 
patients.
Alternative Approaches or Treatments
What other choices do I have if I do not take part in this study? 
Instead of being in this study, you have these options:

Getting treatment or care for your cancer, without being in a study, with standard of care 
chemotherapy regimens 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
12-C-0118
CONTINUATION: page 11 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

Taking part in another study

Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible.
Please talk to your doctor about these and other options.
Stopping Therapy 
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease gets worse during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you.  However, according to FDA guidelines, 
information collected on you up until that point may still be provided to the NCI or Pfizer, or 
designated representatives. 
If you withdraw from the study early, you may be asked if you will allow further medical 
information to be collected for study purposes. In that case, we would ask you to enroll on a 
separate protocol.
Research Subject’s Rights
What are the costs of taking part in this study? 
If you choose to take part in the study, the following will apply, in keeping with the NIH policy:

You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH. 

There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
12-C-0118
CONTINUATION: page 12 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH.

Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH.
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include:

The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor or their agent(s)

Qualified representatives from Pfizer, the pharmaceutical company who produces 
sunitinib.
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the 
Web site will include a summary of the results.  You can search this Web site at any time. 
Certificate of Confidentiality 
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below.
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information: 

will be used for auditing or program evaluation internally by the NIH; or 

must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA). 

is necessary for your medical treatment and you have consented to this disclosure; 

is for other research. 
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent. 
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER:
12-C-0118
CONTINUATION: page 13 of 16 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information.
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others.
Conflict of Interest
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest. 
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.  
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.  
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.


MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY:
•  Adult Patient or    •  Parent, for Minor Patient
STUDY NUMBER:
12-C-0118
CONTINUATION: page 14 of 16 pages
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
(Continuation Sheet)
•
Adult Patient or
•Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
OTHER PERTINENT INFORMATION
1. Confidentiality.  When results of an NIH research study are reported in medical journals or 
at scientific meetings, the people who take part are not named and identified.  In most cases, the 
NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance.
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations.
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term 
medical care for any injury resulting from your participation in research here.  In general, no 
long-term medical care or financial compensation for research-related injuries will be provided 
by the National Institutes of Health, the Clinical Center, or the Federal Government.  However, 
you have the right to pursue legal remedy if you believe that your injury justifies such action.
3. Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines.
4. Problems or Questions.  If you have any problems or questions about this study, or about 
your rights as a research participant, or about any research-related injury, contact the Principal 
Investigator, Arun Rajan, M.D., Building 10, Room 12N226, Telephone: 240 760-6236. You 
may also call the Clinical Center Patient Representative at 301-496-2626.  If you have any 
questions about the use of your specimens or data for future research studies, you may also 
contact the Office of the Clinical Director, Telephone:  240-760-6070.
5. Consent Document.  Please keep a copy of this document in case you want to read it again.


•  Adult Patient or  •  Parent, for Minor Patient
MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL
RESEARCH STUDY (Continuation Sheet)
  Adult Patient or   •  Parent, for Minor Patient
P.A.: 09-25-0099
File in Section 4: Protocol Consent
COMPLETE APPROPRIATE ITEM(S) BELOW:
A. Adult Patient’s Consent
B. Parent’s Permission for Minor Patient.
I have read the explanation about this study and 
have been given the opportunity to discuss it 
and to ask questions.  I hereby consent to take 
part in this study.
I have read the explanation about this study and 
have been given the opportunity to discuss it 
and to ask questions.  I hereby give permission 
for my child to take part in this study.  
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.)
Signature of Adult Patient/
Legal Representative
Date
Print Name
Signature of Parent(s)/Guardian
Date
Print Name
C. Child’s Verbal Assent (If Applicable)
The information in the above consent was described to my child and my child agrees to 
participate in the study.
Signature of Parent(s)/Guardian
Date
Print Name
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE 
FROM JULY 22, 2019 THROUGH AUGUST 20, 2020. 
Signature of Investigator
Date
Print Name
Signature of Witness
Date
Print Name