untitled h1
7.1 comprehensive adverse events and

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 3219 patients. Below is the CAEPR for XL184 (Cabozantinib).  
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 2.4, December 17, 20181  
| Adverse Events with Possible                                    |                                                              |                        |
|-----------------------------------------------------------------|--------------------------------------------------------------|------------------------|
| Relationship to XL184 (Cabozantinib) (CTCAE 5.0 Term) [n= 3219] | Specific Protocol Exceptions to  Expedited Reporting (SPEER) |                        |
| Likely (>20%)                                                   | Less Likely (<=20%)                                          | Rare but Serious (<3%) |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia ENDOCRINE DISORDERS |                                                              |                        |  
| Adverse Events with Possible                                                                                                                                                            |                                                              |                        |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|------------------------|
| Relationship to XL184 (Cabozantinib) (CTCAE 5.0 Term) [n= 3219]                                                                                                                         | Specific Protocol Exceptions to  Expedited Reporting (SPEER) |                        |
| Likely (>20%)                                                                                                                                                                           | Less Likely (<=20%)                                          | Rare but Serious (<3%) |
| Hypothyroidism                                                                                                                                                                          | Hypothyroidism (Gr 2)                                        |                        |
| GASTROINTESTINAL DISORDERS Abdominal pain                                                                                                                                               | Abdominal pain (Gr 3)                                        |                        |
| Constipation                                                                                                                                                                            | Constipation (Gr 2)                                          |                        |
| Diarrhea                                                                                                                                                                                | Diarrhea (Gr 3)                                              |                        |
| Dry mouth                                                                                                                                                                               | Dry mouth (Gr 2)                                             |                        |
| Dyspepsia                                                                                                                                                                               | Dyspepsia (Gr 2)                                             |                        |
| Gastrointestinal fistula2 Gastrointestinal hemorrhage3 Gastrointestinal perforation4                                                                                                    |                                                              |                        |
| Mucositis oral                                                                                                                                                                          | Mucositis oral (Gr 3)                                        |                        |
| Nausea                                                                                                                                                                                  | Nausea (Gr 3)                                                |                        |
| Oral pain                                                                                                                                                                               | Oral pain (Gr 2)                                             |                        |
| Vomiting                                                                                                                                                                                | Vomiting (Gr 3)                                              |                        |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Edema limbs Fatigue                                                                                                                | Fatigue (Gr 3)                                               |                        |
| INFECTIONS AND INFESTATIONS Infection5 INJURY, POISONING AND PROCEDURAL COMPLICATIONS Wound complication INVESTIGATIONS Alanine aminotransferase increased                              | Alanine aminotransferase increased  (Gr 3)                   |                        |
| Aspartate aminotransferase                                                                                                                                                              | Aspartate aminotransferase increased                         |                        |
| increased                                                                                                                                                                               | (Gr 3)                                                       |                        |
| Lipase increased                                                                                                                                                                        | Lipase increased (Gr 4)                                      |                        |
| Platelet count decreased                                                                                                                                                                | Platelet count decreased  (Gr 3)                             |                        |
| Weight loss                                                                                                                                                                             | Weight loss (Gr 3)                                           |                        |
| METABOLISM AND NUTRITION DISORDERS Anorexia                                                                                                                                             | Anorexia (Gr 3)                                              |                        |
| Dehydration Hypocalcemia Hypokalemia Hypomagnesemia Hypophosphatemia                                                                                                                    |                                                              |                        |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia Generalized muscle weakness Muscle cramp Osteonecrosis of jaw Pain in extremity NERVOUS SYSTEM DISORDERS Dizziness Dysgeusia | Dysgeusia (Gr 2)                                             |                        |
| Headache                                                                                                                                                                                | Intracranial hemorrhage  Ischemia cerebrovascular42          |                        |  
| Adverse Events with Possible                                                                                                              |                                                              |                        |
|-------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|------------------------|
| Relationship to XL184 (Cabozantinib) (CTCAE 5.0 Term) [n= 3219]                                                                           | Specific Protocol Exceptions to  Expedited Reporting (SPEER) |                        |
| Likely (>20%)                                                                                                                             | Less Likely (<=20%)                                          | Rare but Serious (<3%) |
| Reversible posterior  leukoencephalopathy syndrome Stroke Transient ischemic attacks                                                      |                                                              |                        |
| RENAL AND URINARY DISORDERS Hematuria                                                                                                     | Proteinuria                                                  |                        |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough Dyspnea Pneumothorax6 Respiratory fistula7 Respiratory hemorrhage8 Voice alteration | Voice alteration (Gr 3)                                      |                        |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia Dry skin                                                                                  | Dry skin (Gr 2)                                              |                        |
| Hair color changes                                                                                                                        | Hair color changes (Gr 1)                                    |                        |
| Palmar-plantar erythrodysesthesia                                                                                                         | Palmar-plantar erythrodysesthesia                            |                        |
| syndrome                                                                                                                                  | syndrome (Gr 3)                                              |                        |
| Rash maculo-papular                                                                                                                       | Rash maculo-papular (Gr 3)                                   |                        |
| VASCULAR DISORDERS Hypertension                                                                                                           | Hypertension (Gr 3)                                          |                        |
| Thromboembolic event9                                                                                                                     |                                                              |                        |  
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, Enterovesical fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS SOC.  
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC.  
4Gastrointestinal 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.  
5Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 6Pneumothorax has been observed at a higher than expected frequency (15-20%) in a study treating patients with relapsed Ewing sarcoma and osteosarcoma all of whom had pulmonary metastases.  
7Respiratory fistula includes Bronchial fistula, Bronchopleural fistula, Laryngeal fistula, Pharyngeal fistula, Pulmonary fistula, and Tracheal fistula under the RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS SOC.  
8Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Hemoptysis, Laryngeal hemorrhage, Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS SOC.  
9Thromboembolic event includes pulmonary embolism which may be life-threatening.  
Adverse events reported on XL184 (Cabozantinib) trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that XL184 (Cabozantinib) caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other
(pancytopenia); Disseminated intravascular coagulation; Eosinophilia; Febrile neutropenia; Hemolytic uremic syndrome CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Cardiac arrest; Cardiac disorders - Other (hypokinetic cardiomyopathy); Chest pain - cardiac; Heart failure; Left ventricular systolic dysfunction; Myocardial infarction; Myocarditis; Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo ENDOCRINE DISORDERS - Endocrine disorders - Other (autoimmune thyroiditis); Endocrine disorders -
Other (thyroiditis); Endocrine disorders - Other (thyrotoxicosis); Hyperthyroidism; Hypopituitarism EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other (corneal epithelium defect) GASTROINTESTINAL DISORDERS - Abdominal distension; Anal fissure; Anal mucositis; Anal pain; Anal ulcer; Cheilitis; Colitis; Colonic obstruction; Duodenal ulcer; Dysphagia; Enterocolitis; Esophageal ulcer; Esophagitis; Flatulence; Gastric ulcer; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (glossitis); Gastrointestinal disorders - Other (pneumoperitoneum); Gastrointestinal pain; Gingival pain; Hemorrhoids; Ileus; Pancreatitis; Periodontal disease; Rectal pain; Rectal ulcer; Toothache GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema face; Fever; Gait disturbance; General disorders and administration site conditions - Other (general physical health deterioration); General disorders and administration site conditions - Other (implant site inflammation); Hypothermia; Malaise; Multi-organ failure; Non-cardiac chest pain; Pain; Sudden death NOS
HEPATOBILIARY DISORDERS - Budd-Chiari syndrome; Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other (cholelithiasis); Hepatobiliary disorders - Other (hepatic cirrhosis); Hepatobiliary disorders - Other (hepatic thrombus); Hepatobiliary disorders - Other (hepatitis toxic); Hepatobiliary disorders - Other (hepatorenal syndrome); Portal vein thrombosis IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Autoimmune disorder INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and procedural complications - Other (post procedural hemorrhage); Injury, poisoning and procedural complications - Other (tendon injury); Wound dehiscence; Wrist fracture INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Blood lactate dehydrogenase increased; CPK increased; Cardiac troponin I increased; Creatinine increased; Ejection fraction decreased; Electrocardiogram QT corrected interval prolonged; GGT increased; Investigations - Other (D-dimer); Investigations - Other (urine ketone body present); Lymphocyte count decreased; Neutrophil count decreased; Serum amylase increased; Thyroid stimulating hormone increased; White blood cell decreased METABOLISM AND NUTRITION DISORDERS - Glucose intolerance; Hyperglycemia; Hypernatremia; Hyperuricemia; Hypoalbuminemia; Hyponatremia; Metabolism and nutrition disorders - Other (failure to thrive); Metabolism and nutrition disorders - Other (hypoproteinemia)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Buttock pain; Chest wall pain; Flank pain; Muscle weakness lower limb; Musculoskeletal and connective tissue disorder - Other (muscle hemorrhage); Myalgia; Neck pain; Osteonecrosis; Osteoporosis; Rhabdomyolysis NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) -
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (lip and/or oral cavity cancer); Tumor hemorrhage; Tumor pain  
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Concentration impairment; Dysarthria; Dysesthesia; Dysphasia; Encephalopathy; Lethargy; Memory impairment; Nervous system disorders - Other (hemiparesis); Nervous system disorders - Other (vocal cord paralysis); Peripheral motor neuropathy; Peripheral sensory neuropathy; Presyncope; Seizure; Somnolence; Spinal cord compression; Syncope PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; Insomnia; Psychiatric disorders - Other (mental status changes)
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Glucosuria; Renal and urinary disorders - Other (hemorrhage urinary tract); Urinary tract obstruction REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain; Reproductive system and breast disorders - Other (scrotal ulcer/erythema/edema); Scrotal pain; Vaginal fistula; Vaginal inflammation; Vaginal perforation RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; Allergic rhinitis; Aspiration; Atelectasis; Hoarseness; Hypoxia; Laryngeal edema; Oropharyngeal pain; Pharyngeal mucositis; Pleural effusion; Pneumonitis; Productive cough; Pulmonary hypertension; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (nasal septum perforation);
Respiratory, thoracic and mediastinal disorders - Other (pneumomediastinum); Respiratory, thoracic and mediastinal disorders - Other (rales); Sore throat SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Nail changes; Pain of skin; Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (pain, sloughing of skin and erythema); Skin and subcutaneous tissue disorders - Other (psoriasis); Skin hypopigmentation; Skin ulceration VASCULAR DISORDERS - Hematoma; Hypotension; Superior vena cava syndrome; Vascular disorders -
Other (bleeding varicose vein); Vasculitis Note: XL184 (Cabozantinib) 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.
untitled h1
7.2 ctep reporting requirements

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 7.1.1) should be reported through CTEP-AERS only if the grade is above the grade provided in the SPEER.  
o Other AEs for the protocol that do not require expedited reporting are outlined in Section 7.2.4.  
- **Attribution** of the AE:
1. Definite - The AE *is clearly related* to the study treatment.  
2. Probable - The AE *is likely related* to the study treatment.  
3. Possible - The AE *may be related* to the study treatment. 4. Unlikely - The AE *is doubtfully related* to the study treatment. 5. Unrelated - The AE *is clearly NOT related* to the study treatment.  
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/protocolDevelopment/electronic_applications/adverse_events.htm ). These requirements are briefly outlined in the tables below (Section 7.2.3).  
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.
untitled h1
distribution of adverse event reports

CTEP-AERS is programmed for automatic electronic distribution of reports to the following individuals: Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the Corresponding Organization or Lead Organization, the local treating physician, and the Reporter and Submitter. CTEP-AERS provides a copy feature for other e-mail recipients Expedited Reporting Guidelines Use the NCI protocol number and the protocol-specific patient ID assigned during trial registration on all reports.  
Note**: A death on study requires both routine and expedited reporting regardless of**
causality, unless as noted below. Attribution to treatment or other cause must be provided.  
Death due to progressive disease should be reported as **Grade 5 "Disease progression"**
in the system organ class (SOC) "General disorders and administration site conditions." Evidence that the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor growth or progression: clinical deterioration associated with a disease process) should be submitted.  
Phase 1 and Early Phase 2 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/Intervention 1, 2  
```
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1) Death
2) A life-threatening adverse event
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24
hours
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
5) A congenital anomaly/birth defect.
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
(FDA, 21 CFR 312.32; ICH E2A and ICH E6).

```  
ALL **SERIOUS** adverse events that meet the above criteria MUST be immediately reported to the NCI via  
CTEP-AERS within the timeframes detailed in the table below.  
| CTEP-AERS within the timeframes detailed in the table below. Hospitalization Grade 1 and Grade 2 Timeframes   | Grade 3-5 Timeframes   |                          |
|---------------------------------------------------------------------------------------------------------------|------------------------|--------------------------|
| Resulting in Hospitalization  ≥ 24 hrs                                                                        | 10 Calendar Days       | 24-Hour; 5 Calendar Days |
| Not resulting in Hospitalization  ≥ 24 hrs                                                                    | Not required           |                          |  
```
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR.
Expedited AE reporting timelines are defined as:
o "24-Hour; 5 Calendar Days" - The AE must initially be reported via CTEP-AERS within 24 hours of
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report.
o "10 Calendar Days" - A complete expedited report on the AE must be submitted within 10 calendar
days of learning of the AE.

```  
Expedited 24-hour notification followed by complete report within 5 calendar days for:  
  
- All Grade 3, 4, and Grade 5 AEs Expedited 10 calendar day reports for:
- Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 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
Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions  
  
  
Lymphopenia (any grade), alopecia (any grade), anemia (grade 2), electrolytes (grade 2: sodium, potassium, phosphorous, and magnesium), albumin (grade 2), hyperuricemia (grade 3), INR (grade 2), and PTT (grade 2) will NOT be reported through CTEP-AERS but will be reported in the routine data submissions.  
Routine Adverse Event Reporting All Adverse Events **must** be reported in routine study data submissions. **AEs reported**
expeditiously through CTEP-AERS must also be reported in routine study data submissions.
untitled h1
pregnancy

Although not an adverse event in and of itself, pregnancy as well as its outcome must be documented via **CTEP-AERS**. In addition, the *Pregnancy Information Form* included within the NCI Guidelines for Adverse Event Reporting Requirements must be completed and submitted to CTEP. Any pregnancy occurring in a patient or patient's partner from the time of consent to 90 days after the last dose of study drug must be reported and then followed for outcome. Newborn infants should be followed until 30 days old. Please see the "NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs" (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more details on how to report pregnancy and its outcome to CTEP.
untitled h1
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.
untitled h1
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.  
Multicenter Guidelines for Expedited Adverse Event Reporting
untitled h1
7.2.10.1 expedited adverse event reporting

Follow sponsor expedited AE reporting requirements in Section 7.2 and copy Ashley Bruns (ashley.bruns@nih.gov) and Dr. Alice Chen (chenali@mail.nih.gov) on all CTEPAERS reports.
untitled h1
adverse event reporting to nih

The Coordinating Center will review CTEP-AERS reports and submit to the NIH-IRB via iRIS (https://iris.nci.nih.gov/iMedris/). The site PI must immediately report to the Coordinating Center PI any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the drug caused the event within 24 hours of PI awareness of the event. The site PI must also report any protocol deviations or violations to the Coordinating Center PI within 7 days of PI awareness. Participating centers must also submit the report to their IRB in accordance with their institutional policies. Follow NIH IRB expedited AE reporting requirements in this section. Complete the NIH IRB Expedited AE form supplied by the Coordinating Center. Send the completed form to Ashley Bruns either by e-mail to ashley.bruns@nih.gov or by fax to (301) 451-5625.
untitled h1
7.3 nih reporting requirements definitions

Please refer to definitions provided in Policy 801: Reporting Research Events (https://irbo.nih.gov/confluence/display/IRBO/Policies+and+SOPs).
untitled h1
ohsrp office of compliance and

Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found at https://irbo.nih.gov/confluence/display/IRBO/Policies+and+SOPs Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported per these policies.  
IRB Requirements for PI Reporting at Continuing Review Please refer to the reporting requirements in Policy 801: Reporting Research Events found at https://irbo.nih.gov/confluence/display/IRBO/Policies+and+SOPs NCI Clinical Director Reporting Problems expeditiously reported to the OHSRP/IRB in iRIS will also be reported to the NCI Clinical Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical Director. In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut at dahutw@mail.nih.gov and to NCICCRQA@mail.nih.gov within one business day of learning of the death.
untitled h1
8 pharmaceutical information

A list of the adverse events and potential risks associated with cabozantinib can be found in Section 7.1.
untitled h1
8.1 cabozantinib (nsc 761968)

Chemical Name: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)
cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate Other Names: XL184, EXEL-7184, EXEL-02977184 Classification: Receptor Tyrosine Kinases Inhibitor (RTK) CAS Registry Number: 1140909-48-3 Molecular Formula: C28H24FN3O5.C4H6O5 Molecular Weight: 635.6 Mode of Action: Cabozantinib inhibits multiple RTKs implicated in tumor growth, metastasis, and angiogenesis, and targets primarily MET and VEGFR2. Other targets are RET, AXL, KIT, TIE-2, and FLT-3.  
How Supplied: Cabozantinib is supplied by Exelixis and distributed by the DCTD.  
Cabozantinib is available in 20-mg and 60-mg tablets. The tablets are yellow film coated containing cabozantinib malate equivalent to 20 mg and 60 mg of cabozantinib. The 20-mg tablets have a round shape and the 60-mg tablets have an oval shape, and they are packaged 30 tablets per bottle.  
| Ingredient                                                                                                               | Function          | % w/w   |
|--------------------------------------------------------------------------------------------------------------------------|-------------------|---------|
| Cabozantinib malate (25% drug load as cabozantinib)                                                                      | Active Ingredient | 31.7    |
| Microcrystalline Cellulose (Avicel PH-102)                                                                               | Filler            | 38.9    |
| Lactose Anhydrous (60M)                                                                                                  | Filler            | 19.4    |
| Hydroxypropyl Cellulose (EXF)                                                                                            | Binder            | 3.0     |
| Croscarmellose Sodium (Ac-Di-Sol)                                                                                        | Disenegrant       | 6.0     |
| Colloidal Silicon Dioxide,                                                                                               | Glidant           | 0.3     |
| Magnesium Stearate                                                                                                       | Lubricant         | 0.75    |
| Opadry Yellow Film Coating which includes: HPMC 2910 / Hypromellose 6 cp  Titanium dioxide  Triacetin  Iron Oxide Yellow | Film Coating      | 4.00    |
untitled h1
cabozantinib tablet components and composition

Storage: Store intact bottles at controlled room temperature, 20° to 25°C (68° F to 77° F);
temperature excursions are permitted between 15° C and 30° C (59° F to 86° F) [see USP Controlled Room Temperature].  
If a storage temperature excursion is identified, promptly return cabozantinib to 20° to 25°C (68° to 77° F) and quarantine the supplies. Provide a detailed report of the excursion (including documentation of temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for determination of suitability.  
Stability: Stability testing of the intact bottles is ongoing. Cabozantinib is stable up to 24 hours when dispensed in an open container such as a pill cup, and up to 7 days when dispensed in a closed container such as a pharmacy bottle other than the original container.  
Route of Administration: Oral cabozantinib should be taken on an empty stomach, 1 hour before or 2 hours after food. Do not crush or chew. Potential Drug Interactions: See Section 5.1.1
untitled h1
8.2 agent ordering

NCI-supplied agents may be requested by the responsible 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), Biosketch, Agent Shipment Form, 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. 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://ctepcore.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.
untitled h1
8.3 agent accountability

Agent Inventory Records - The investigator, or a responsible party designated by the investigator, must maintain a careful record of the receipt, dispensing and final disposition of all agents received from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP forms page. Store and maintain separate NCI Investigational Agent Accountability Records for each agent, strength, formulation and ordering investigator on this protocol.
untitled h1
8.4 investigator brochure availability

The current versions of the IBs for the agents will be accessible to site investigators and research staff through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of an "active" account status and a "current" password. Questions about IB access may be directed to the PMB IB coordinator via email.
untitled h1
8.5 useful links and contacts

- CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/
- NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov - PMB policies and guidelines:
http://ctep.cancer.gov/branches/pmb/agent_management.htm
- PMB Online Agent Order Processing (OAOP) application: https://eappsctep.nci.nih.gov/OAOP/pages/login.jspx
- CTEP Identity and Access Management (IAM) account:
https://ctepcore.nci.nih.gov/iam
- CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov - PMB email: PMBAfterHours@mail.nih.gov - IB Coordinator: IBCoordinator@mail.nih.gov - PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET)
untitled h1
9 correlative studies 9.1 pharmacodynamics

Blood will be obtained from all patients for PD assessment as described in Section 9.1.1. Optional blood samples will also be collected for isolation of CTCs as defined in Section 9.1.2. Record the date, planned time, and actual time of collection for each specimen on the PK/PD Sample Collection Sheet in Appendix H, the CTEP tracking number (P9284), unique patient accession number, and 3-digit sample number should be included on this form. In addition, the date and exact time when study drug was administered should be recorded on the form. At the NCI, at least 24 hours prior to blood sample collection, the research nurse will contact the NCI Phase I/II PK/PD Support Group in NIH Building 10: E-mail NCIPKPDsupportgroup@mail.nih.gov Pager: 102-12798 Phone: 301-451-1169 Fax: 301-480-5871.  
Blood Samples (mandatory at the NCI but optional at participating sites)
Assays to be performed: sMET, HGF, VEGF-A, and sVEGFR2. These research blood tests are mandatory at the NCI but optional at participating sites: Samples will be obtained at the following time points:  
- Before drug administration on study (baseline)
- Cycle 1 day 1; 3-6 hours post dose
- Cycle 2 day 1; 3-6 hours post-dose 1. Blood samples should be obtained using EDTA as an anticoagulant; the minimum volume of blood needed for analysis of all four markers is 3 mL
2. Plasma should be prepared from the blood samples within 1 hour (with interim storage and handling at 4oC).  
3. Plasma should be transferred to a sterile screw cap cryovial (silicon gasket); prelabeled with bar code is preferred.  
4. Plasma should be frozen and stored at -80°C within 1 hour of blood processing. 5. Samples should be shipped on dry ice in batches at periodic intervals (if local storage is limiting or interim analysis is performed) or after all samples have been collected.
Samples should be shipped to: Donald P. Bottaro, PhD Urologic Oncology Branch National Cancer Institute Bldg 10, Rm 1W-5832 10 Center Drive MSC 1210 Bethesda, MD 20892-1210 301-496-6353 (UOB Office & paging) 301-402-6499 (direct & voice mail) 301-402-0922 (fax)
bottarod@mail.nih.gov Participating sites should e-mail the research nurse, Ashley Bruns, at ashley.bruns@nih.gov prior to sending samples to obtain a FedEx account number to use for shipment.  
Blood Collection for Circulating Tumor Cells (optional)
Whole blood will be collected aseptically by venipuncture or from a venous port into one 6-mL sodium heparin tube.  
Blood samples for CTCs (optional) will be collected at the following times:
- cycle 1 prior to drug administration (baseline)
- cycle 1 day 1 4 hours (+/- 1 hour) after drug administration
- day 1 of every subsequent cycle prior to drug administration (every 3 cycles after 1 year on study and every 4 cycles after 3 years on study)
- one additional blood sample will be collected at time of disease progression Testing and data analysis will be performed by Dr. Bob Kinders (PADIS/FNLCR).
untitled h1
samples should be shipped to

Attention: Dan Danner NCI-F/FNLCR 1073 Beasley Street, Building 1073 Fort Detrick Frederick, MD 21701 Phone: 301-846-5748 NCI_PD_Support_CellSearch@mail.nih.gov Blood for CTC analysis will be shipped to the PADIS laboratory on the day it is collected. Shipping arrangements will be made by sending an email to NCI_PD_Support_CellSearch@mail.nih.gov. For NCI Clinical Center specimens only: arrangements will be made for pickup with the CSP courier service (301-846-5893)
untitled h1
sample collection and processing

Biospecimens will be collected and processed using validated SOPs that will ensure both specimen quality and patient confidentiality pursuant to informed consent provisions. Using a computerized inventory system and a backup hardcopy process, all specimen collection and processing steps will be documented and the specific location of each specimen will be tracked. Each new specimen collected will be assigned a unique barcode identifier that can be linked to the original specimen collected and other relevant information within the inventory system. To ensure patient confidentiality, only containers used for the initial specimen collections will be labeled with patient identifiers.  
Only the barcode identifier will be applied to all subsequent specimen containers. When specimens are processed and aliquoted, no patient information will be included on the new containers. Original specimen containers will be discarded. Only barcode-labeled specimens without patient identifiers will be shipped for analysis and/or storage.  
Specimen labels will indicate: CTEP protocol number, unique patient accession number, 3-digit sample number (see list below), collection time, and total volume collected, as appropriate. Samples from sets of at least three patients will be grouped for scientific analysis. Standardized 3-digit sample collection numbers: 300 series: blood for PD 400 series: blood for circulating tumor cells (CTCs) The inventory process contains other security provisions sufficient to safeguard patient privacy and confidentiality. Access to the inventory system and associated documents will be restricted to appropriate individuals. Requests to use specimens stored in the repository must be approved. The only patient information available in the inventory system will be the patient sex, diagnosis, and level of informed consent given. SOPs ensure that any changes in informed consent made by a patient and relayed to the PI will be reflected in the inventory system to ensure that specimens are destroyed as appropriate. All laboratory personnel will be trained to adhere to SOPs and will be monitored for high-quality performance. Any new use of these samples will require prospective IRB review and approval. Access to these samples will only be granted following IRB approval of an additional protocol, granting the rights to use the material. If at any time, a patient withdraws from the study and does not wish for their existing samples to be utilized, the individual must provide a written request. Following receipt of this request, the samples will be destroyed (or returned to the patient, if so requested), and reported as such to the IRB. Any samples lost (in transit or by a researcher) or destroyed due to unknown sample integrity (i.e., broken freezer allows for extensive sample thawing, etc.) will be reported as such to the IRB.
untitled h1
human data sharing plan

What data will be shared? We will share human data generated in this research for future research as follows: X De-identified data in an NIH-funded or approved public repository X Identified data in BTRIS (automatic for activities in the Clinical Center)
X De-identified or identified data with approved outside collaborators under appropriate agreements How and where will the data be shared? Data will be shared through: X An NIH-funded or approved public repository: clinicaltrials.gov X BTRIS (automatic for activities in the Clinical Center)
X Approved outside collaborators under appropriate individual agreements X Publication and/or public presentations When will the data be shared?  
X At the time of publication or shortly thereafter
untitled h1
10 study calendar

Eligibility screening evaluations are to be conducted within 8 days prior to enrollment, with the exception of informed consent and tumor imaging scans, which must be done within 28 days prior to enrollment (see Section 3.4). Baseline history, physical examination, laboratory evaluations, urinalysis, pregnancy test, and EKG are to be conducted within 8 days prior to the start of protocol therapy. If protocol therapy is started within 8 days of the eligibility screening evaluations, values from the screening evaluations may be used as baseline measurements; if > 8 days have passed since the screening evaluations, the medical history, physical examination, laboratory evaluations, urinalysis, pregnancy test, and EKG must be repeated prior to starting protocol therapy. Baseline imaging scans and must be done within 28 days prior to the start of protocol therapy. A new cycle may begin up to 1 week later than it would otherwise be scheduled based on the 28day cycle, to allow for flexibility for days the clinic is closed and other unexpected events. 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.  
| Pre-Study                          | C1                                                                                                                                                                                                                               | C1                                                                              | C1                                                                              | C1   | C2   | C2   | C2   | C2   | C3   | C3   | Off       |
|------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------|---------------------------------------------------------------------------------|------|------|------|------|------|------|------|-----------|
| Screening                          | W1                                                                                                                                                                                                                               | W2                                                                              | W3                                                                              | W4   | W1   | W2   | W3   | W4   | W1   | W3   | Treatment |
| Cabozantiniba                      | X                                                                                                                                                                                                                                | X                                                                               | X                                                                               | X    | X    | X    | X    | X    | X    | X    |           |
| Informed consent                   | X                                                                                                                                                                                                                                |                                                                                 |                                                                                 |      |      |      |      |      |      |      |           |
| Archival tumorb                    | X                                                                                                                                                                                                                                |                                                                                 |                                                                                 |      |      |      |      |      |      |      |           |
| Demographics                       | X                                                                                                                                                                                                                                |                                                                                 |                                                                                 |      |      |      |      |      |      |      |           |
| Medical history                    | X                                                                                                                                                                                                                                |                                                                                 |                                                                                 |      |      |      |      |      |      |      |           |
| Concurrent meds                    | X                                                                                                                                                                                                                                |                                                                                 | X-----------------------------------------------------------------------------X |      |      |      |      |      |      |      |           |
| Physical examc,m                   | X                                                                                                                                                                                                                                | Xn                                                                              | X                                                                               | X    | X    |      |      |      |      |      |           |
| Vital signsd,m                     | X                                                                                                                                                                                                                                | Xn                                                                              | X                                                                               | X    | X    |      |      |      |      |      |           |
| Height                             | X                                                                                                                                                                                                                                |                                                                                 |                                                                                 |      |      |      |      |      |      |      |           |
| Weightm                            | X                                                                                                                                                                                                                                | Xn                                                                              | X                                                                               | X    | X    |      |      |      |      |      |           |
| Performance  statusm               | X                                                                                                                                                                                                                                | Xn                                                                              | X                                                                               | X    | X    |      |      |      |      |      |           |
| CBC w/diff,  pltse,m               | X                                                                                                                                                                                                                                | Xn                                                                              | X                                                                               | X    | X    |      |      |      |      |      |           |
| Serum  chemistrye,m                | X                                                                                                                                                                                                                                | Xn                                                                              | X                                                                               | X    | X    |      |      |      |      |      |           |
| B12, folateo                       | X                                                                                                                                                                                                                                |                                                                                 |                                                                                 |      |      |      |      |      |      |      |           |
| Urine protein/ creatinine ratiof,m | X                                                                                                                                                                                                                                | Xn                                                                              | X                                                                               | X    | X    |      |      |      |      |      |           |
| Adverse event  evaluation          |                                                                                                                                                                                                                                  | X-----------------------------------------------------------------------------X |                                                                                 |      |      |      |      |      |      |      |           |
| Tumor                              | Tumor measurements as indicated below. Documentation (radiologic) must                                                                                                                                                           |                                                                                 |                                                                                 |      |      |      |      |      |      |      |           |
| measurementsg,m                    | X                                                                                                                                                                                                                                | be provided for patients removed from study for progressive disease.            |                                                                                 |      |      |      |      |      |      |      |           |
| EKGh,m                             | X                                                                                                                                                                                                                                | Xn                                                                              | X                                                                               | X    |      |      |      |      |      |      |           |
| B-HCGi,m                           | X                                                                                                                                                                                                                                | Xn                                                                              | X                                                                               | X    |      |      |      |      |      |      |           |
| PD blood  samplingj                | X                                                                                                                                                                                                                                | X                                                                               |                                                                                 |      |      |      |      |      |      |      |           |
| TSHk,m                             | X                                                                                                                                                                                                                                | Xn                                                                              | X                                                                               | X    |      |      |      |      |      |      |           |
| Blood for CTCsl,m                  | X                                                                                                                                                                                                                                | X                                                                               | X                                                                               | X    |      |      |      |      |      |      |           |
| a:                                 | Cabozantinib once daily at 60 mg po daily. A new cycle may begin up to 1 week later than it would otherwise  be scheduled based on the 28-day cycle, to allow for flexibility for days the clinic is closed and other unexpected |                                                                                 |                                                                                 |      |      |      |      |      |      |      |           |  
X  
f: Evaluation of urine protein/creatinine ratio should occur at baseline, within 8 days prior to the start of each new cycle, and as clinically indicated. If patient has urine protein/creatinine ratio >1+, obtain a 24 hour urine for protein and creatinine clearance.  
g: Tumor measurements are repeated every 2 cycles (every 3 cycles for patients on study for more than 1 year; every 4 cycles for patients on study more than 3 years).  
h: EKG will be performed at baseline and within 8 days prior to the start of each new cycle. i: Serum or urine pregnancy test (women of childbearing potential) at baseline and within 8 days prior to the start of each new cycle.  
j: Blood samples will be obtained at the following time points: at baseline, on C1D1 3-6 hours after dose of cabozantinib and C2D1 3-6 hours post drug (mandatory at the NCI but optional at participating sites).  
k: TSH at baseline and within 8 days prior to the start of each new cycle. l: Blood for circulating tumor cells (CTCs) will be collected (optional) as described in Section 9.1.2.  
m: The history and physical exam, pregnancy test, CT scan, EKG, TSH, and all other protocol-required labs and CTC blood collections will be done every 3 cycles after 1 year on study and every 4 cycles after 3 years on study.  
n: Eligibility screening results may be used for these baseline measurements if conducted within 8 days prior to the start of protocol therapy. See Sections 3.4 and 5.  
o: B12 and folate at baseline and every 12 weeks (every 3 cycles, within 8 days prior to the start of the cycle; every 4 cycles after 3 years on study).
untitled h1
11 measurement of effect 11.1

For the purposes of this study, patients should be re-evaluated for response every 8 weeks or 2 cycles (every 3 cycles for patients on study for more than 1 year; every 4 cycles for patients on study more than 3 years). In addition to a baseline scan, confirmatory scans should also be obtained 4 weeks following initial documentation of objective response. Bone scans will be done at baseline for patients with known bone tumors and at restaging if clinically needed. 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) [*Eur J Ca* 45:228-247, 2009]. 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.
untitled h1
definitions

Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first treatment with cabozantinib. Evaluable for objective response. Only those patients who have measurable disease present at baseline, 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.)
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
untitled h1
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 >20 mm by chest x-ray or as >10 mm with CT scan, MRI, or calipers by clinical exam. 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. If the investigator thinks it appropriate to include them, the conditions under which such lesions should be considered must be defined in the protocol. 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 noncystic 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 nonnodal 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 60 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.
untitled h1
11.2 methods for evaluation of

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. PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT
introduces additional data which may bias an investigator if it is not routinely or serially performed. 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.  
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD
based on a new lesion.  
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDGPET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDGPET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.  
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively described in the protocol and supported by disease-specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.
Note: A 'positive' FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image.
untitled h1
11.3 response criteria

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.                                                                                                                                                                                                                                         |
| 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 nonpathological in size (<10 mm short axis). Note: If tumor markers are initially above the upper  normal limit, they must normalize for a patient to be  considered in complete clinical response.                                                                                                                                                                                                                                                                                                                                                                                                    |
| Non-CR/Non-PD:                   | Persistence of one or more non-target lesion(s) and/or  maintenance of tumor marker level above the normal  limits.                                                                                                                                                                                                                                                                                |
| Progressive Disease (PD):        | Appearance of one or more new lesions and/or unequivocal  progression of existing non-target lesions. Unequivocal  progression should not normally trump target lesion status.  It must be representative of overall disease status change,  not a single lesion increase.                                                                                                                         |  
Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator).  
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.  
| Target    | NonTarget                                                                                                                      |                           |                       |                                                   |
|-----------|----------------------------------------------------------------------------------------------------------------------|---------------------------|-----------------------|---------------------------------------------------|
| Lesions   | Lesions                                                                                                              | New                       | Overall               | Best Overall Response when                        |
| Lesions   | Response                                                                                                             | Confirmation is Required* |                       |                                                   |
| CR        | CR                                                                                                                   | No                        | CR                    | >4 wks. Confirmation**                            |
| CR        | Non-CR/                                                                                                              | No                        | PR                    |                                                   |
| Non-PD    |                                                                                                                      |                           |                       |                                                   |
| CR        | Not                                                                                                                  | No                        | PR                    |                                                   |
| evaluated | >4 wks. Confirmation**                                                                                               |                           |                       |                                                   |
| PR        | Non                                                                                                                      |                           |                       |                                                   |
| CR/NonPD/not  evaluated           | No                                                                                                                   | PR                        |                       |                                                   |
| SD        | Non-CR/ Non-PD/ not  evaluated                                                                                       | No                        | SD                    | Documented at least once >4  wks. from baseline** |
| PD        | Any                                                                                                                  | Yes or                    | PD                    |                                                   |
| No        |                                                                                                                      |                           |                       |                                                   |
| Any       | PD***                                                                                                                | Yes or                    | no prior SD, PR or CR |                                                   |
| 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 non-target lesions  may be accepted as disease progression. |                           |                       |                                                   |
| Note:     | Patients with a global deterioration of health status requiring discontinuation                                      |                           |                       |                                                   |  
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as "*symptomatic deterioration."* Every effort should be made to document the objective progression even after discontinuation of treatment.  
| 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 |               |                    |  
For Patients with Non-Measurable Disease (i.e.**, Non-Target Disease)**
untitled h1
11.4 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.
untitled h1
11.5 progression-free survival

PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
untitled h1
12 data reporting / regulatory

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: List and Reporting Requirements).
untitled h1
12.1 data reporting method

Data will be collected in the Center for Cancer Research C3D database. 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).  
Note: All adverse events that have occurred on the study, including those reported through CTEP-AERS, must be reported via the monitoring method identified above.
untitled h1
responsibility for data submission

Study participants are responsible for submitting CDUS data and/or data forms to the Coordinating Center quarterly to allow time for Coordinating Center compilation, Principal Investigator review, and timely submission to CTEP. The Coordinating Center is responsible for compiling and submitting CDUS data to CTEP for all participants and for providing the data to the Principal Investigator for review.
untitled h1
12.2 data safety and monitoring

The investigators at each participating center will be responsible for the collection, maintenance, and quality control of the study data. Adverse events observed in patients enrolled on the trial will be monitored in real time by the Principal and Associate Investigators, and attribution of these events to the research will be determined at the end of each treatment cycle in each subject. The clinical research team (PI, adjunct PI, research nurses, data managers) will meet weekly when patients are being actively treated on the trial to discuss each patient in detail and ensure that all events are graded appropriately, and that the attribution to study drug is correct. The Coordinating Center is responsible for establishing conference calls between participating sites at least on a monthly basis to discuss the observed toxicities and protocol issues. All SAEs will be reported through CTEP-AERS to CTEP, to the Coordinating Center PI at NCI, and forwarded to the IRB per Section 7.0. In all cases where the dose of the study treatment has been reduced/modified or the patient withdrawn due to unusual or unusually severe toxicity considered related to the study treatment, the investigator must contact and inform the Coordinating Center PI. All sites will be monitored by the CTEP drug monitor, who will receive data from all participating sites. Data will be monitored regularly by the PI in order to identify significant toxicity trends. Any new significant finding that may affect the patient's willingness to continue in the study will be shared with patients. Confidentiality will be maintained as much as possible, consistent with applicable regulations. Names of participants or identifying material will not be released without patient permission, except when such release is required by law. No patient's name or identifying information will be released in any publication or presentation. Records are maintained according to current legal requirements, and are made available for review according to the requirements of the FDA or other authorized user, only under guidelines established by the Federal Privacy Act. Safety Monitoring Committee: Because this is a multi-institutional protocol for which the NCI CCR is the Coordinating Center, it will be monitored by the DTC Safety Monitoring Committee, NCI.
untitled h1
12.3 multicenter guidelines

This protocol opened initially at the NCI. The NIH IRB will be notified once the participating centers' IRBs have approved the studies to open. This protocol will follow the CCR's Clinical Research Operations' SOPs for multicenter trials.
untitled h1
irb approvals

As the Coordinating Center for a trial, it is the PI's responsibility to ascertain that no patients are entered on the trial at a participating institution without full IRB approval. Thus, the NIH IRB must approve the addition of each participating institution to the protocol and will require a copy of the local IRB approval from each participating institution before NIH IRB approval will be granted. The PI will provide the NIH 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 IRB.
untitled h1
amendments and consents

The NCI PI will provide the NIH IRB with copies of all amendments, consents, and approvals from each participating institution.
untitled h1
data collection

The investigators will be responsible for the collection, maintenance, and quality control of the study data. All data collected for each study subject will be entered into the Cancer Central Clinical Database (C3D), an NCI electronic case report form/database, every 2 weeks. The participating sites will be able to enter the data remotely into the webbased C3D system. Each site investigator is also responsible for maintaining all source documentation related to the study, including any films, tracings, computer discs or tapes.  
NCI will be responsible for data management, data analysis, and reporting. Data collection forms will be provided to the participating institutions. Required data include, not exclusively: prior disease-related therapies with dates, disease type, stage, disease sites, with measurements, and concurrent medications.
untitled h1
data and center audits

Audits will be conducted yearly to ensure data integrity and provide quality control. These audits will be conducted by the NCI research team. Selected patient charts should be audited as well as the participating institution's Standard Operating Procedures (SOP) at the time of the visit. Data from participating institutions should be available when the protocol is audited at the NCI.
untitled h1
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).
untitled h1
12.4 collaborative agreements language

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 "Multi-Party Data"):
a. NCI will provide all Collaborators with prior written notice regarding the existence and nature of any agreements governing their collaboration with NCI, the design of the proposed combination protocol, and the existence of any obligations that would tend to restrict NCI's participation in the proposed combination protocol.  
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain regulatory approval or commercialize its own Agent.  
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in writing prior to the commencement of the trials that it will use the Multi-Party Data solely for development, regulatory approval, and commercialization of its own Agent.
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional disclosure is required by law or court order as described in the IP Option to Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all applicable federal statutes and regulations for the protection of human subjects, including, if applicable, the *Standards for Privacy of* Individually Identifiable Health Information set forth in 45 C.F.R. Part 164.  
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact them.  
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial.  
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group office for Cooperative Group studies or by the principal investigator for non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and comment prior to submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential and proprietary data, in addition to Collaborator(s)'s intellectual property rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other media presentations must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press release/ media presentation should be sent to:
Email: ncicteppubs@mail.nih.gov The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of Collaborator's confidential/ proprietary information.
untitled h1
13 statistical considerations 13.1 study

The study will be conducted as a dual-endpoint two-stage Phase II trial to target objective tumor response rate (CR+PR) of 30% against an unacceptably low rate of 10%, and 6-month PFS rate of 65% against an unacceptably low rate of 45% (corresponding to median PFS of 9.6 vs. 5.2 months). The trial is designed to accrue up to 50 evaluable patients and judge the agent as promising if either tumor response rate or 6-month PFS rate is promising. If at least 11 objective responses (at least 22%), or at least 27 instances of 6-month PFS (at least 54%), are observed among the 50 evaluable patients, this agent will be considered worthy of further testing in this disease. If no more than 3 objective responses (12%), and no more than 12 instances of 6-month PFS (no more than 48%), are observed among the initial 25 patients, the study will be terminated early and declared negative. This design yields at least 90% power to detect a true objective response rate of at least 30%. It yields at least 92% power to detect a true 6-month PFS rate of at least 65% (median PFS of 9.6 months). It yields at least .89 probability of a negative result if the true objective response rate is no more than 10% and the true 6-month PFS rate is no more than 45% (median PFS of 5.2 months), with approximately .53 probability, at least, of early negative stopping in this case. These last two probabilities (of a negative result and early negative stopping, both under the null hypothesis) are calculated assuming that tumor response rate and PFS rate are uncorrelated. If they are positively correlated, as is likely, the probabilities will be a bit higher.
untitled h1
13.2 sample size/accrual rate

The study will accrue 50 evaluable patients at the rate of 2-3 patients per month. To allow for a small number of unevaluable patients, the accrual ceiling has been set at 55 patients.
untitled h1
13.3 stratification factors

Patients will be stratified based on prior VEGF/TKI therapy. In order to ensure accrual of multiple different histological types of STS to this trial (including histologic types that are felt to be driven by angiogenesis or the MET pathway), following accrual of the first 20 patients, discussions will be held with CTEP to review which other histologic types of STS should be enrolled.
untitled h1
13.4 analysis of secondary endpoints

- Determine and compare circulating levels of HGF, soluble MET (sMET), VEGF-A, and soluble VEGFR2 (sVEGFR2) prior to and following administration of cabozantinib.  
- All PD changes from baseline will be assessed descriptively by calculating the mean and the 95% confidence interval of the change. PD measures derived from blood samples will be used to assess the change from baseline 3-6 hours after the first dose of the first cycle of treatment and 3-6 hours after the first dose of the second cycle of treatment.
untitled h1
13.5 reporting and exclusions

Evaluation of toxicity - All patients will be evaluable for toxicity from the time of their first treatment with cabozantinib. Evaluation of response - All patients included in the study will 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) will be included in the main analysis of the response rate. Patients in response categories 4-9 will 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 will 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 violations, etc.). However, these subanalyses will not serve as the basis for drawing conclusions concerning treatment efficacy, and the reasons for excluding patients from the analysis will be clearly reported. The 95% confidence intervals will also be provided.
untitled h1
14 human subjects protections 14.1

This study will be open to all individuals regardless of gender, ethnicity, or race, provided that the aforementioned inclusion and exclusion criteria are met. Patients for this study will be recruited through internal referral, our physician referral base, and through various cancer information hotlines (i.e., Clinical Studies Support Center, 1-800-4Cancer). To date, there is no information that suggests that differences in drug metabolism or effect on tumor would be expected in one ethnic group compared to another. Efforts will be made to extend accrual to each representative population, but a balance must be struck between participant safety considerations and limitations on the number of individuals exposed to potentially 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, a follow-up study may be written to investigate those differences more fully. Due to lack of knowledge of the effects of cabozantinib on the fetus or infants, as well as the possibility of teratogenic effects, pregnant and nursing women will be excluded from this trial. Patients with unstable or serious medical conditions are excluded due to the possibility that  
cabozantinib may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events with respect to cabozantinib. HIV-positive patients on combination antiretroviral therapy are excluded from the study because of possible interactions with cabozantinib
untitled h1
participation of children

This study includes patients 18 years of age and older. Because insufficient dosing or adverse event data are currently available on the use of cabozantinib in patients <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials. Studies will be performed in patients <18 years of age when it is appropriate to do so.
untitled h1
14.2 evaluation of benefits and

There may or may not be any clinical benefit to a patient from participation in this trial. Their participation will benefit future cancer patients. Potential risks include the possible occurrence of any of a range of side effects that are listed in the consent document. The procedure for protecting against or minimizing risks will be to medically evaluate patients as described in Sections 5 and Section 6. Although no compensation is available, any injury will be fully evaluated and treated in keeping with the benefits or care to which participants are entitled under applicable regulations.
untitled h1
14.3 consent and assent process

An associate or principal investigator on the trial will inform patients of the purpose, alternatives, drug administration 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. The original signed consent goes to Medical Records; a copy will be placed in the research record. Patients will not be consented by telephone.  
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. 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, all subjects ≥ age 18 **at the NCI only** 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. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
untitled h1
14.4 procedure for protecting against

All care will be taken to minimize side effects, but they can be unpredictable in nature and severity. This study may involve risks to patients, which are currently unforeseeable. All patients will be monitored for side effects from taking study medication. This research represents a greater than minimal risk to participants, but presents the prospect of direct benefit to individual subjects.
untitled h1
14.5 patient advocate

The patients' rights representative is available to patients receiving treatment on this protocol at the NIH Clinical Center at (301) 496-2626 in Building 10 of the Clinical Research Center, Room 1-3521, on the Bethesda NIH campus. Patients will be informed that they can contact the study PI or RN at any time with questions about their medical care, and that the patients' rights representative is also available to answer non-medical questions about the study.
references
14.5 patient advocate

1. Jemal A, Siegel R, Xu J, et al: Cancer statistics, 2010. CA Cancer J Clin 60:277-300, 2010 2. Coindre JM, Terrier P, Guillou L, et al: Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer 91:1914-26, 2001 3. Antman K, Crowley J, Balcerzak SP, et al: An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 11:1276-85, 1993 4. Antman KH, Elias A: Dana-Farber Cancer Institute studies in advanced sarcoma. Semin Oncol 17:7-15, 1990 5. Bramwell VH, Anderson D, Charette ML: Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft tissue sarcoma. Cochrane Database Syst Rev:CD003293, 2003 6. Edmonson JH, Ryan LM, Blum RH, et al: Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 11:1269-75, 1993 7. Elias A, Ryan L, Sulkes A, et al: Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol 7:1208-16, 1989 8. Lorigan P, Verweij J, Papai Z, et al: Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 25:3144-50, 2007 9. Santoro A, Tursz T, Mouridsen H, et al: Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 13:1537-45, 1995 10. Zalupski M, Metch B, Balcerzak S, et al: Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: a Southwest Oncology Group study. J Natl Cancer Inst 83:926-32, 1991 11. Maki RG, Wathen JK, Patel SR, et al: Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol 25:2755-63, 2007 12. Leu KM, Ostruszka LJ, Shewach D, et al: Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol 22:1706-12, 2004 13. Scurr M: Histology-driven chemotherapy in soft tissue sarcomas. Curr Treat Options Oncol 12:32-45, 2011 14. Hayes AJ, Mostyn-Jones A, Koban MU, et al: Serum vascular endothelial growth factor as a tumour marker in soft tissue sarcoma. Br J Surg 91:242-7, 2004 15. Potti A, Ganti AK, Tendulkar K, et al: Determination of vascular endothelial growth factor (VEGF) overexpression in soft tissue sarcomas and the role of overexpression in leiomyosarcoma. J Cancer Res Clin Oncol 130:52-6, 2004 16. Yudoh K, Kanamori M, Ohmori K, et al: Concentration of vascular endothelial growth factor in the tumour tissue as a prognostic factor of soft tissue sarcomas. Br J Cancer 84:1610-5, 2001 17. Chao C, Al-Saleem T, Brooks JJ, et al: Vascular endothelial growth factor and soft tissue sarcomas: tumor expression correlates with grade. Ann Surg Oncol 8:260-7, 2001 18. Wang J, Coltrera MD, Gown AM: Cell proliferation in human soft tissue tumors correlates with platelet-derived growth factor B chain expression: an immunohistochemical and in situ hybridization study. Cancer Res 54:560-4, 1994 19. Verschraegen CF, Arias-Pulido H, Lee SJ, et al: Phase IB study of the combination of docetaxel, gemcitabine, and bevacizumab in patients with advanced or recurrent soft tissue sarcoma: the Axtell regimen. Ann Oncol, 2011 20. Park MS PS, Ludwig JA et al. : Combination therapy with temozolomide and bevacizumab in the treatment of hemangiopericytoma/malignant solitary fibrous tumor. J Clin Oncol 26(Suppl): 10512., 2008 21. Sleijfer S, Ray-Coquard I, Papai Z, et al: Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol 27:3126-32, 2009 22. al WTVDGe: J Clin Oncol suppl; abstr LBA10002, 2011 23. Trusolino L, Comoglio PM: Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2:289-300, 2002 24. Birchmeier C, Birchmeier W, Gherardi E, et al: Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915-25, 2003 25. Rong S, Jeffers M, Resau JH, et al: Met expression and sarcoma tumorigenicity. Cancer Res 53:5355-60, 1993 26. Gao CF, Xie Q, Zhang YW, et al: Therapeutic potential of hepatocyte growth factor/scatter factor neutralizing antibodies: inhibition of tumor growth in both autocrine and paracrine hepatocyte growth factor/scatter factor:c-Met-driven models of leiomyosarcoma. Mol Cancer Ther 8:2803-10, 2009 27. Davis IJ, McFadden AW, Zhang Y, et al: Identification of the receptor tyrosine kinase cMet and its ligand, hepatocyte growth factor, as therapeutic targets in clear cell sarcoma. Cancer Res 70:639-45, 2010 28. Yakes FM, Chen J, Tan J, et al: Cabozantinib (XL184), a Novel MET and VEGFR2 Inhibitor, Simultaneously Suppresses Metastasis, Angiogenesis, and Tumor Growth. Mol Cancer Ther 10:2298-308, 2011 29. Sennino B NR, Tabruyn SP, You W-K, Aftab DT, McDonald, DM.: Reduction of tumor invasiveness and metastasis and prolongation of survival of RIP-Tag2 mice after inhibition of VEGFR plus c-Met by XL184. . Mol Cancer Ther ;8(12 Suppl):A13, 2009 30. Lee R: Investigator-sponsored trial of efficacy and tolerability of cabozantinib (cabo) at lower dose: A dose-finding study in men with castration-resistant prostate cancer (CRPC) and bone metastases. J Clin Oncol 2012 31. Kurzrock R, Sherman SI, Ball DW, et al: Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol 29:2660-6, 2011 32. Athauda G, Giubellino A, Coleman JA, et al: c-Met ectodomain shedding rate correlates with malignant potential. Clin Cancer Res 12:4154-62, 2006 33. Cecchi F, Rabe DC, Bottaro DP: Targeting the HGF/Met signalling pathway in cancer. Eur J Cancer 46:1260-70, 2010 34. Shojaei F, Lee JH, Simmons BH, et al: HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res 70:10090-100, 2010 35. di Tomaso E, Snuderl M, Kamoun WS, et al: Glioblastoma recurrence after cediranib therapy in patients: lack of "rebound" revascularization as mode of escape. Cancer Res 71:1928, 2011 36. Ebos JM, Lee CR, Cruz-Munoz W, et al: Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232-9, 2009 37. Paez-Ribes M, Allen E, Hudock J, et al: Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220-31, 2009 38. MR S: Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration resistant prostate cancer (mCRPC): Results from a phase II nonrandomized expansion cohort (NRE). J Clin Oncol (suppl; abstr 4513), 2012 39. Dowlati A, Haaga J, Remick SC, et al: Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation. Clin Cancer Res 7:2971-6, 2001  
| ECOG Performance Status Scale                                                                                                                                                               | Karnofsky Performance Scale                     |                                                                                                                                              |             |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------|-------------|
| Grade                                                                                                                                                                                       | Descriptions                                    | Percent                                                                                                                                      | Description |
| 100                                                                                                                                                                                         | Normal, no complaints, no evidence of  disease. |                                                                                                                                              |             |
| Normal activity. Fully active,  able to carry on all predisease performance without  restriction.                                                                                                                                                                                             |                                                 |                                                                                                                                              |             |
| 0                                                                                                                                                                                           | 90                                              | Able to carry on normal activity; minor  signs or symptoms of disease.                                                                       |             |
| Symptoms, but ambulatory.  Restricted in physically  strenuous activity, but  ambulatory and able to carry  out work of a light or  sedentary nature (e.g., light  housework, office work). | 80                                              | Normal activity with effort; some signs  or symptoms of disease.                                                                             |             |
| 1                                                                                                                                                                                           | 70                                              | Cares for self, unable to carry on normal  activity or to do active work.                                                                    |             |
| In bed <50% of the time.  Ambulatory and capable of  all self-care, but unable to  carry out any work activities.  Up and about more than 50%  of waking hours.                             | 60                                              | Requires occasional assistance, but is  able to care for most of his/her needs. Requires considerable assistance and  frequent medical care. |             |
| 2                                                                                                                                                                                           | 50                                              |                                                                                                                                              |             |
| In bed >50% of the time.  Capable of only limited selfcare, confined to bed or chair  more than 50% of waking  hours.                                                                                                                                                                                             | 40                                              | Disabled, requires special care and  assistance.                                                                                             |             |
| 3                                                                                                                                                                                           | Severely disabled, hospitalization              |                                                                                                                                              |             |
| 30                                                                                                                                                                                          | indicated. Death not imminent.                  |                                                                                                                                              |             |
| 100% bedridden. Completely  disabled. Cannot carry on  any self-care. Totally  confined to bed or chair.                                                                                    | 20                                              | Very sick, hospitalization indicated.  Death not imminent.                                                                                   |             |
| 4                                                                                                                                                                                           | 10                                              | Moribund, fatal processes progressing  rapidly.                                                                                              |             |
| 5                                                                                                                                                                                           | Dead.                                           | 0                                                                                                                                            | Dead.       |
appendix b potential drug interactions
14.5 patient advocate

| CYP3A4 Inhibitors Acetazolamide Amiodarone Amlodipine Amprenavir Anastrozole Aprepitant Atazanavir Atorvastatin Azelastine Azithromycin Betamethasone Bortezomib Bromocriptine Caffeine Cerivastatin Chloramphenicol Chlorzoxazone Cimetidine Ciprofloxacin Cisapride Clarithromycin Clemastine Clofazimine Clotrimazole Clozapine Cocaine Conivaptan Cyclophosphamide Cyclosporine   | Danazol Dasatinib  Delavirdine Desipramine Dexmedetomidine Diazepam  Diclofenac  Dihydroergotamine Diltiazem Disulfiram Docetaxel Doxorubicin Doxycycline Drospirenone Efavirenz Enoxacin Entacapone Ergotamine Erythromycin Ethinyl estradiol Etoposide Felodipine Fentanyl Fluconazole Fluoxetine Fluvastatin Fluvoxamine Fosamprenavir Glyburide   | Grapefruit juice  Haloperidol Hydralazine Ifosfamide Imatinib Indinavir Irbesartan Isoniazid Isradipine Itraconazole Ketoconazole Lansoprazole Lidocaine  Lomustine Losartan  Lovastatin Mefloquine Mestranol Methadone Methimazole Methoxsalen Methylprednisolone Metronidazole Miconazole Midazolam Mifepristone Mirtazapine Mitoxantrone Modafinil   | Nefazodone Nelfinavir Nevirapine Nicardipine Nifedipine Nisoldipine Nizatidine Norfloxacin Olanzapine Omeprazole Orphenadrine Oxybutynin Paroxetine Pentamidine Pergolide Phencyclidine Pilocarpine Pimozide Pravastatin Prednisolone  Primaquine Progesterone Propofol  Propoxyphene Quinidine Quinine Quinupristin Rabeprazole Ranolazine   | Risperidone Ritonavir Saquinavir Selegiline Sertraline Sildenafil Sirolimus Sulconazole Tacrolimus Tamoxifen Telithromycin Teniposide Testosterone Tetracycline Ticlopidine Tranylcypromine Trazodone Troleandomycin Valproic acid Venlafaxine Verapamil Vinblastine Vincristine Vinorelbine Voriconazole Zafirlukast Ziprasidone   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Because the lists of these agents are constantly changing, frequently-updated lists available at http://medicine.iupui.edu/clinpharm/ddis/table.asp **will be consulted.**  
| CYP3A4 Inducers Aminoglutethimide Carbamazepine Fosphenytoin   | Nafcillin  Nevirapine Oxcarbazepine   | Pentobarbital Phenobarbital  Phenytoin   | Primidone Rifabutin Rifampin   | Rifapentine St. John's wort   |
|----------------------------------------------------------------|---------------------------------------|------------------------------------------|--------------------------------|-------------------------------|  
| CYP3A4 Substrates Albuterol Alfentanil Alprazolam Amlodipine Amprenavir Aprepitant Aripiprazole Atazanavir Atorvastatin Benzphetamine Bisoprolol Bortezomib Bosentan Bromazepam Bromocriptine Buprenorphine Buspirone Busulfan Carbamazapine Cerivastatin Chlordiazepoxide Chloroquine Chlorpheniramine Cisapride Citalopram Clarithromycin Clobazam Clonazepam Clorazepate Cocaine Colchicine Cyclophosphamide Cyclosporine Dantrolene Dapsone Delavirdine Diazepam Digitoxin Dihydroergotamine Diltiazem Disopyramide   | Docetaxel Doxepin Doxorubicin Doxycycline Efavirenz Eletriptan Enalapril Eplerenone Ergoloid mesylates Ergonovine Ergotamine Erythromycin Escitalopram Estradiol Estrogens, conj.,  synthetic Estrogens, conj.,  equine Estrogens, conj.,  esterified Estrone Estropipate Ethinyl estradiol Ethosuximide Etoposide Felbamate Felodipine Fentanyl Flurazepam Flutamide Fosamprenavir Fulvestrant Gefitinib Halofantrine Haloperidol Ifosfamide Imatinib Indinavir Irinotecan Isosorbide dinitrate Isosorbide mononitrate Isradipine Itraconazole Ketamine   | Ketoconazole Lansoprazole Letrozole Levomethadyl acetate  hydrochloride Levonorgestrel Lidocaine Losartan Lovastatin Medroxyprogesterone  Mefloquine Mestranol Methadone Methylergonovine Methysergide Miconazole Midazolam Miglustat Mirtazapine Modafinil Montelukast Moricizine Nateglinide Nefazodone Nelfinavir Nevirapine Nicardipine Nifedipine Nimodipine Nisoldipine Nitrendipine Norethindrone Norgestrel Ondansetron Paclitaxel Pergolide Phencyclidine Pimozide Pioglitazone Primaquine Progesterone   | Quetiapine Quinidine Rabeprazole Repaglinide Rifabutin Rifampin Ritonavir Saquinavir Sertraline Sibutramine Sildenafil Simvastatin Sirolimus Sufentanil Tacrolimus Tamoxifen Tamsulosin Telithromycin Teniposide Terbinafine Tetracycline Theophylline Tiagabine Ticlopidine Tolterodine Toremifene Trazodone Triazolam Trimethoprim Trimipramine Troleandomycin Vardenafil Venlafaxine Verapamil Vinblastine Vincristine Vinorelbine Zolpidem Zonisamide Zopiclone   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
appendix b potential drug interactions
appendix c study diary

Patient Name_____________________(*initials acceptable)* **Patient Study ID** ___________________
INSTRUCTIONS TO THE PATIENT:
1. Complete one form for each cycle of treatment. 2. Cabozantinib should be taken with water at least 1 hour before or 2 hours after a meal. The drug tablets should be swallowed whole with water and may not be crushed or broken.  
3. Do not chew the tablets. If the tablet is broken and the powder of the tablets gets on skin, wash the exposed area with as much water as necessary. Inform investigator or nurse if that occurs.  
3. Record the date and times when you took the tablet/s. 4. If you have any comments or notice any side effects, please record them in the Comments column. 5. Please bring this form and your bottle of cabozantinib when you return for your Day 28 appointment.  
6. In case of errors, please place a single slash mark through the error and initial it. Please do not white out any error or scribble it out with ink. Please do not write the correct information directly over the error, but on a separate line next to the error.  
Today's date _____________________ Agent: Cabozantinib  
| Clinical Center Protocol #13-C-0044 Day Date Cabozantinib tablet strength 20 mg 60mg Time of  Cabozantinib dose   | Blood Pressure   | Comments                    |
|-------------------------------------------------------------------------------------------------------------------|------------------|-----------------------------|
| Morning                                                                                                           | Evening          | Side effects / missed  dose |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18                                                                      | 81               |                             |  
| 19                  |
|---------------------|
| 20                  |
| 21                  |
| 2                   |
| 23                  |
| 24                  |
| 25                  |
| 26                  |
| 27                  |
| 28                  |
| Patient's signature |
appendix b potential drug interactions
appendix d drug interactions

| Oral Antihypertensive Medications: Agents in bold characters are suggested as optimal choices to avoid  or minimize potential drug-interactions with cabozantinib through CYP450. Agent Agent Initial Intermediate  Maximum Hepatic class dose dose dose metabolism Dihydro-pyridine  Calcium-Channel  Blockers (DHP CCB) nifedipine  30 mg daily 60 mg daily 90 mg daily CYP 3A4  XL substrate amlodipine 2.5 mg daily 5 mg daily 10 mg daily CYP 3A4  substrate felodipine 2.5 mg daily 5 mg daily 10 mg daily CYP 3A4  substrate and  inhibitor metoprolol 25 mg twice  50 mg twice  100 mg twice  CYP 2D6  daily daily daily substrate atenolol 25 mg daily 50 mg daily 100 mg daily No acebutolol 100 mg twice  200-300 mg  400 mg Yes (CYP450  daily twice daily twice daily unknown) bisoprolol 2.5 mg daily 5-10 mg daily 20 mg daily Yes (CYP450  unknown) Selective  Blockers (BB) captopril 12.5 mg 3x  25 mg 3x daily 50 mg 3x daily CYP 2D6  daily substrate enalapril 5 mg daily 10-20 mg daily 40 mg daily CYP 3A4  substrate ramipril 2.5 mg daily 5 mg daily 10 mg daily Yes (CYP450  unknown) lisinopril 5 mg daily 10-20 mg daily 40 mg daily No fosinopril 10 mg daily 20 mg daily 40 mg daily Yes (CYP450  unknown) Rarely used: 4 mg daily none 8 mg daily Yes, but not  perindopril CYP450 Rarely used: 10 mg daily 20 mg daily 40 mg daily No quinapril Angiotensin Converting Enzyme Inhibitors (ACEIs) losartan 25 mg daily 50 mg daily 100 mg daily CYP 3A4  substrate candesartan 4 mg daily 8-16 mg daily 32 mg daily CYP 2C9  substrate irbesartan 75 mg daily 150 mg daily 300 mg daily CYP 2C9  substrate telmisartan 40 mg daily none 80 mg daily Yes, but not  CYP450 valsartan 80 mg daily none 160 mg daily Yes, but not  CYP450  and  labetolol 100 mg twice  200 mg twice  400 mg twice  CYP 2D6  Blocker daily daily daily substrate and  inhibitorAngiotensin II  Receptor Blockers (ARBs) 83   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
appendix b potential drug interactions
appendix e ctep multicenter guidelines

If an institution wishes to collaborate with other participating institutions in performing a CTEP
sponsored research protocol, then the following guidelines must be followed.
appendix b potential drug interactions
responsibility of the protocol chair

- The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office
(PIO). The Protocol Chair is responsible for the coordination, development, submission, and approval of the protocol as well as its subsequent amendments. The protocol must not be rewritten or modified by anyone other than the Protocol Chair. There will be only one version of the protocol, and each participating institution will use that document. The Protocol Chair is responsible for assuring that all participating institutions are using the correct version of the protocol.  
- The Protocol Chair is responsible for the overall conduct of the study at all participating institutions and for monitoring its progress. All reporting requirements to CTEP are the responsibility of the Protocol Chair.  
- The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure safety of the patients.  
- The Protocol Chair will be responsible for the review of and timely submission of data for study analysis.
appendix b potential drug interactions
responsibilities of the coordinating center

- Each participating institution will have an appropriate assurance on file with the Office for Human Research Protection (OHRP), NIH. The Coordinating Center is responsible for assuring that each participating institution has an OHRP assurance and must maintain copies of IRB approvals from each participating site.  
- Prior to the activation of the protocol at each participating institution, an OHRP Form 310
(documentation of IRB approval) must be submitted to the CTEP PIO.  
- The Coordinating Center is responsible for central patient registration. The Coordinating Center is responsible for assuring that IRB approval has been obtained at each participating site prior to the first patient registration from that site.  
- The Coordinating Center is responsible for the preparation of all submitted data for review by the Protocol Chair.  
- The Coordinating Center will maintain documentation of AE reports. There are two options for AE reporting: (1) participating institutions may report directly to CTEP with a copy to the Coordinating Center, or (2) participating institutions report to the Coordinating Center who in turn report to CTEP. The Coordinating Center will submit AE reports to the Protocol Chair for timely review.  
- Audits may be accomplished in one of two ways: (1) source documents and research records for selected patients are brought from participating sites to the Coordinating Center for audit, or (2) selected patient records may be audited on-site at participating sites. If the NCI chooses to have an audit at the Coordinating Center, then the Coordinating Center is responsible for having all source documents, research records, all IRB approval documents, NCI Drug Accountability Record forms, patient registration lists, response assessments scans, x-rays, etc. available for the audit.  
Inclusion of Multicenter Guidelines in the Protocol
- The protocol must include the following minimum information: - The title page must include the name and address of each participating institution and the name, telephone number and e-mail address of the responsible investigator at each participating institution.  
- The Coordinating Center must be designated on the title page. - Central registration of patients is required. The procedures for registration must be stated in the protocol.  
- Data collection forms should be of a common format. Sample forms should be submitted with the protocol. The frequency and timing of data submission forms to the Coordinating Center should be stated.  
- Describe how AEs will be reported from the participating institutions, either directly to CTEP or through the Coordinating Center.  
- Describe how Safety Reports and Action Letters from CTEP will be distributed to participating institutions.
appendix b potential drug interactions
agent ordering

Except in very unusual circumstances, each participating institution will order DCTD-supplied investigational agents directly from CTEP (See Section 8). Investigational agents may be ordered by a participating site only after the initial IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO.
appendix b potential drug interactions
appendix f eligibility/pre-registration worksheet

Coordinating Center: NCI Bethesda, MD 20892 PI: A. P. Chen, MD Contact: Ashley Bruns 240-781-3320 Tel: (240) 858-3162 chenali@mail.nih.gov Fax: (301) 451-5625 ashley.bruns@nih.gov  
| Patient's Name: (FML)                                                                                              | Institution:                       |                                    |
|--------------------------------------------------------------------------------------------------------------------|------------------------------------|------------------------------------|
| Medical Record Number:                                                                                             | Investigator:                      |                                    |
| Patient's Birth date:                                                                                              | Signature of Treating  Physician   |                                    |
| Sex: ______male ______female                                                                                       | Date Informed Consent was  signed: |                                    |
| IRB approval valid until (date):  Race:                                                                            | Ethnicity:                         | Projected start date of treatment: |
| _____ Black                                                                                                        | ___Hispanic                        |                                    |
| _____ Caucasian                                                                                                    | ___Non-Hispanic                    |                                    |
| _____ Asian                                                                                                        | ___Other:                          |                                    |
| _____ American Indian  _____ Native Hawaiian/Pacific  Islander  _____  Other_________________  Continued next page |                                    |                                    |  
| Yes                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | No                             | N/A   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------|-------|
| Does the patient have histologically or cytologically confirmed soft  tissue sarcoma that is metastatic or unresectable and for which  standard treatment that prolongs survival does not exist or is no  longer effective? Does the patient have measurable or evaluable disease? Has the diagnosis of malignancy been confirmed by the department  of pathology at the institution where the patient is being enrolled? Has the patient completed any previous anticancer therapy,  including kinase inhibitors or any investigational agent, at least 4  weeks or 5 half-lives (whichever is shorter) (6 weeks for  nitrosoureas or mitomycin C) prior to entering the study and recovered to baseline from adverse events (except alopecia and  other non-clinically significant AEs)? Patients who have received  prior cabozantinib or inhibitors of c-MET or HGF are ineligible. Does the subject have blood pressure (BP) no greater than 140  mmHg (systolic) and 90 mmHg (diastolic)? Age ≥ 18 years? Karnofsky score > 70% (see Appendix A) score______ or ECOG ≤ 1? Life expectancy > 3 months? Has the patient, if a woman of childbearing potential or a man,  agreed to use adequate birth control? Has a signed informed consent/assent been obtained? |                                |       |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Able to swallow whole tablets? |       |
appendix b potential drug interactions
inclusion criteria all responses must

| EXCLUSION CRITERIA: Responses should be NO                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |     |    |     |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----|----|-----|
| Does the patient have any clinically significant illnesses which would  compromise participation in the study, including, but not limited to  known HIV infection requiring combination antiretroviral therapy, symptomatic congestive heart failure, uncontrolled hypertension,  unstable angina pectoris, myocardial infarction within the past 6  months, uncontrolled cardiac arrhythmia, gastrointestinal disorders  associated with a high risk of perforation or fistula formation, or  psychiatric illness/social situations that would limit compliance with  study requirements?                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Yes | No | N/A |
| Does the patient have known brain metastases, carcinomatous  meningitis, or epidural disease? Patients whose brain metastatic  disease status has remained stable for 4 weeks after treatment and do  not require steroid treatment for at least 2 weeks before starting the  study are eligible.  Is the patient taking enzyme-inducing anticonvulsant agents? Does the patients have refractory nausea and vomiting, chronic  gastrointestinal diseases (e.g., inflammatory bowel disease), or  significant bowel resection that could interfere with absorption? Does the subject require concomitant treatment, in therapeutic doses,  with anticoagulants such as warfarin or warfarin-related agents,  heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel)? Low dose aspirin (≤81 mg/day), low-dose warfarin (≤1  mg/day), and prophylactic low molecular weight heparin (LMWH)  are permitted. Has the subject experienced any of the following - clinically-significant gastrointestinal bleeding within 3 months before the first dose of study treatment; the participant must be  maintained on a prophylactic regimen for management of an  upper GI bleeding event with no evidence of recurrence and/or  endoscopic confirmation of resolution of the source of a lower GI  bleed? •hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3  months before the first dose of study treatment? - any other signs indicative of pulmonary hemorrhage within 3  months before the first dose of study treatment? Does the subject have a corrected QT interval calculated by the  Fridericia formula (QTcF) >500 ms? Note: if initial QTcF (within 28 days before enrollment) is found to  be >500 ms, two additional EKGs separated by at least 3 minutes  should be performed. If the average of these three consecutive |     |    |     |  
| results for QTcF is ≤500 ms, the subject meets eligibility in this  regard. Pregnant? Pregnancy Test Date: Radiographic evidence of cavitating pulmonary lesion(s)? Does the subject have tumor invading or encasing any major blood  vessels? Breastfeeding? Receiving any other investigational agents?   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Pre Study Evaluations:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Date Done:   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|
| History and Physical Exam (within 8 days prior to starting drug) Height, weight, vital signs, EKG, and performance status (within 8 days prior to starting study drug) CBC, Diff, Plts; biochemical profile: albumin, alkaline phosphatase,  total bilirubin, BUN, sodium, chloride, bicarbonate, calcium, creatinine,  glucose, phosphorus, magnesium, potassium, total protein, SGOT  [AST], SGPT [ALT], amylase, lipase, TSH: Send actual lab results Urinalysis within 8 days prior to starting study drug Diagnostic imaging studies (within 28 days prior to starting study drug) Pregnancy test within 8 days prior to starting study drug |              |
appendix b potential drug interactions
descriptive factors

| Primary:                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Histology:   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|
| Other Chronic Diseases: Y / N (If yes, please explain):  PRIOR THERAPY (Please specify date, procedure, agent, and dose, response; date of last  treatment is required.) YES NO 1. Surgery/Biopsy: 2. Chemotherapy: 3. Radiotherapy: 4. Hormonal Therapy: 5. Immunotherapy: Physician's Signature: ____________________________ Date: _________________ Printed Name of Physician: ________________________ To be completed by participating center when registering a patient: |              |  
To be completed by participating center when registering a patient: Date Registered with NCI ______/_______/_______ Spoke With: ______________________________________ Study ID: _________________________________________ Eligibility Checklist Completed By: ___________________ Assigned CRA / Data Manager: ______________________ A confirmation of registration will be sent to you by the NCI.  
Participant Status Updates Form Complete form and send via encrypted email to:
NCI Central Registration Office (HOIS) at ncicentralregistration-l@mail.nih.gov and **fax or email to the Coordinating Center Research Nurse**
(Fax: 301-451-5625, ashley.bruns@nih.gov)
Patient Information:
First name Last name Middle initial ID number:________________________________________
Local Protocol Number (P9284):_______________________
Off Study Date (mm/dd/yy): _________________________  
Choose one of the following off-study reasons:  
C: Completed Study L: Lost to follow-up R: Refused Further Treatment T: Toxicity D: Death P: Progressive Disease O: Other  
Death Date: (mm/dd/yy): ______________________________
Choose one or more of the following DOD Sources:
Social Security Death Index SS\#:____________________*http://ssdi.rootsweb.com/*
Obituaries Document:_________________ *http://www.legacy.com/washingtonpost/DeathNotices* Cause of Death__________________________________________________________ Place of Death:__________________________________________________________ Family/staff member name notifying DOD:____________________________________  
Registrar:  
Name:___________________________________________  
Work Phone:________________________ *Today's Date***: ___________________________**  
Comments:
appendix b potential drug interactions
appendix g informed consent template

Study Title: A Phase 2 Study of Cabozantinib (XL184), a Dual Inhibitor of MET and VEGFR,
in Patients With Metastatic Refractory Soft Tissue Sarcoma
appendix b potential drug interactions
introduction

We invite you to take part in a research study. First, we want you to know that:
Taking part in this research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time. In either case, you will not lose any benefits to which you are otherwise entitled. You may receive no benefit from taking part. The research may give us knowledge that may help people in the future.  
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments they would want to receive (such as blood transfusions). If you have such beliefs, please discuss them with your doctors or research team before you agree to the study. Now we will describe this research study. Before you decide to take part, please take as much time as you need to ask any questions and discuss this study with family, friends or your personal physician or other health professional.
appendix b potential drug interactions
why is this study being

We are doing this study to try to develop better treatments for cancer. In this study, the experimental drug **cabozantinib** will be given to you. The purpose of this study is to find out if the drug is effective in a particular type of tumor called soft tissue sarcoma, which is what your doctor has diagnosed you with. We are trying to understand how these drugs work in soft tissue sarcomas. For that, this study will look at how cabozantinib may affect the levels of certain proteins in your tumor.  
The use of cabozantinib in soft tissue sarcoma is experimental. **Cabozantinib** works by two mechanisms. Firstly, it acts by blocking the formation of new blood vessels in tumors, a process called angiogenesis. New blood vessels provide oxygen and nutrients to growing cancers, and blocking this process can cause cancer cells or the supporting blood vessels to stop growing. A drug that works by the same mechanism, pazopanib, has already been approved by the FDA for the treatment of patients with sarcoma. In laboratory studies, some drugs that block angiogenesis increase the production of c-MET in tumors, which helps cancer cells adapt to not having enough oxygen, so the tumor can keep growing. **Cabozantinib** also blocks c-MET in tumors. By both these mechanisms the ability of the sarcoma tumor cells to survive may be markedly reduced by the drug. Although we hope this drug will decrease the size of your tumor, we cannot promise or predict the benefits of the treatment at this time. The drug used in this study has known side effects that will be reviewed with you by your medical team before you sign the consent form. Why are you being asked to take part in this study? You are being asked to take part in this research study because you have advanced cancer that has progressed after receiving standard treatment, or for which no effective therapy exists. Have these drugs been given to other people?  
Cabozantinib has been studied in many different cancer types like prostate cancer. So far, more than 1300 patients have received cabozantinib in clinical trials for different types of cancers. How many people will take part in this study? Up to 55 patients will take part in this study at 4 centers across the United States.
appendix b potential drug interactions
description of research study what

You will need to have the following examinations, tests, or procedures to find out if you can be in the study. These tests are part of your regular cancer care and should be done by your health care team even if you do not join the study. If you have had them recently, they may not need to be repeated. This will be up to your study doctor. If you decide that you would like to participate in this study, you will be asked to sign this consent form. You will then have the examinations, tests, and procedures listed below done to see if you can take part in the study (this is called the screening/baseline evaluation).  
- **Complete medical history.**
- **Physical examination,** including height, weight, blood pressure, pulse, and temperature.  
- **Standard blood tests** (requiring about 1 tablespoon of blood in total), which include measurement of your white blood cells, red blood cells, platelets, blood sugar and electrolytes, how your liver and kidneys work, and how well your blood clots.  
- **Pregnancy test** in women who are able to become pregnant.  
- **Urine tests:** A urine test will be done every 4 weeks to check the level of protein excreted by your kidneys. Depending on the results of blood tests, you may be asked to collect your urine for 24 hours for further testing.  
- **EKG** to check your heart.  
- **CT scans** (a computerized x-ray examination) of your chest, abdomen, and pelvis to measure your tumor(s). Other imaging tests may be done as needed.  
- **Pathology slides:** Before starting on the study, we will request tumor slides or blocks to confirm your diagnosis.
appendix b potential drug interactions
during the study

If you are accepted and choose to take part, you will begin taking the study drug cabozantinib. Cabozantinib is taken by mouth. The study drug will be given in cycles. All cycles are 4 weeks (28 days) long. Cabozantinib is taken 1 hour before or 2 hours after food. Each day that you take study drug, you will be asked to fill in a diary to show when you took the study drugs, how many pills you took, and report any side effects you may have had. For some study procedures we will need you to come to the ________________[name of center] You will also have tests performed because you are in the study to see how the study drug is affecting your body and to find out how your body handles the study drug. This will include imaging studies (for example, CT scans) to find out if your cancer has responded.  
We will ask that you come to the __________________[name of center] for at least 2 days during the first cycle, and then at the beginning of each cycle after that (less often if you have been on study for more than one year). During the first cycle, you may be admitted for the first 2 days of drug administration to make it easier to perform study test and procedures to see how the drugs are affecting your body. If you develop any side effects, you may be asked to visit more often. Please see the study chart for more details. Standard procedures being done because you are in this study; these may be done more often because you are in the study:
- **Clinic visit** to ask how you are feeling and to evaluate you with a physical examination at the beginning of each cycle (up to 8 days before the start of each cycle; less often if you have been on study for more than one year).  
- **Vital signs and physical examination:** will be performed during the clinic visits.  
We will ask that you buy a blood pressure monitor (the cost of may be reimbursed to you; discuss with your study team) and measure your own blood pressure at home at least once a day (preferably twice a day) throughout the study. You will record the readings in a diary. If your systolic blood pressure (top number) is ever more than 150 or your diastolic blood pressure (bottom number) more than 90, you should re-measure your blood pressure 1 to 4 hours later. If your systolic pressure is still greater than 150 or your diastolic blood pressure is still greater than 90, please contact your study team for instructions. You should also call the research team if you experience any symptoms of high blood pressure, such as chest pain, shortness of breath, headache, blood in the urine, or double vision.  
- **Blood tests:** Measurement of your white blood cells, red blood cells and platelets, and measurements of your blood sugar, electrolytes, and how your liver and kidneys work will be done each time you are seen in the outpatient clinic. All of these blood tests combined will require 1-2 tablespoons (20-30 mL) of blood each time.  
- **Urine test** to check urine protein will be done during the first cycle and then before you start each new cycle (less often if you have been on study for more than one year). You may need it more frequently if the study doctor thinks it is needed to check for signs of possible damage to your kidneys. Depending on the results of urine tests, you may be asked to collect your urine for 24 hours for further testing.  
- **CT scans** or other imaging tests such as ultrasound (an examination using sound waves) or MRI (an examination using magnetic field and radio waves) that detect your tumor will be done every 2 cycles (about every 8 weeks; every 12 weeks if you have been on study for more than 1 year or every 16 weeks if on study for more than 3 years) while you are receiving treatment. This is done so that any benefit of the treatment can be determined, and so that if your cancer is not responding to the treatment, the study team can tell you and help you move to a different treatment program (discussed further below).
appendix b potential drug interactions
tests and procedures being done

- Research blood samples **(optional):** We may collect blood samples to help us find out if cabozantinib affects the levels of certain proteins. Blood will be collected before you first  
take the drug and on the first day of cycles 1 and 2 only. Please see the study chart for more details. The total blood for all these tests will be about 2 teaspoons.  
- We will also be collecting optional blood samples to find out the effects of the drug on any tumor cells in your blood. Blood samples will be collected before you first take the drug, on the first day of cycle 1, and on the first day of every cycle for as long as you are on study (every 3 cycles if you have been on study for more than one year or every 4 cycles if more than 3 years). Each blood collection is about 2 teaspoons.
appendix b potential drug interactions
study chart

The treatment is given over periods called cycles. All cycles are 4 weeks long. Treatment cycles will be repeated as long as you are tolerating the drugs and your cancer is either stable or getting better. Each cycle is numbered in consecutive order. The chart below shows what will happen during Cycle 1 and future cycles. The left-hand column shows the day in the cycle, and the right-hand column tells you what will happen on that day. This schedule shows what will happen to you after you sign the consent and start the study.  
Cabozantinib should be taken with water at least 1 hour before or 2 hours after a meal.  
The drug tablets should be swallowed whole with water and may not be crushed or broken.  
| Day                      | What to do and what will happen to you                                                                                                                                                       |                                                        |
|--------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------|
| Before starting          | -                                                                                                                                                                                            | Check in at __________________________[name of center] |
| study drugs              | -                                                                                                                                                                                            | Get routine blood and urine tests                      |
| -                        | Pregnancy test for women who are able to become pregnant                                                                                                                                     |                                                        |
| -                        | Have a history taken of how you feel and undergo a physical  examination including vital signs by a Health Care Provider (can be  completed up to 8 days before the start of the study)      |                                                        |
| -                        | CT or MRI scan will be done                                                                                                                                                                  |                                                        |
| -                        | EKG will be done                                                                                                                                                                             |                                                        |
| -                        | Research blood samples (optional) may be taken                                                                                                                                               |                                                        |
| Cycle 1,                 | -                                                                                                                                                                                            | Admitted to __________________________[name of center] |
| Day 1                    | -                                                                                                                                                                                            | Begin taking cabozantinib 60 mg PO by mouth each day   |
| -                        | Research blood samples will be taken                                                                                                                                                         |                                                        |
| -                        | You will be asked to keep a record of pill consumption and any new  symptoms                                                                                                                 |                                                        |
| -                        | Receive study diary                                                                                                                                                                          |                                                        |
| Cycle 1,                 | -                                                                                                                                                                                            | Continue taking cabozantinib by mouth each day         |
| Day 2-28 Cycles 2 and 3, | -                                                                                                                                                                                            | Check in at __________________________[name of center] |
| Day 1                    | -                                                                                                                                                                                            | Return study diary                                     |
| -                        | Have a history taken of how you feel and undergo a physical  examination including vital signs by a Health Care Provider (can be  completed up to 8 days before the start of each new cycle) |                                                        |
| -                        | Pregnancy test for women who are able to become pregnant                                                                                                                                     |                                                        |
| -                        | Get routine blood and urine tests (up to 8 days before)                                                                                                                                      |                                                        |
| -                        | Get a routine EKG (up to 8 days before)                                                                                                                                                      |                                                        |
| -                        | Research blood samples (optional) may be taken                                                                                                                                               |                                                        |  
| Day                                                                                                                                                                                                       | What to do and what will happen to you                                                                                                                                                                                     |                                                |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------|
| -                                                                                                                                                                                                         | Continue taking cabozantinib by mouth each day                                                                                                                                                                             |                                                |
| Cycles 2 and 3,                                                                                                                                                                                           | -                                                                                                                                                                                                                          | Continue taking cabozantinib by mouth each day |
| Day 2-28 Cycle 4 onwards,  D1                                                                                                                                                                             | -                                                                                                                                                                                                                          | Continue taking cabozantinib by mouth each day |
| -                                                                                                                                                                                                         | Check in at __________________________[name of center]                                                                                                                                                                     |                                                |
| -                                                                                                                                                                                                         | Return study diary                                                                                                                                                                                                         |                                                |
| -                                                                                                                                                                                                         | Research blood samples (optional) may be taken on the first day of  each cycle                                                                                                                                             |                                                |
| -                                                                                                                                                                                                         | Have a history taken of how you feel and undergo a physical  examination including vital signs by a Health Care Provider (can be  completed up to 8 days before the start of each new cycle)                               |                                                |
| -                                                                                                                                                                                                         | Pregnancy test for women who are able to become pregnant                                                                                                                                                                   |                                                |
| -                                                                                                                                                                                                         | Get routine blood and urine tests (up to 8 days before)                                                                                                                                                                    |                                                |
| -                                                                                                                                                                                                         | EKG tests (up to 8 days before)                                                                                                                                                                                            |                                                |
| -                                                                                                                                                                                                         | CT scans to determine how your tumor is responding to the treatment  will be done every 2 cycles (every 8 weeks; every 12 weeks if you  have been on study for more than one year or every 16 weeks if more  than 3 years) |                                                |
| Clinic visits on D1  will be every 3  cycles (every 12  weeks) if you have  been on study for  more than one  year or every 4  cycles (every 16  weeks) if you have  been on study for  more than 3 years |                                                                                                                                                                                                                            |                                                |
appendix b potential drug interactions
risks or discomforts of participation

If you choose to take part in this study, there is a risk that the XL184 (cabozantinib) may not be as good as the usual approach for your cancer or condition at shrinking or stabilizing your cancer.  
You also may have the following discomforts:
- Spend more time in the hospital or doctor's office.  
- Be asked sensitive or private questions about things you normally do not discuss.  
- May not be able to take part in future studies.
The XL184 (cabozantinib) used in this study may affect how different parts of your body work such as your liver, kidneys, heart, and blood. The study doctor will test your blood and will let you know if changes occur that may affect your health. There is also a risk that you could have side effects from the study drug(s)/study approach.  
Here are important things to know about side effects:
- The study doctors do not know who will or will not have side effects. - Some side effects may go away soon, some may last a long time, and some may never go away.  
- Some side effects may make it hard for you to have children. - Some side effects may be mild. Other side effects may be very serious and even result in death.  
You can ask your study doctor questions about side effects at any time. Here are important ways to make side effects less of a problem:
- If you notice or feel anything different, tell your study doctor. He or she can check to see if it is a side effect.  
- Your study doctor will work with you to treat your side effects.  
- Your study doctor may adjust the study drugs to try to reduce side effects.
The tables below show the most common and the most serious side effects doctors know about. Keep in mind that there might be other side effects doctors do not yet know about. If important new side effects are found, the study doctor will discuss these with you. High blood pressure is one common side effect of cabozantinib. Your blood pressure will be closely watched while you are taking this drug. You will also be checking your blood pressure at home at least once a day (preferable twice a day) for the entire study. If you have high blood pressure while taking cabozantinib, your study doctor may recommend follow-up with your primary care physician and/or starting or increasing medication to lower your blood pressure. Some patients on this study have experienced blood clots in the lungs, possibly related to the study drug. Let your doctor know immediately if you experience any shortness of breath or chest pain. In addition, some patients on this study have experienced sepsis, or an infection in the bloodstream, possibly related to the study drug. This condition can cause fever, increased heart rate, increased breathing rate, and confusion. Sepsis can be life-threatening. Grapefruit juice has been shown to affect how the body handles some drugs by blocking the activity of the body's cytochrome P450 (CYP450) system. CYP450 is important in breaking down substances in the body, including cabozantinib. Do not take grapefruit/ grapefruit juice or Seville oranges while participating in this trial. Inform physician and study healthcare team about current medications including over the counter drugs, herbals, or natural medicines. We do not know if taking cabozantinib will cause other drugs you may be taking to work differently. **It is**
very important that you talk to a member of the research team before beginning any new drugs, over-the-counter medications, vitamins, or alternative therapies. Risks and side effects related to cabozantinib may include:  
| COMMON, SOME MAY BE SERIOUS                                                        |                                                                          |
|------------------------------------------------------------------------------------|--------------------------------------------------------------------------|
| In 100 people receiving XL184 (cabozantinib), more than 20 and up to 100 may have: |                                                                          |
| -                                                                                  | Diarrhea, nausea, vomiting                                               |
| -                                                                                  | Tiredness                                                                |
| -                                                                                  | Weight loss, loss of appetite                                            |
| -                                                                                  | Changes in taste                                                         |
| -                                                                                  | Redness, pain or peeling of palms and soles                              |
| -                                                                                  | High blood pressure which may cause headaches, dizziness, blurred vision |
appendix b potential drug interactions
reproductive risks

If you are a woman who is breast feeding or pregnant, you may not take part in the study because we don't know how cabozantinib would affect your baby or your unborn child. If you are a woman who can become pregnant, or are the partner of a woman who can become pregnant, you will need to practice **two** effective forms of birth control before starting study treatment, during study treatment, and for 4 months after you finish study treatment. Your study team will talk with you about the kinds of birth control that can be used in this study. If you think that you or your partner is pregnant, you should tell your study doctor or nurse at once. Effective forms of birth control include:
- abstinence - intrauterine device (IUD)
- hormonal [injections, or implants]: estrogen containing pills are not allowed due to the risk of blood clotting  
- tubal ligation
- vasectomy
appendix b potential drug interactions
side effects of blood draw

Infrequent (occurs in 1 to 10 out of 100 people): persistent pain and discomfort at the injection or needle insertion site as well as possible infection, bleeding, bruising, and soreness.
appendix b potential drug interactions
potential benefits of participation are

Taking part in this study may or may not make your health better. We do not know if you will receive personal, medical benefit from taking part in this study. These potential benefits could include shrinking of your tumor or lessening of your symptoms, such as pain, that are caused by the cancer. You should discuss other treatment options with the study team and your home doctor before deciding to take part in this study. We do know that information from this study will help doctors learn more about these study drugs. This information will also help future cancer patients.
appendix b potential drug interactions
alternative approaches or treatments what

Instead of being in this study, you have these options
- Getting treatment or care for your cancer without being in a study
- Taking part in another study - Getting comfort care, also called palliative care. This type of care helps reduce pain, tiredness, appetite problems, and other problems caused by the cancer. It does not treat the cancer directly. Instead, it tries to improve how you feel. Comfort care tries to keep you as active and comfortable as possible.  
Please talk to your doctor about these and other options.
appendix b potential drug interactions
research subject's rights what are

Taking part in this study is your choice. You may choose either to take part or not to take part in this study. If you decide to take part, you may leave the study at any time. No matter what decision you make, there will be no penalty to you, and you will not lose any of your regular benefits. Leaving the study will not affect your medical care. You can still get your medical care from our institution if you are eligible and choose to participate in another trial. We will tell you about new information or changes in the study that may affect your health or your willingness to continue in the study. In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing this form. You and/or your health plan/insurance company will need to pay for some or all of the costs of treating your cancer in this study. Some health plans will not pay these costs for people taking part in studies. Check with your health plan or insurance company to find out what they will pay for. Taking part in this study may or may not cost your insurance company more than the cost of getting regular cancer treatment. The NCI will supply cabozantinib at no charge while you take part in this study. Even though it is unlikely, there is a possibility that at some point the supply of study agents may run out, necessitating taking you off-study. [If applicable, inform the patient of any tests, procedures, *or agents for which there is no charge.*
The explanation, when applicable, should clearly state that there are charges resulting from performance of the test or drug administration that will be billed to the patient and/or health plan. For example, "The NCI is supplying (drug) at no cost to you. However, you or your health plan may need to pay for costs of the supplies and personnel who give you the (drug)."]
appendix b potential drug interactions
you will not be paid

For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site. Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy.  
Stopping Therapy Your doctor may decide to stop your therapy for the following reasons:
- if he/she believes that it is in your best interest
- if your disease comes back during treatment
- if you have side effects from the treatment that your doctor thinks are too severe
- if new information shows that another treatment would be better for you
- if too many patients in the study experience severe side effects
- if you become pregnant
In this case, you will be informed of the reason therapy is being stopped. You can stop taking part in the study at any time. However, if you decide to stop taking part in the study, we would like you to talk to the study doctor and your regular doctor first. If you decide at any time to withdraw your consent to participate in the trial, we will not collect any additional medical information about you. However, according to FDA guidelines, information collected on you up to that point may still be provided to the Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute (NCI) or designated representatives. If you withdraw your consent and leave the trial, any samples of yours that have been obtained for the study and stored at the NCI can be destroyed upon request. However, any samples and data generated from the samples that have already been distributed to other researchers or placed in the research databases cannot be recalled and destroyed. You will be followed for 30 days after taking the last dose of study drug. We will call you after about 30 days to ask about any side effects that were ongoing when you stopped therapy, or any new side effects that might be related to the study therapy. If you have side effects that might be related to the study drugs that have not gotten better after 30 days, we will call you every 2 weeks until the side effects have become stable or gotten better. The follow-up period will end if you enroll on another protocol or start receiving standard therapy.