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comprehensive adverse events and potential

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 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                                                                                         | Eye disorders - Other (macular edema) (Gr |
| edema)                                                                          | 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)                                                                                                        |                                           |
| 43                                                                              |                                                                                                                        |                                           |  
| 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)                            |                        |
| 44                                                                                                                  |                                                              |                        |  
| 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                                                                                                                                                             | 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%) 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                                                                                                                                                                                                                             | Palmar-plantar erythrodysesthesia                            |                                                                           |
| erythrodysesthesia syndrome                                                                                                                                                                                                                | 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                                                                                                                                                                                                  |                                                              |                                                                           |
| 1 This 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. |                                                              |                                                                           |  
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.  
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 CTEPAERS 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.  
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.
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note a death on study

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  
| ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEPAERS within the timeframes detailed in the table below. Hospitalization Grade 1  Timeframes Grade 3 Timeframes Grade 4 & 5  Grade 2  Timeframes Timeframes Resulting in  Hospitalization  10 Calendar Days ≥ 24 hrs 24-Hour 5  Not resulting in Calendar Days Hospitalization  Not required 10 Calendar Days ≥ 24 hrs 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   |
|---|  
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 24hour 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 CTEPAERS. 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   | Electrolyte     | 2 to 4  |                                                      |               |            |
| and          | abnormalities   |         |                                                      |               |            |  
| nutrition  disorders Nervous   | 2               |        |
|--------------------------------|-----------------|--------|
| system                         | Disguesia       |        |
| disorders  Dermatology/        | Rash            |        |
| Skin                           | 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.
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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.
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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

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.
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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.
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8.1 sunitinib [sunitinib malate (nsc

**Chemical Name**
N-[2-(Diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, compound with (S)-2hydroxybutanedioic 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
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aqueous solubility

| Solvent   | Solubility (mg/mL)   |
|-----------|----------------------|
| 0.1 M HCl | 59.1                 |  
| 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       | 6.2                  |
| v/v)  N,N-Dimethylacetamide | 37                   |
| N,NDimethylformamide                             | 18.4                 |  
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).  
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.
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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.
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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).
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8.2 agent ordering and agent

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 the NCI Investigator's Handbook for Procedures for Drug Accountability and Storage.)
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9 biomarker correlative and special

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).
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9.1 serum vegfr2 plgf il-4

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.
untitled h1
note subsets marked with an

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, CD4, CD56, CD68 and analyze by multiparameric flow cytometry.  
e. Site(s) Performing Correlative Study; Trepel Lab, DTB, Building 10, Room 12N218.
untitled h1
9.4 sample storage tracking and

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.
untitled h1
10 data collection and evaluation

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.  
- 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**.
untitled h1
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.  
| Wk                                                       | Follow-up  Evaluationsi                                                                         |                                                                                                                                                   |    |    |    |    |    |    |    |    |    |    |     |                |
|----------------------------------------------------------|-------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|----|----|----|----|----|----|----|----|----|----|-----|----------------|
| Pre                                                          |                                                                                                 |                                                                                                                                                   |    |    |    |    |    |    |    |    |    |    |     |                |
| Group 1                                                  | Wk                                                                                              | Wk                                                                                                                                                | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk | 13m | Off- Treatment |
| Study                                                    | 1                                                                                               | 2                                                                                                                                                 | 3j | 4  | 5  | 6  | 7  | 8  | 9  | 10 | 11 | 12 |     |                |
| 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                                       | Tumor measurements are repeated every 6 weeks for patients on treatment < 1 year; every         |                                                                                                                                                   |    |    |    |    |    |    |    |    |    |    |     |                |
| X                                                        | 12 weeks for patients on treatment ≥ 1 year. Documentation (radiologic) must be provided        | X                                                                                                                                                 |    |    |    |    |    |    |    |    |    |    |     |                |
| for patients removed from study for progressive disease. |                                                                                                 |                                                                                                                                                   |    |    |    |    |    |    |    |    |    |    |     |                |
| 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  |    |    |    |    |    |    |    |    |    |     |                |  
57  
| Wk                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Follow-up  Evaluationsi                                                                                                                                                                                                                                                                                              |                                                      |    |    |    |    |    |    |    |    |    |    |     |                |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------|----|----|----|----|----|----|----|----|----|----|-----|----------------|
| Pre                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                      |                                                      |    |    |    |    |    |    |    |    |    |    |     |                |
| Group 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Wk                                                                                                                                                                                                                                                                                                                   | Wk                                                   | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk | 13m | Off- Treatment |
| Study                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | 1                                                                                                                                                                                                                                                                                                                    | 2                                                    | 3j | 4  | 5  | 6  | 7  | 8  | 9  | 10 | 11 | 12 |     |                |
| 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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | X                                                                                                                                                                                                                                                                                                                    | X                                                    |    |    |    |    |    |    |    |    |    |    |     |                |
| infiltrate g Follow-up Evaluations per                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | X                                                                                                                                                                                                                                                                                                                    |                                                      |    |    |    |    |    |    |    |    |    |    |     |                |
| Section 5.4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | 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 |                                                                                                                                                                                                                                                                                                                      |                                                      |    |    |    |    |    |    |    |    |    |    |     |                |  
| Wk                                                       | Follow-up                                                                                       |                                                                                                 |    |    |    |    |    |    |    |    |    |    |    |
|----------------------------------------------------------|-------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------|----|----|----|----|----|----|----|----|----|----|----|
| Off- Treatment                                           | Evaluationsh                                                                                    |                                                                                                 |    |    |    |    |    |    |    |    |    |    |    |
| 13                                                       |                                                                                                 |                                                                                                 |    |    |    |    |    |    |    |    |    |    |    |
| Pre                                                          |                                                                                                 |                                                                                                 |    |    |    |    |    |    |    |    |    |    |    |
| Group 2                                                  | Wk                                                                                              | Wk                                                                                              | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk |    |
| Study                                                    | 1                                                                                               | 2                                                                                               | 3  | 4  | 5  | 6  | 7  | 8  | 9  | 10 | 11 | 12 |    |
| 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                                       | Tumor measurements are repeated every 6 weeks for patients on treatment < 1 year; every         |                                                                                                 |    |    |    |    |    |    |    |    |    |    |    |
| X                                                        | 12 weeks for patients on treatment ≥ 1 year. Documentation (radiologic) must be provided        | X                                                                                               |    |    |    |    |    |    |    |    |    |    |    |
| for patients removed from study for progressive disease. |                                                                                                 |                                                                                                 |    |    |    |    |    |    |    |    |    |    |    |  
| Wk                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Follow-up                                                                                                                                                                                                                                          |                                                                                                                                                   |    |    |    |    |    |    |    |    |    |    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|----|----|----|----|----|----|----|----|----|----|
| Off- Treatment                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Evaluationsh                                                                                                                                                                                                                                       |                                                                                                                                                   |    |    |    |    |    |    |    |    |    |    |
| 13                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                    |                                                                                                                                                   |    |    |    |    |    |    |    |    |    |    |
| Pre                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                    |                                                                                                                                                   |    |    |    |    |    |    |    |    |    |    |
| Group 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Wk                                                                                                                                                                                                                                                 | Wk                                                                                                                                                | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk | Wk |
| Study                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | 1                                                                                                                                                                                                                                                  | 2                                                                                                                                                 | 3  | 4  | 5  | 6  | 7  | 8  | 9  | 10 | 11 | 12 |
| 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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | X                                                                                                                                                                                                                                                  |                                                                                                                                                   |    |    |    |    |    |    |    |    |    |    |
| Section 5.4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | 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. |                                                                                                                                                                                                                                                    |                                                                                                                                                   |    |    |    |    |    |    |    |    |    |    |
untitled h1
12 measurement of effect 12.1

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.  
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 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.  
12.1.4 Response Criteria 12.1.4.1 Evaluation of Target Lesions  
| 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 64 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                                                                                                                                                                                       | NonTarget                                                                                     |                                           |                                                    |              |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------|-------------------------------------------|----------------------------------------------------|--------------|
| Lesions                                                                                                                                                                                      | Lesions                                                                             | New                                       | Overall                                            | Best Overall |
| Lesions                                                                                                                                                                                      | Response                                                                            | Response when  Confirmation is  Required* |                                                    |              |
| CR                                                                                                                                                                                           | CR                                                                                  | No                                        | CR                                                 | >4 wks.      |
| Confirmation**                                                                                                                                                                               |                                                                                     |                                           |                                                    |              |
| CR                                                                                                                                                                                           | Non                                                                                     |                                           |                                                    |              |
| CR/NonPD                                                                                                                                                                                              | No                                                                                  | PR                                        |                                                    |              |
| CR                                                                                                                                                                                           | Not                                                                                 | No                                        | PR                                                 | >4 wks.      |
| evaluated                                                                                                                                                                                    | Confirmation**                                                                      |                                           |                                                    |              |
| PR                                                                                                                                                                                           | Non                                                                                     |                                           |                                                    |              |
| CR/NonPD/not  evaluated                                                                                                                                                                                              | No                                                                                  | PR                                        |                                                    |              |
| SD                                                                                                                                                                                           | Non                                                                                     |                                           |                                                    |              |
| CR/NonPD/not  evaluated                                                                                                                                                                                              | No                                                                                  | SD                                        | Documented at least  once >4 wks. from  baseline** |              |
| PD                                                                                                                                                                                           | Any                                                                                 | Yes or                                    | PD                                                 |              |
| No                                                                                                                                                                                           | no prior SD, PR or  CR                                                              |                                           |                                                    |              |
| Any                                                                                                                                                                                          | PD***                                                                               | Yes or                                    | PD                                                 |              |
| No                                                                                                                                                                                           |                                                                                     |                                           |                                                    |              |
| 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 nontarget 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 65 |                                                                                     |                                           |                                                    |              |  
"*symptomatic deterioration."* Every effort should be made to document the objective progression even after discontinuation of treatment.  
| For Patients with Non-Measurable Disease (i.e., Non-Target Disease) Non-Target Lesions New Lesions Overall Response CR No CR Non-CR/non-PD No Non-CR/non-PD* Not all evaluated No not evaluated Unequivocal PD Yes or No PD Any Yes PD * 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease  since SD is increasingly used as an endpoint for assessment of efficacy in  some trials so to assign this category when no lesions can be measured is not  advised   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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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.
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13 data reporting / regulatory

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 (Adverse Events: List and Reporting Requirements).
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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 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.
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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.
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15 ccr multi-institutional guidelines 15.1

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.
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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.
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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:
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 "MultiParty 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 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:
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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.
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17 statistical considerations 17.1 study

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.
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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 2stage 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).  
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%.
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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.
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17.3 stratification factors n/a 17.4

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 KaplanMeier 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 adjustment for multiple comparisons.
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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.
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18 human subjects protections 18.1

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. 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, 1-8004Cancer). 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.
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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.
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18.3 participation of subjects unable

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 predetermined substitute decision maker, the procedures described in NIH HRPP SOP 14E for 73 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.
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18.4 evaluation of benefits and

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.
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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.
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18.6 consent and assent process

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.
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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.