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management of treatment emergent proteinuria

| Urine Protein/Creatinine Ratio             | Action To Be Taken                                                                                                                                                                                                                                                                                                                                                            |                                                                                  |
|--------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------|
| ≥ 3.5                                      | x                                                                                                                                                                                                                                                                                                                                                                             | Hold cabozantinib immediately and confirm with 24 hour urine  protein excretion. |
| x                                          | Evaluate for nephrotic syndrome. If present, discontinue  cabozantinib treatment permanently, and monitor subject for  resolution of nephrotic syndrome.                                                                                                                                                                                                                      |                                                                                  |
| x                                          | If proteinuria of ≥ 3.5 g/24 hours is confirmed without diagnosis  of nephrotic syndrome, continue to hold cabozantinib and  monitor UPCR weekly. If UPCR decreases to < 2.5, restart  cabozantinib at a reduced dose. Continue monitoring UPCR  once every week until two consecutive readings are < 2, then  revert to UPCR monitoring frequency specified in the protocol. |                                                                                  |
| UPCR, urine protein/urine creatinine ratio |                                                                                                                                                                                                                                                                                                                                                                               |                                                                                  |
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6.1.10 guidelines for the prevention

Hemorrhagic events have been reported with approved drugs that inhibit VEGF pathways as well as with cabozantinib. As preventive measures, subjects should be evaluated for potential bleeding risk factors prior to initiating cabozantinib treatment and monitored for bleeding events with serial complete blood counts and physical examination while on study. Risk factors for hemorrhagic events may include (but may not be limited to) the following:
x Tumor lesions with cavitations or tumor lesions which invade, encase, or abut major blood vessels. The anatomic location and characteristics of primary tumors or metastases as well as the medical history should be carefully reviewed in the selection of subjects for treatment with cabozantinib.  
x Recent or concurrent radiation to the thoracic cavity. x Active peptic ulcer disease, ulcerative colitis, and other inflammatory GI diseases.  
x Underlying medical conditions which affect normal hemostasis (e.g., deficiencies in clotting factors and/or platelet function, or thrombocytopenia).  
x Concomitant medication with anticoagulants or other drugs which affect normal hemostasis.  
x History of clinically significant hemoptysis.  
Cabozantinib should be discontinued in subjects with serious and life-threatening bleeding events or recent hemoptysis (≥0.5 teaspoon (2.5mL) of red blood). Treatment with cabozantinib should be interrupted if less severe forms of clinically significant hemorrhage occur and may be restarted after the cause of hemorrhage has been identified and the risk of bleeding has subsided at a dose agreed to by the sponsor and the investigator. Therapy of bleeding events should include supportive care and standard medical interventions. Furthermore, subjects who develop tumors invading a major blood vessel while on study treatment must be discontinued from cabozantinib treatment.
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6.1.11 rectal and perirectal abscess

Rectal and perirectal abscesses have been reported, sometimes in subjects with concurrent diarrhea. These should be treated with appropriate local care and antibiotic therapy. Cabozantinib should be held until adequate healing has taken place.
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6.1.12 guidelines for prevention of

GI perforation/fistula and Non-GI fistula formation have been reported with approved drugs that inhibit VEGF pathways as well as with cabozantinib. Carefully monitor for episodes of abdominal pain, especially in subjects with known risk factors for developing GI perforation/fistula or nonGI fistula, to allow for early diagnosis. Such risk factors include (but may not be limited to) the following: 6.1.12.1 GI-perforation/fistula:  
x Intra-abdominal tumor/metastases invading GI mucosa. x Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis or symptomatic cholangitis, or appendicitis .  
x History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess x Prior GI surgery (particularly when associated with delayed or incomplete healing).  
Complete healing following abdominal surgery or resolution of intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib.  
Additional risk factors include concurrent chronic use of steroid treatment or non-steroidal anti-inflammatory drugs. Constipation indicative of bowel obstruction should be monitored and effectively managed.
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6.1.12.2 non-gi fistula

x Radiation therapy has been identified as a possible predisposing risk factor for non-GI
fistula formation in subjects undergoing treatment with drugs that inhibit VEGF pathways. In addition, subjects who have undergone extensive surgery may be at increased risk of developing a fistula of the involved organs Non-GI fistula should be ruled out as appropriate in cases of onset of mucositis after start of therapy.  
Discontinue all study treatment in subjects who have been diagnosed with GI or non-GI perforation/fistula.
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6.1.13 wound healing and surgery

VEGF inhibitors can cause wound healing complications and wound dehiscence which may occur even long after a wound has been considered healed. Therefore, surgical and traumatic wounds must have completely healed prior to starting cabozantinib treatment and be monitored for wound dehiscence or wound infection while the subject is being treated with cabozantinib. Treatment with cabozantinib must be interrupted for any wound healing complication which needs medical intervention. Treatment with cabozantinib can be resumed once wound healing has occurred unless otherwise prohibited in specific protocols. Cabozantinib should be discontinued in subjects with serious or chronic wound healing complications. The appropriate dose hold interval prior to elective surgery to reduce the risk for wound healing complications has not been determined. In general, cabozantinib should be stopped at least 3 weeks (5 half lives) prior to elective surgery.
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6.1.14 endocrine disorders

Prospective studies of markers of thyroid functions are currently ongoing in two single-agent studies to characterize the effects of cabozantinib on thyroid function. Preliminary data indicate that cabozantinib affects thyroid function tests (TFTs) in a high number of subjects (see Cabozantinib Investigator's Brochure). Routine monitoring of thyroid function and assessments for signs and symptoms associated with thyroid dysfunction is recommended for subjects treated with cabozantinib. Management of thyroid dysfunction (*e.g.*, symptomatic hypothyroidism) should follow accepted clinical practice guidelines. Other endocrine disorders such as hypocalcemia and hyperglycemia, and associated laboratory changes, have been observed in less than 10% of subjects. Monitoring with standard laboratory tests for endocrine disorders and clinical examination prior to initiation and during treatment with cabozantinib is required. Cabozantinib should be discontinued in subjects with severe or lifethreatening endocrine dysfunction.
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6.1.15 guidelines for prevention of

Osteonecrosis of the jaw (ONJ) has been reported with use of antiangiogenic drugs and bisphosphonates and denosumab in cancer patients. Additional risk factors for ONJ have been identified such as use of corticosteroids, chemotherapy, local radiotherapy, poor oral hygiene, smoking, dental or orofacial surgery procedures, and cancer disease itself. Cases of osteonecrosis have been reported in subjects treated with cabozantinib, the details of which are provided in the current version of Investigator's Brochure. As a preventive measure, invasive dental procedures should be avoided if possible in subjects who have previously been treated with or concomitantly receive bisphosphonates or denosumab. In cases where dental procedures are unavoidable, the risks and benefits of a dental procedure and the extent of the procedure as well as the risk of developing osteonecrosis of the jaw need to be considered when deciding on the duration of a temporary treatment interruption of cabozantinib. If clinically possible, treatment with cabozantinib should be held for at least 2 weeks prior to a dental procedure and resumed after complete wound healing occurred. Subjects with any documented case of osteonecrosis should have study treatment interrupted, and appropriate clinical management should be initiated. Reinitiation of study treatment must be discussed with and approved by the Sponsor on a case by case basis.
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6.1.16 guidelines for management of

Treatment with cabozantinib has been associated with a mild prolongation of the QTc interval. Other factors which may contribute to QTc prolongation include  
x Treatment with other drugs associated with QTc prolongation (see http://www.qtdrugs.org)
x Treatment with CyP 3A4 inhibitors (which may increase cabozantinib drug levels)
x Electrolyte changes (hypokalemia, hypocalcemia, hypomagnesemia).
x Medical conditions which can alter electrolyte status e.g., severe or prolonged diarrhea.  
Subjects having any of these additional risk factors while on cabozantinib must have ECGs performed approximately one week after the onset of these factors.  
If at any time on study there is an increase in QTc interval to an absolute value >500 msec, two additional ECGs should be performed within 30 minutes after the initial ECG with intervals not less than 3 minutes apart. If the average QTcF from the three ECGs is >500 msec, study treatment must be withheld and the following actions should be taken:  
x Check electrolytes, especially potassium, magnesium and calcium. Correct abnormalities as clinically indicated.  
x If possible, discontinue any QTc-prolonging concomitant medications.  
x Repeat ECG triplets hourly until the average QTcF is ≤500 msec or otherwise determined by consultation with a cardiologist.  
The Sponsor should be notified immediately of any QTc prolongation event.
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc elevation has resolved. Cardiology consultation is recommended for evaluation and subject management. Symptomatic subjects must be treated according to standard clinical practice. No additional study treatment is to be given to the subject until after the event has resolved, the subject has been thoroughly evaluated, and further treatment has been agreed to by the Sponsor. If any additional study treatment is given (*e.g.*, after correction of electrolyte abnormalities and normalization of QTcF), it will be at a reduced dose as agreed to by the investigator and the Sponsor.
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6.2 cabozantinib drug holiday

Patients who achieve a complete response by RECIST lasting > 3 years, can have study therapy held (drug holiday) until they relapse. Scan intervals for patients achieving a complete response for > 3years will be changed from every 8 weeks to every 12 weeks. At the time of progressive disease, cabozantinib will be resumed and scan showing progressive disease will become the new baseline scan.
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7 adverse events list and

Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of AEs (Section 7.1) and the characteristics of an observed AE (Section **7.2.1.1**) will determine whether the event requires expedited reporting (via CTEP-AERS) **in addition** to routine reporting.
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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 53  
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 s-malate).  
NOTE: Report AEs on the SPEER **ONLY IF** they exceed the grade noted in parentheses next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.  
| Version 2.4, 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  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                                                                                                                              | 54                                                           |                        |  
| 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%) |
| 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 cerebrovascular  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                                                                                                                                                                                                                                                                                                                             |                                                                                                                                           |                        |
| 1 This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal  Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  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
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ear and labyrinth disorders -

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.
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7.2 definitions 7.2.1 adverse event

Any untoward medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject's participation in research, whether or not considered related to the subject's participation in the research.
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7.2.1.1 adverse event characteristics

x **CTCAE term (AE description) and grade:** The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. 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.  
x 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.  
x **Attribution** of the AE:
- Definite - The AE *is clearly related* to the study treatment. - Probable - The AE *is likely related* to the study treatment. - Possible - The AE *may be related* to the study treatment. - Unlikely - The AE *is doubtfully related* to the study treatment. - Unrelated - The AE *is clearly NOT related* to the study treatment.
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7.2.2 suspected adverse reaction

Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 'reasonable possibility' means there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.
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7.2.3 unexpected adverse reaction

An adverse event or suspected adverse reaction is considered "unexpected" if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application. "Unexpected", also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation.
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7.2.4 serious

An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious Adverse Event or if it compromises the safety, welfare or rights of subjects or others.
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7.2.5 serious adverse event

An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
x Death, x A life-threatening adverse drug experience x Inpatient hospitalization or prolongation of existing hospitalization  
x Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions x A congenital anomaly/birth defect.
x Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate 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.
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7.2.6 disability

A substantial disruption of a person's ability to conduct normal life functions.
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7.2.7 life-threatening adverse drug experience

Any adverse event or suspected adverse reaction that places the patient or subject, in the view of the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, might have caused death.
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7.2.9 non-compliance (nih definition)

The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, IRB requirements, or regulatory requirements for the protection of human research subjects.
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7.2.10 unanticipated problem

Any incident, experience, or outcome that:
x Is unexpected in terms of nature, severity, or frequency in relation to
(a) the research risks that are described in the IRB-approved research protocol and informed consent document; Investigator's Brochure or other study documents, and (b) the characteristics of the subject population being studied; AND
x Is related or possibly related to participation in the research; AND  
x Suggests that the research places subjects or others at a g*reater risk of harm* (including physical, psychological, economic, or social harm) than was previously known or recognized.
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7.3 expedited adverse event reporting

Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting System), accessed via the CTEP Web site (http://ctep.cancer.gov). The reporting procedures to be followed are presented in the "NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs" which can be downloaded from the CTEP Web site (http://ctep.cancer.gov). These requirements are briefly outlined in the tables below (Section **7.3.3**).
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7.3.2 in the event of

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.
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7.3.3 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 "Neoplasms benign, malignant** and unspecified (including cysts and polyps) - **Other (Progressive Disease)"** under the system organ class (SOC) of the same name. 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.  
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention1, 2 FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
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 CTEPAERS within the timeframes detailed in the table below.  
| Hospitalization               | Grade            | 1                | Timeframes   | Grade 3 Timeframes   | Grade 4 & 5   |
|-------------------------------|------------------|------------------|--------------|----------------------|---------------|
| Grade                         | 2                |                  |              |                      |               |
| Timeframes                    | Timeframes       |                  |              |                      |               |
| Resulting in  Hospitalization | 10 Calendar Days |                  |              |                      |               |
| ≥ 24 hrs                      | 24-Hour 5        |                  |              |                      |               |
| Not resulting in              | Calendar Days    |                  |              |                      |               |
| Hospitalization               | Not required     | 10 Calendar Days |              |                      |               |
| ≥ 24 hrs                      |                  |                  |              |                      |               |  
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR
Expedited AE reporting timelines are defined as:
o "24-Hour; 5 Calendar Days" - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report.  
o "10 Calendar Days" - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE.  
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:
Expedited 24-hour notification followed by complete report within 5 calendar days for:
x All Grade 4, and Grade 5 AEs Expedited 10 calendar day reports for:
x Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization x Grade 3 adverse events 2For 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
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7.4 routine adverse event reporting

All Adverse Events **must** be reported in routine study data submissions. **AEs reported through** CTEP-AERS must also be reported in routine study data submissions.
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7.5 nih intramural irb and

x All deaths, except deaths due to progressive disease x All Protocol Deviations x All Unanticipated Problems x All non-compliance Reports must be received within 7 days of PI awareness via iRIS.
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7.5.2 nih intramural irb requirements

The protocol PI will report to the NIH Intramural IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation occurred, a brief description of the deviation and any corrective action.  
2. A summary of any instances of non-compliance 3. A tabular summary of the following adverse events:
x All Grade 2 **unexpected** events that are possibly, probably or definitely related to the research; x All Grade 3 and 4 events that are possibly, probably or definitely related to the research; x All Grade 5 events regardless of attribution; x All Serious Events regardless of attribution.
NOTE: Grade 1 events are not required to be reported.
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7.5.3 nih intramural irb reporting

Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported to the NIH Intramural IRB.
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7.6 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:
x Leukemia secondary to oncology chemotherapy (*e.g.*, acute myelocytic leukemia [AML])
x Myelodysplastic syndrome (MDS)
x Treatment-related secondary malignancy Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via the routine reporting mechanisms outlined in each protocol.
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7.7 second malignancy

A second malignancy is one unrelated to the treatment of a prior malignancy (and is **NOT** a metastasis from the initial malignancy). Second malignancies require **ONLY** routine reporting via CDUS unless otherwise specified.
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7.8 data and safety monitoring

The clinical research team will meet on a regular basis when patients are being actively treated on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if applicable will be made based on the toxicity data from prior patients. All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Adverse events will be reported as required above. Any safety concerns, new information that might affect either the ethical and or scientific conduct of the trial, or protocol deviations will be immediately reported to the IRB using iRIS. The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.
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8 pharmaceutical and imaging agent

Chemical Name: N-[4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl]-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate Other Names: Cabozantinib, EXEL-7184, EXEL-02977184 Classification: Receptor Tyrosine Kinases Inhibitor (RTK) CAS Registry Number: 1140909-48-3 Molecular Formula: C28H24FN3O5.C4H6O5 **M.W.:** 635.6 Mode of Action: XL184 inhibits multiple RTKs implicated in tumor growth (progression of tumors in bone), metastasis, and angiogenesis, and targets primarily MET and VEGFR2. Other targets are RET, AXL, KIT, TIE-2, and FLT-3. How Supplied: XL184 is supplied by Exelixis and distributed by the DCTD. XL184 is available in 20 mg and 60 mg tablet. 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 as 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    |  
Storage: Store intact bottles at controlled room temperature, 200 to 250C.  
Stability: XL184 should be dispensed in its original container. XL184 tablets are stable for up to 24 hours when dispensed in an open container, such as in a pill cup, and are stable for up to 7 days when dispensed in a closed container, such as a pharmacy dispensing bottle.
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route of administration oral.

Method of Administration: Take cabozantinib on an empty stomach, (fasting is required 2 hours before and 1 hour after each cabozantinib dose). Do not crush or chew. Potential Drug Interactions: XL184 is a substrate of CYP3A4. Coadministration of XL184 with medications that are strong inhibitors/inducers of CYP3A4 should be avoided. Examples of strong CYP3A4 inducers are rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifampentin, Phenobarbital, and St. John's Wort. Strong CYP3A4 inhibitors are ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir. Use alternative medications. Avoid grapefruit/ grapefruit juice and Seville oranges while participating in this trial. In vitro data, XL184 is not a P-gp substrate but may inhibit the P-gp transport activity. XL184 is highly protein bound, 99.9%. Use caution when coadminister XL184 with medications that are highly protein-bound (e.g., diazepam, furosemide, dicloxacillin, and propranolol). Avoid administration of warfarin with XL184 as warfarin is highly protein-bound and has a very narrow therapeutic index.  
Avoid concomitant use of XL184 with proton pump inhibitors (PPIs) and H2 -antagonists if possible. The PPIs and H2 –antagonists decrease XL184 plasma exposure levels and its effectiveness in vivo. Examples of PPIs are omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole; examples of H2 –antagonists are ranitidine, famotidine, and nizatidine. Cimetidine is a moderate CYP3A4 inhibitor. Avoid using cimetidine with XL184. If antacids, H2 blockers, or PPIs are needed, take them at least 2 hours (preferably 4 hours) after taking cabozantinib but at least 14 hours before the next dose of cabozantinib if possible. Patient Care Implications: 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. Cimetidine or omeprazole is also available over-the-counter (OTC). Do not use cimetidine. If need an antacid, take it at least 2 hours (preferably 4 hours) after taking XL184 but at least 14 hours before the next dose of XL184 if possible.
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availability

XL184 (cabozantinib) is an investigational agent supplied to investigators by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. XL184 (cabozantinib) is provided to the NCI under a Collaborative Agreement between the Pharmaceutical Collaborator and the DCTD, NCI (see Section **12.5**).
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8.1.1 agent ordering and agent

8.1.1.1 NCI-supplied agents may be requested by the Principal Investigator (or their authorized designee) at each participating institution. Pharmaceutical Management Branch (PMB) policy requires that agent be shipped directly to the institution where the patient is to be treated. PMB does not permit the transfer of agents between institutions (unless prior approval from PMB is obtained). The CTEP-assigned protocol number must be used for ordering all CTEP-supplied investigational agents. The responsible investigator at each participating institution must be registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP-supplied investigational agents for the study should be ordered under the name of one lead investigator at that institution.  
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://eappsctep.nci.nih.gov/OAOP/pages/login.jspx). Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account (https://eappsctep.nci.nih.gov/iam/) and the maintenance of an "active" account status and a "current" password. For questions about drug orders, transfers, returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime.  
8.1.1.2 Agent Inventory Records - The investigator, or a responsible party designated by the investigator, must maintain a careful record of the inventory and disposition of all agents received from DCTD using the NCI Drug Accountability Record Form (DARF). (See the NCI Investigator's Handbook for Procedures for Drug Accountability and Storage.)
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9 biomarker correlative and special

(Please see **Appendix F** for the blood and tissue collection schedule in chart form)
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9.1 biomarker studies

All collection pre-treatment collection times are within 5 days prior to treatment; all other collection times and within ± 5 days of stated collection. The blood biomarker studies will be prioritized as follows: Plasma HGF and MET, VEGF levels, immune subset, genetic biomarker, IL-8 circulating cytokine levels, c-Met analysis by real-time RT-PCR and CTC/CEC.
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9.1.1 circulating endothelial cells (cec)

CEC, CEP and CTC will be analyzed by multiparameter flow cytometry. Mononuclear cells will be isolated and run fresh or viably frozen. Immune subsets, including MDSC and Tregs, may be analyzed if sample permits. 9.1.1.1 Collection & Handling of Specimens: Collect 2 times: at C1D1 pre-treatment and C3D1 pre-treatment Draw whole blood into three 8 mL BD Vacutainer Cell Preparation Tube (CPT) with Sodium Citrate and two 10 mL EDTA lavender top tubes.  
x Immediately after collection, mix the blood sample by gentle inversion several times.  
x The date and exact time of each blood draw should be recorded on the tube.  
x Please email Jane.Trepel@nih.hhs.gov, lees@pop.nci.gov and leemin@mail.nih.gov about expected samples and call Jane Trepel's lab at 240760-6330 to arrange for immediate pick-up.
9.1.1.2 Site Performing the Assay The assays will be performed by Dr. Min-Jung Lee and Dr. Yeong Sang Kim in Jane Trepel's laboratory in the Medical Oncology Branch, Building 10, Room 12N218.
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9.1.2 c-met analysis by real-time

x Peripheral blood for analysis of c-Met mRNA will be collected in a PAXgene tube on C1D1 pre-treatment and C3D1 pre-treatment x (PreAnalytix; 2.5 cc peripheral blood per tube) per the manufacturer's instructions.  
x After the blood is drawn, the tube should be inverted several times, placed at 4°C. RNA
will be isolated using the PAXgene Blood RNA Kit according to the manufacturer's instructions. The first strand cDNA will be synthesized from total RNA by using a HC reverse transcription kit (Applied Biosystems). The reaction mixture is diluted to 100 μL with TE. PCR will be performed using the c-met primers).  
x Please email Jane.Trepel@nih.hhs.gov, lees@pop.nci.gov and leemin@mail.nih.gov 24 hours prior to anticipated collection and call Jane Trepel's lab at 240-760-6330 to arrange for immediate pickup when drawn.
9.1.2.2 Site Performing the Assay cMet mRNA levels in peripheral blood will be analyzed by the Trepel Lab, Medical Oncology Branch, Building 10, Room 12N218.
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9.1.3 il-8 circulating cytokine levels

We will be collecting blood samples to determine whether IL-8 levels are associated with cabozantinib treatment outcome measures. 9.1.3.1 Collection & Handling of Specimens:  
x Peripheral blood will be drawn in a 5 mL red top tube pretreatment on C1D1, cycle 1 day 15 and at cycle 2 day 1.  
x The date and exact time of each blood draw should be recorded on the tube. x Please email Jane.Trepel@nih.hhs.gov, lees@pop.nci.gov and leemin@mail.nih.gov 24 hours prior to anticipated collection and call Jane Trepel's lab at 240-760-6330 to arrange for immediate pickup when drawn.
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9.1.3.2 site performing the assay

Il-8 levels in peripheral blood will be analyzed using the ELISA technique by the Trepel Lab, Medical Oncology Branch, Building 10, Room 12N218
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9.1.4 genetic biomarkers

We will determine if *VEGFR2* genetic variants may be correlated to toxicity and clinical outcomes as we have previously shown in patients treated with bevacizumab and sorafenib62.  
9.1.4.1 Collection and Handling of Specimens  
x One 10 mL EDTA lavender top tube will be collected on day 1 of cycle 2.  
x Immediately after collection, invert the blood tube 8-10 times.  
x Place the tube on wet ice and then store at 4rC in the refrigerator until processing.  
x The date and exact time of each blood draw should be recorded on the tube. x Please email NCIBloodcore@mail.nih.gov 24 hours prior to anticipated collection and page 102-11964 for immediate pickup.
9.1.4.2 Site Performing the Assay These studies will be done by the Molecular Pharmacology Program, under the direction of Dr. Figg.
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9.1.5 angiogenesis markers

Plasma levels of several angiogenic biomarkers, including VEGF-A, soluble VEGFR2 (sVEGFR2), and placental growth factor (PIGF), have been shown to be significantly altered after single agent cabozantinib treatment (Investigator's brochure). The analysis will be done with assays developed on electrochemiluminescence platform that provides ultra-high sensitivity and very large signal dynamic range. 9.1.5.1 Collection and Handling of Specimens
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serum vegf

x Collect on cycle 1 day 1 pretreatment, cycle 1 day 15 pretreatment, cycle 2 day 1 and at the time of progression.  
x Venous blood samples will be collected in one 6mL EDTA tube per protocol time points.  
x Immediately after collection, invert the EDTA tube 2-4 times and place the tube on wet ice and store at 4qC in the refrigerator until processing for a maximum of 30-60 minutes.  
x The date and exact time of each blood draw should be recorded on the tube. x Please email NCIBloodcore@mail.nih.gov 24 hours prior to anticipated collection and page 102-11964 for immediate pick-up.  
9.1.5.2 Sample Processing Upon arrival in the Blood Processing Core (BPC), blood samples will be centrifuged for 5 minutes at 1200 x g, at 4qC. The serum will be transferred into two cryovials and immediately frozen. Serum samples will be stored at -80qC until the time of analysis.  
9.1.5.3 Site Performing the Assay These studies will be done by the Molecular Pharmacology Program, under the direction of Dr. Figg.
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9.1.6 plasma and tissue hgf

To determine whether urinary hepatocyte growth factor (HGF), urinary soluble MET receptor (sMet), plasma HGF and plasma Met levels are biomarkers of bladder cancer (transitional cell carcinoma; TCC) and/or response to systemic treatment with the experimental Met/VEGFR inhibitor cabozantinib. In *fresh frozen tissue* (FFT), HGF, and the cabozantinib targets MET, phosphoMET, VEGFR2, RET, KIT, AXL and FLT3 will be quantitatively analyzed using two-site electrochemiluminescent immunoassays developed for use with a Meso Scale Discovery (MSD) SectorImager 2400 plate reader at baseline from patients on study with cabozantinib. Use of purified recombinant protein standards permits quantitation of receptor mass per mass total extracted cell protein. 9.1.6.1 Sample Collection Protocols
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a. urine samples

1. Collect at least 2 mL of urine prior to treatment at every visit while on study The source of the urine will need to be documented i.e. normally voided urine, without internal stent, Foley, percutaneous nephrostomy, ileal conduit, Indian pouch or neobladder.  
2. Determine urine creatinine values per standard clinical laboratory testing protocol. 3. The date and exact time of the urine collection should be recorded on the tube. 4. Please email NCIBloodcore@mail.nih.gov 24 hours prior to anticipated collection and page 102-11964 for immediate pick-up.  
5. sMet analysis requires 1-2 ml per sample. Adjust urine to pH 7.5 with TrizmaHCl (Sigma, St. Louis, MO), 2 mol/L, pH 7.5 using 50 microliters per 2 ml urine volume.  
6. Centrifuge urine samples at 3000 x g for 10 min at room temperature to remove cells and debris; store samples in appropriately sized plastic cryovials (Nunc or Sargent; bar coded vials are preferred for optimal sample identification) at -80°C.
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b. plasma samples

1. Blood samples should be collected in a 3 mL EDTA tube at every visit while on study.  
2. The date and exact time of the urine collection should be recorded on the tube. 3. Blood samples should be centrifuged within 30 min at 1,300 RCF at room temperature for 10 minutes. Do not use braking to stop the centrifuge. This will give three layers: (from top to bottom) plasma, leucocytes (buffy coat), erythrocytes.  
4. Carefully aspirate the supernatant (plasma) at room temperature and transfer to a new centrifuge tube. Take care not to disrupt the cell layer or transfer any cells.  
5. Inspect the plasma for turbidity. Turbid samples should be centrifuged and the clarified supernatant should be transferred to cryovials and stored at –80°C. Ensure that the cryovials are properly labeled.  
6. Please email NCIBloodcore@mail.nih.gov 24 hours prior to anticipated collection and page 102-11964 for immediate pickup.
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c. fresh tissue samples

1. A post treatment biopsy (as referenced in section **9.1.8.1.2**) will be performed on a voluntary basis, and cabozantinib target levels will be compared to baseline measurements on fresh tissue (see collection in section **9.1.7**). MET and HGF expression by IHC will be compared to MET, phosphoMET, and HGF expression by quantitative two-site electrochemiluminescent immunoassay. Results will be correlated with baseline prognostic factors such as tumor grade, stage, size, sites of metastatic disease, response to prior cisplatin therapy, response to cabozantinib, progression free survival and overall survival.  
2. Please contact Dr. Bottaro to notify of biopsy date and time (301-402-6499) and to arrange for pick up of sample during biopsy.  
3. Fresh tissue samples should be collected in empty cryovials on dry ice. The minimum tissue volume required for HGF or Met analysis is 50 ul (approx 50 ug); analysis for phospho-Met requires 100 ul.  
4. The interval between sample acquisition and freezing on dry ice must not exceed 2 minutes. Frozen, vialed samples should be transferred to -80°C storage within 2 hours. Stored vials must be bar coded ONLY for sample identification.
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9.1.6.2 hgf and met electrochemiluminescent

1. Block with I Block solution (1X) 300 ul/well for 1 h at RT. Use 300 ul multichannel pipette and disposable trough.  
2. Wash 3 times with 150ul/well Ca2+/Mg2+ free PBS.  
3. Add capture antibody at 5 ug/ml, 25 ul/well and shake for 1 h. 4. Put out 20 previously frozen samples to thaw on ice at this time.  
5. Wash 3 times with 150ul/well Ca2+/Mg2+ free PBS.  
6. Add samples and standards at 25 ul/well for 1 h with shaking. Adding the standards first; when the standards are done, mix the thawed samples well before adding to wells. If volume is insufficient to fill triplicate wells at 25 ul/well, note any lesser amount added.  
7. Wash 3 times with 150ul/well Ca2+/Mg2+ free PBS.  
8. Add detection antibody at 1ug/ml, 25 ul/well for 1 h with shaking.  
9. Wash 4 times with 150ul/well Ca2+/Mg2+ free PBS.
10. Set up the MSD Sector 2400's computer for reading the plates.  
11. Add MSD Read Buffer T with Surfactant (1X) 150ul/well, read plate immediately in MSD Sector 2400.
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b. detection of human hgf

1. To a standard MSD streptavidin-coated 96-well plate, add biotinylated capture antibody diluted in 0.5% BSA in Ca2+/Mg2+ free PBS at 5 mcg/ml final, 25 mcL/well for 1 hour at RT with shaking.  
2. Wash three times with 150 mcL/well Ca2+/Mg2+ free PBS. 3. Block with 5% BSA in Ca2+/Mg2+ free PBS, 300 mcL/well for 1 hour at RT.  
4. Wash three times with 150 mcL/well Ca2+/Mg2+ free PBS.  
5. Add samples and standards: 100 ul/well for 1 hour at RT with shaking.  
6. Wash three times with 150 mcL/well Ca2+/Mg2+ free PBS.  
7. Add detection antibody diluted in 0.5% BSA in Ca2+/Mg2+ free PBS) 1 ug/ml final, 25 ul/well for 1 hour at RT with shaking.  
8. Wash four times with 150 mcL/well Ca2+/Mg2+ free PBS.  
9. Add MSD Read Buffer T with Surfactant, 150 mcL/well, read plate in MSD Sector 2400.
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c. reagents

sMet DETECTION
1. MSD streptavidin-coated 96-well plate catalog no. L15SA-1.  
2. Capture antibody: R&D BAF358 biotinylated anti-Met antibody diluted in Ca2+/Mg2+ free PBS + 0.5% BSA.  
3. Standards: R&D 358-MT purified recombinant human Met ectodomain-Ig fusion protein diluted in Ca2+/Mg2+ free PBS + 0.5% BSA.  
4. Detection antibody: R&D AF276 anti-Met antibody labeled w/ MSD Sulfotag.  
Sulfo-tagging is performed per the manufacturer's protocol.  
5. MSD Read Buffer T with Surfactant: prepare 20 ml of Read Buffer for 1 plate, using 5 ml of 4X Read Buffer and 15 ml of ultra pure water.
HGF DETECTION
1. MSD streptavidin-coated 96-well plate catalog no. L15SA-1.  
2. Capture antibody: R&D Systems MAB694, biotinylated using Pierce EZ-Link Maleimide-PEO Solid Phase Biotinylation Kit, catalog no. 21920.  
3. Standards: R&D Systems 294-HG purified recombinant human HGF diluted in 0.5% BSA in Ca2+/Mg2+ free PBS, standard curve covers range from 0.003 ng/ml to 3 ng/ml in semi-log increments.  
4. Detection antibody: R&D Systems AF294NA, tagged with MSD Sulfo-Tag NHS
Ester, catalog no. R91AN-1, per the manufacturer's protocol.  
5. MSD Read Buffer T with Surfactant, catalog no. R92TC-3; 4x.
9.1.6.3 Site Performing the Assay These studies will be done by the Urologic Oncology Branch, under the direction of Dr. Donald Bottaro.
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9.1.7 met expression in tissue

All patients will have their tumors analyzed for Met expression by immunohistochemistry (IHC) either with a tumor block, 10 unstained slides or a fresh tumor biopsy. Fresh biopsies, if archival samples are unavailable, will be obtained at baseline from primary tumor sites (bladder) and/or metastatic visceral sites. 4 - 6 core biopsies (or as available) will be taken from a single site. Please contact trepel@helix.nih.gov, lees@pop.nci.gov, leemin@mail.nih.gov and maria_merino@nih.gov when scheduled and call the Trepel Lab (240) 760 6330 for pickup. All material will be obtained for review. H&E slides, and one paraffin block or 10 unstained slides will be requested. In house tissue biopsies or resections will be obtained when indicated and tissues process routinely. Immunohistochemistry will be performed. For this procedure, 5-Pm, formalin fixed, paraffin-embedded sections will be deparaffinized, and used. Antigen retrieval will be utilized using a microwave oven. Antibodies against c-MET will be used with proper positive and negative controls. Tissue blocks from outside pathology departments will be stored in the NIH pathology department with attention to Dr. Maria Merino. Unstained slides will be stored by Dr. Andrea Apolo for staining. Biopsies obtained by surgery or interventional radiology will be processed for IHC met staining.
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9.1.8 immune subsets angiogenesis and

Circulating and intratumoral immune subsets and other markers of the microenvironment, hypoxia-inducible factor (HIF) 1α and 2α and other angiogenesis and/or immunologic markers will be analyzed at 8-18 weeks after treatment.  
x Blood will be collected in a 6 mL EDTA lavender top tube at baseline and at 8 - 18 weeks after treatment. Blood should only be collected at these timepoints if a tumor biopsy is also performed.  
x Please email Jane.Trepel@nih.hhs.gov, lees@pop.nci.gov and leemin@mail.nih.gov 24 hours prior to anticipated collection and call Jane Trepel's lab at 240-760-6330 to arrange for immediate pickup when drawn.
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9.1.8.1.2 tissue

Tissue will be analyzed 8 - 18 weeks after treatment. Any remaining tissue from biopsies obtained on this protocol will also be evaluated. Tissue blocks and slides obtained from outside pathology departments will be analyzed as available. Tissue biopsies, limited to 4 - 6 cores, will be encouraged but done strictly on a voluntary basis. Biopsies will be obtained from primary tumor sites and/or metastatic sites.
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9.1.8.2 processing

Samples will be processed immediately by the Trepel laboratory. Biospecimens will be collected and processed using validated SOPs that will ensure both specimen quality and patient confidentiality. 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. Specimen labels will indicate: protocol number, order in which the patient enrolled on the trial, type of sample, collection time, and total volume collected, as appropriate. 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. 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. As soon as possible after the patient is scheduled please send email notification to the Trepel lab at trepel@helix.nih.gov, lees@pop.nci.gov and leemin@mail.nih.gov that the biopsy is scheduled. A member of the Trepel Lab will come to the OR/IR suite as soon as the biopsy is available for optimally rapid procurement to maximize tumor viability Patients will undergo a baseline FDG PET/CT of metastatic lesions only along with standard imaging-CT of the chest abdomen and pelvis with or without Na18F PET CT. FDG-PET/CT of metastases will be repeated after 4 (alone) and 8 weeks (along with CT CAP) or until progression 72
(whichever comes first). The FDG-PET CT will be required, but may be waived at the discretion of the PI. The rationale for an FDG-PET at 4 weeks is that little is known about FDG-PET response to therapy in UC. We believe this is an important potential use of PET given the low objective RECIST response rate in studies in UC. The 8 week scan is taken to assess response to therapy and to assure that we capture progression of disease. The PET will be correlated with standard imaging modality. Patients will have the option of also undergoing a FDG PET/MR the same day of the PET/CT.  
PET-MR is a new technology that has recently become available at NIH. Unlike PET-CT, PETMRI fuses the PET image to an MRI for attenuation correction. In order to explore the value of this technology the patient may be asked whether they are willing to undergo a PET-MRI after completion of their standard PET-CT. After the patient has completed the PET-CT examination, they will be offered additional scanning on a PET-MRI scanner located in the CC/DRD emphasizing that this is optional. No additional injections of radioactivity will be administered and, because the MRI does not utilize ionizing radiation, there will be no additional exposure to the patient. The patient will be escorted to Radiology. The post-injection scan time for PET/MR will be 2 to 2.5 hours. Approximately 1 hour of additional scanning (PET and MR obtained simultaneously) will be performed. Results of the PET-CT and PET-MRI will be compared. These studies will be done by the Molecular Imaging Program, under the direction of Dr. Peter Choyke.
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9.1.10 comparison of target lesion

We will compare RECIST with semi-automated volume (SAV) / HU measurements, size and attenuation criteria (SACT), mass, attenuation, size and structure (MASS) criteria and Choi criteria in metastatic urothelial lesions. SAV will be measured and standardized utilizing the Lesion Management Application (LMA) of CareStream experimental PACS algorithm. The LMA results will be assessed by two independent radiologists. Differing assessments will be resolved by a third radiologist who will review the results. We will correlate SAV/HU, SACT, MASS and Choi criteria to therapeutic response and determine the practicability of PACS to extract measurement markups that create RECIST reports.
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9.1.11 htg molecular 1378

HTG Molecular has a platform to obtain RNA from FFPE tissues and from Paxgene tubes. NCI would send HTG Molecular paired coded samples of pre treatment and post treatment Paxgene samples and FFPE slides (H&E and serial unstained slides) for analysis. In this study, we will access the performance of the HTG EdgeSeq Immuno-Oncology Assay and OBP Assays on 20 trial cases with both pre and post treatment samples. Each case will have FFPE tissue and matched PaxGene samples to be assessed. A small number of additional samples corresponding to atypical histologies and MET lesions will also be analyzed in parallel as additional data points and controls. Our priority is to demonstrate the performance of FFPE and Paxgene samples for further utilization in clinical trials and secondary to determine if pathway and immune expression biomarkers are differentially expressed between pre and post treated samples. 9.1.11.1 Processing at HTG: Lysates:
x Lysis method. Sample lysis shall be performed in accordance to OP-00034, HTG EdgeSeq Processing.  
x Sample input volumes for each sample type: Cells = 20,000/well, FFPE = 5mm2/well x Unstained slides to be macro-dissected per NIH pathology recommendations, focusing on tumoral and peritumoral regions.  
x Lysates shall be aliquoted into several tubes so in order to minimize freeze/thaw cycles throughout the experiment and store sample for further analysis via OBP, IO assays and if required re-runs.
Specimens, data or information will be coded so that the provider of the samples/data can link them to specific individuals but the receiver will not be able to do so. Coded samples will be sent under an MTA to: TG Molecular Diagnostics, Inc. Attention: Mark Stern, Ph.D. Vice President, Head of Immuno-Oncology Franchise HTG Molecular Diagnostics 3430 E Global Loop Tucson, AZ 85706 C: (848) 213-5051 T: (877) 289-2615 F: (520) 547-2837
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9.1.12 xenobiotic metabolism

Previously we have identified the role of hypermethylation in decreasing the expression of cytochromes P450 1A1 (CYP1A1) and P450 1B1 (CYP1B1) in tumors compared to matched benign tissues. Furthermore, using a data mining approach on the TCGA data, we have recently uncovered yet another enzyme involved in xenobiotic metabolism, aldehyde oxidase (AOX1), as being progressively down-regulated during progression of bladder cancer through various clinical stages (T2-T4). AOX1 is known to play an essential role in amino acid synthesis and xenobiotic metabolism and metabolizes N-heterocycles and nitrosamines, azo dyes or nitropolycyclic aromatic hydrocarbons, many of which are known to increase the risk for bladder cancer. Importantly, using Tissue Microarrays on 190 BCa patients we confirmed a loss of AOX1 protein expression in advanced stages of bladder cancer. Based on all of the above data, we hypothesize that xenobiotic metabolism plays a key role in bladder cancer progression, its enzymes like AOX1 regulate tumor progression and xenobiotic metabolites could function as non-invasive markers to monitor tumor progression. Our aims include:
x Define stage-specific profiles of key xenobiotic metabolites in bladder cancer plasma samples.  
x Develop a first-generation multiplex panel of tissue-derived xenobiotic metabolites in plasma that correlates with clinical staging of the disease.  
Other aims included  
x Identify race specific metabolic markers in bladder cancer plasma. x Identify a metabolic signature for the bladder cancer smoker
9.1.12.1 Sample Processing Plasma - 100 uL Please aliquot in Eppendorf tube - Prefer not to have EDTA. Please store in -80 and ship on dry ice. Specimens, data or information will be coded so that the provider of the samples/data can link them to specific individuals but the receiver will not be able to do so. Shipping:
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nagireddy putluri ph.d

Associate Professor 120D, Jewish Building One Baylor Plaza, Houston, TX, 77030
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9.2 correlative studies 9.2.1 quality

Patients will be asked to complete the MDA Anderson Symptom Inventory (MDASI) Core items (See **Appendix G**) in order to assess their symptoms. Surveys will be completed at baseline and on day 1 (± 5 days) of cycle 3 of cabozantinib. Each survey should take about 5 - 10 minutes to complete.
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9.3 sample storage tracking and

Samples will be ordered and tracked in CRIS and tracked through a Clinical Trial Data Management system. Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples will not be sent outside NIH without IRB notification and an executed MTA.
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9.3.1 blood processing core (bpc)

Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred). For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.
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sample data collection

All samples sent to the Blood Processing Core (BPC) will be bar-coded, with data entered and stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure program, with access to LABrador limited to defined Figg lab personnel, who are issued individual user accounts. Installation of LABrador is limited to computers specified by Dr. Figg. These computers all have a password restricted login screen. All Figg lab personnel with access to patient information annually complete the NIH online Protection of Human Subjects course. LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced back to patients without LABrador access. The data recorded for each sample includes the patient ID, name, trial name/protocol number; time drawn, cycle time point, dose, material type, as well as box and freezer location. Patient demographics associated with the clinical center patient number are provided in the system. For each sample, there are notes associated with the processing method (delay in sample processing, storage conditions on the ward, etc.).
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sample storage and destruction

Bar-coded samples are stored in bar-coded boxes in a locked freezer at either -20° or -80qC
according to stability requirements. These freezers are located onsite in the BPC and offsite at NCI Frederick Central Repository Services in Frederick, MD. Saliva samples will be stored at room temperature. Samples will be stored until requested by a researcher named on the protocol. All requests are monitored and tracked in LABrador. All researchers are required to sign a form stating that the samples are only to be used for research purposes associated with this trial (as per the IRB approved protocol) and that any unused samples must be returned to the BPC. Following completion of this study, samples will remain in storage as detailed above. 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. Sample barcodes are linked to patient demographics and limited clinical information. This information will only be provided to investigators listed on this protocol, via registered use of the LABrador. It is critical that the sample remains linked to patient information such as race, age, dates of diagnosis and death, and histological information about the tumor, in order to correlate genotype with these variables.
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9.4 samples for genetic/genomic analysis

9.4.1.1 Collection and handling
x 3 mL of saliva will be collected using the Oragene saliva collection kit (DNA Genotek).  
The sample may be collected at any time after informed consent has been obtained, but collection is preferred at baseline.  
x Ideally, the patient should be advised not to eat or drink anything 30 minutes prior to collection.  
x Once the sample is obtained, the top of the device is closed, releasing a preservative, the top is removed and a cap is placed on the tube.
x The date and exact time of the collection should be recorded on the sample.  
x Please email NCIBloodcore@mail.nih.gov 24 hours prior to anticipated collection and page 102-11964 for immediate pick-up.
9.4.1.2 Handling As described in section 9.3, samples will be relabeled with barcoded labels generated by LABrador on arrival in the Figg Lab. 9.4.1.3 Site performing the analysis Genetic/genomic studies will be performed in the laboratory of Michael Dean, Ph.D., CCR, NCI.
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9.4.2 tumor biopsy

9.4.2.1 Collection and handling x Biopsy material remaining from either the baseline collection (see section **9.1.7**) or the collection at 8 - 18 weeks (see section **9.1.8**) should be placed on ice or frozen as soon as possible after collection. In the case that there is limited biopsy material, tissue distribution should be prioritized as follows:
1. Analysis of met expression (Dr. Maria Merino) 2. HGF and cabozantinib target analysis (Dr. Donald Bottaro) 3. Immune subset analysis (Jane Trepel) 4. Genetic/Genomic Analysis (Dr. Michael Dean) 5. HTG Analysis (Dr. Stern)
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9.4.2.2 processing

The sample will be processed in the Trepel lab as described in section **9.1.8.2**. DNA will be extracted from leftover tissue per Trepel lab procedures and will be assigned a unique barcode that can be linked to the original specimen collected, annotated with clinical information. The DNA extracted from the samples will be sent to the Dean lab for analysis. 9.4.2.3 Site performing the analysis Genetic/genomic studies will be performed in the laboratory of Michael Dean, Ph.D., CCR, NCI
and HTG Molecular as per section **9.1.11**. 9.4.2.4 Shipping Extracted DNA from biopsies should be sent to:
Julie Sawitzke Center for Cancer Research, NCI Building 560, Room 21-43 Frederick, MD 21702 Phone: 301 845 1997 Email: sawitzkej@mail.nih.gov
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9.4.3 scope of analysis

Tumor samples will be used as a source of DNA for genetic/genomic studies. Saliva samples will be used as a source of genomic (germline DNA) from the patients to compare with tumor DNA
77 for somatic mutations. Whole genome and whole exome studies may be conducted using the material collected. Studies for the analysis of chromosomal abnormalities may also be performed.
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9.4.4 confidentiality of medical information/biological

Samples will be labeled with unique identifiers generated in the Figg or Trepel labs respectively and transferred to the Dean lab for analysis. No patient identifiers (e.g., medical record number, patient name or initials) will be included with the sample. Dr. Dean's lab will create a separate unique sample ID using Labmatrix that can be linked to the clinically annotated identifiers from the source labs. Samples will be stored in coded, locked freezers in a room that is locked when unoccupied. The storage facility is located in a building that is key card secured. Raw and analyzed sequencing data will be stored on dedicated server and on a hard drive in the investigator's locked office. Analyzed data will also be uploaded into the secure Labmatrix database. Only the PI and study personnel who interact directly with the patients will have access to patient records which include personally identifiable information. Investigators conducting the individual sample testing will only have access to coded identification numbers and coded patient information (i.e. treatment regimens, treatment responses, diagnoses, pathology information). No personally identifiable information will be released to third parties and samples and data will only be shared with other researchers with the permission of the IRB and under the proper Material Transfer Agreements. Sometimes, because a group collaboration or journal policy requires it, a subject's genetic data may be deposited in a database such as dbGaP. Although there is controlled access to such a database, such a submission carries theoretical risks of revealing the identity of the subject. This is discussed in the consent.
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9.4.4.1 certificate of confidentiality

As part of study efforts to provide confidentiality of subject information, this study will obtain a Certificate of Confidentiality which helps to protect personally identifiable research information. The Certificate of Confidentiality allows investigators on this trial to refuse to disclose identifying information related to the research participants, should such disclosure have adverse consequences for subjects or damage their financial standing, employability, insurability or reputation. The informed consent includes the appropriate coverage and restrictions of the Certificate of Confidentiality.
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9.4.5 management of results

In the unlikely event that clinically actionable incidental findings are discovered, living patients will be contacted and asked if they would like to submit a blood sample to be tested at a CLIA certified lab and meet with a certified genetic health care provider to discuss the implications of this type of testing. Patients will be offered the option for a legal next of kin to be contacted if they are deceased at the time of the research finding. The legal next of kin would be offered genetic counseling that would include the distinction between a clinical and research finding and would be offered the opportunity to have those findings confirmed in a living relative of the patient. Note: Clinically actionable findings for the purpose of this study are defined as disorders appearing in the American College of Medical Genetics and Genomics recommendations for the return of incidental findings that is current at the time of primary analysis. (A list of current  
guidelines is maintained on the CCR intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). Incidental findings will only be reported to the patient within the first 5 years of signing the consent.
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9.4.6 genetic counseling

Should any significant incidental findings be discovered, genetic counseling will be provided on a consultation basis by the NHGRI, NIH. Any genetic counseling or testing at a CLIA certified lab will be funded by the Center for Cancer Research at the time of the event (s).  
Abbreviated Title: Ph 2 XL184 in urothelial CA
Version Date: 05/10/2019  
| 10 STUDY CALENDAR                                           | Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy. Scans and x-rays must be done <4 weeks prior  to the start of therapy. In the event that the patient's condition is deteriorating, laboratory evaluations should be repeated within 48  hours prior to initiation of the next cycle of therapy.   | The following schedule of assessments applies to all subjects. More frequent assessments should be obtained if clinically indicated.   | Procedure Long Term  Follow Up9 30 - 37 Days  after last dose   |    |    |    |      |    |    |    |    |
|-------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|----|----|----|------|----|----|----|----|
| Study Treatment Period Post-Treatment Period                | 11, 13, and 15 then every 4                                                                                                                                                                                                                                                                                                                  | weeks  (± 7 days)                                                                                                                      |                                                                 |    |    |    |      |    |    |    |    |
| Day 1 of Weeks 3, 5, 7, 9,                                  | X                                                                                                                                                                                                                                                                                                                                            | X                                                                                                                                      | X                                                               | X  | X  | X  |      |    |    |    |    |
| Within 1 week prior to  the first dose of Study  Treatment  | 80                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                        |                                                                 |    |    |    |      |    |    |    |    |
| X                                                           | X                                                                                                                                                                                                                                                                                                                                            | X                                                                                                                                      | X                                                               | X  | X  |    |      |    |    |    |    |
| Within 28 days prior to 1st Dose of Study Treatment         | X                                                                                                                                                                                                                                                                                                                                            | X                                                                                                                                      | X                                                               | X  | X  | X  | X  X | X  | X  | X  | X  |
| 24 hour urine collection  if needed (see section  3.1.1.13) |                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                        |                                                                 |    |    |    |      |    |    |    |    |
| Medical and cancer  history/demographics                    | Physical examination                                                                                                                                                                                                                                                                                                                         | Urinalysis (including  UPCR)                                                                                                           |                                                                 |    |    |    |      |    |    |    |    |
| Dental examination  (baseline)1                             | ECOG performance  status Clinical laboratory  tests2                                                                                                                                                                                                                                                                                         |                                                                                                                                        |                                                                 |    |    |    |      |    |    |    |    |
| Informed consent                                            | Demographics                                                                                                                                                                                                                                                                                                                                 | Vital signs                                                                                                                            |                                                                 |    |    |    |      |    |    |    |    |
| Weight                                                      |                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                        |                                                                 |    |    |    |      |    |    |    |    |
| Height                                                      |                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                        |                                                                 |    |    |    |      |    |    |    |    |  
CTEP Study \#: 9236  
| Long Term  Follow Up9 30 - 37 Days  after last dose                                                          | X                         |                  |                                                                                                                                                                                                                                         |                      |    |                    |
|--------------------------------------------------------------------------------------------------------------|---------------------------|------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------|----|--------------------|
| Study Treatment Period Post-Treatment Period                                                                 | X                         |                  |                                                                                                                                                                                                                                         |                      |    |                    |
| 11, 13, and 15 then every 4                                                                                  | weeks  (± 7 days)         |                  |                                                                                                                                                                                                                                         |                      |    |                    |
| Day 1 of Weeks 3, 5, 7, 9,                                                                                   | X (optional, week 8 - 18) |                  |                                                                                                                                                                                                                                         |                      |    |                    |
| X (every 8 weeks)11                                                                                          | X (week 9 only)           |                  |                                                                                                                                                                                                                                         |                      |    |                    |
| X (weeks 4, 8)                                                                                               |                           |                  |                                                                                                                                                                                                                                         |                      |    |                    |
| X (daily)                                                                                                    |                           |                  |                                                                                                                                                                                                                                         |                      |    |                    |
| X3                                                                                                           | X3                        | X3               | X3                                                                                                                                                                                                                                      |                      |    |                    |
| X                                                                                                            | X                         | X6 X6            | ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; UPCR, urine protein/urine creatinine ratio  1 Dental examination required at baseline in patients that have been treated with or are currently taking bisphosphonates |                      |    |                    |
| Continuous                                                                                                   |                           |                  |                                                                                                                                                                                                                                         |                      |    |                    |
| Within 1 week prior to  the first dose of Study  Treatment                                                   | X                         | X                | X                                                                                                                                                                                                                                       |                      |    |                    |
| Within 28 days prior to 1st Dose of Study Treatment                                                          | X                         | X 12-lead ECG4 X | X                                                                                                                                                                                                                                       | X                    | X  | QOL Assessment10 X |
| X                                                                                                            |                           |                  |                                                                                                                                                                                                                                         |                      |    |                    |
| Pregnancy test (in  women of childbearing  potential)  Tumor assessment: CT  CAP or MRI scan ±  NaF PET CT 5 | Research blood, saliva    | and urine        | Biopsy/archival tissue  obtained7                                                                                                                                                                                                       | Follow-up phone call |    |                    |
| Investigational FDG  PET/CT8                                                                                 | Adverse events            |                  |                                                                                                                                                                                                                                         |                      |    |                    |
| PT/INR, PTT                                                                                                  | Cabozantinib              | administration   | Concomitant                                                                                                                                                                                                                             | medications          |    |                    |
| Procedure                                                                                                    | TFTs                      |                  |                                                                                                                                                                                                                                         |                      |    |                    |  
Abbreviated Title: Ph 2 XL184 in urothelial CA
Version Date: 05/10/2019 CTEP Study \#: 9236 Abbreviated Title: Ph 2 XL184 in urothelial CA
Version Date: 05/10/2019 2 Clinical laboratory tests include: a standard hematology panel (CBC, differential, platelets) and chemistry panel (albumin, alkaline phosphatase, ALT, amylase, AST, bicarbonate, bilirubin, blood urea nitrogen, calcium, chloride, creatinine, γ-glutamyltransferase (GGT), glucose, lactate dehydrogenase, lipase, magnesium, phosphorus, potassium, sodium, total bilirubin, total protein). Refer to section **5.3.4**) 3 Every 4 weeks 4 Three ECGs should be obtained within 30 minutes but at least 2 minutes apart if there is an increase in QTc to an absolute value > 500 msec using the Fridericia correction formula. See section **5.3.1**5 All sites of known disease must be assessed. Baseline scans must be repeated if patient is off of study drug for > 6 weeks. 6 Please see section 9 or **Appendix F** for research blood and urine collection 7 Please see sections 9.1.7, 9.1.8.1.2 and 9.4.2 or **Appendix F** for biopsy or archival tissue specifications 8 Performed on patients with metastatic disease. See section **9.1.9**. 9 Will attempt patient contact every 2 months after 30 - 37 day phone call to determine survival status 10 QOL assessments will be performed at baseline and after cycle 3 of cabozantinib. Please see section **9.2.1** for further details. 11 Patients who are off treatment due to complete response after 3 years will have their assessments every 12 weeks.
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11 measurement of effect 11.1

Patients with measurable disease will be assessed primarily by CT scan of the chest, abdomen and pelvis. MRI may be used in subjects unable to tolerate contrast. For the purposes of this study, patients should be re-evaluated every 8 weeks. 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] and Prostate Cancer Clinical Trials Working Group criteria (PCWG2)79. 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.
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11.1.1 definitions

Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first treatment with study agents. Evaluable for objective response. All of the patients who met the eligibility criteria and who have received at least 8 weeks of therapy are evaluable for response. Patients that have: progressive disease, early death from malignant disease, early death from toxicity, early death because of other cause, or unknown (not assessable, insufficient data) should be considered to have a treatment failure (disease progression). Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the analysis of the response rate. 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.
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11.1.2 disease parameters

Measurable disease. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as >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). Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions. Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target lesions** and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up.
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11.1.3 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 t10 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. Tumor markers Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [*JNCI* 96:487-488, 2004; *J Clin* Oncol 17, 3461-3467, 1999; *J Clin Oncol* 26:1148-1159, 2008]. In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with objective tumor assessment for use in first-line trials in ovarian cancer [*JNCI* 92:1534-1535, 2000]. 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-PETWhile 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.
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11.1.4 response criteria

| 11.1.4.1 Evaluation of Target Lesions  Complete Response (CR):   | Disappearance of all target lesions. Any pathological  lymph nodes (whether target or non-target) must have  reduction in short axis to <10 mm.                                                                                                                                                                                             |
|------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Partial Response (PR):                                           | At least a 30% decrease in the sum of the diameters of  target lesions, taking as reference the baseline sum  diameters.                                                                                                                                                                                                                    |
| Progressive Disease (PD):                                        | At least a 20% increase in the sum of the diameters of  target lesions, taking as reference the smallest sum on  study (this includes the baseline sum if that is the  smallest on study). In addition to the relative increase  of 20%, the sum must also demonstrate an absolute  increase of at least 5 mm. (Note: the appearance of one |  
| or more new lesions is also considered progressions).  sufficient increase to qualify for PD, taking as reference  the smallest sum diameters while on study.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|  
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.  
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).  
| 11.1.4.2 Evaluation of Non-Target Lesions  Complete Response (CR):                                                                                                                                                                                                 | Disappearance                                                                                                       | of   | all   | non-target   | lesions   | and   |         |        |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------|------|-------|--------------|-----------|-------|---------|--------|
| normalization of tumor marker level. All lymph nodes  must be non-pathological in size (<10 mm short axis).  Note: If tumor markers are initially above the upper  normal limit, they must normalize for a patient to be  considered in complete clinical response |                                                                                                                     |      |       |              |           |       |         |        |
| Non-CR/Non-PD:                                                                                                                                                                                                                                                     | Persistence of one or more non-target lesion(s) and/or  maintenance of tumor marker level above the normal  limits. |      |       |              |           |       |         |        |
| Progressive Disease (PD):                                                                                                                                                                                                                                          | Appearance                                                                                                          | of   | one   | or           | more      | new   | lesions | and/or |
| unequivocal progression of existing non-target lesions.  Unequivocal progression should not normally trump  target lesion status. It must be representative of overall  disease status change, not a single lesion increase.                                       |                                                                                                                     |      |       |              |           |       |         |        |
| Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating                                                                                                                                                              |                                                                                                                     |      |       |              |           |       |         |        |
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11.1.4.3 metastatic bone lesions

Two new bone lesions on Na18F PET CT that is associated with characteristic bone changes on CT will be defined as progressive disease (PD).79 Na18F uptake changes including changes in SUV or flares of known lesions will not be counted as PD. Only new lesions with associated CT changes will be counted as PD.
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11.1.4.4 evaluation of best overall

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| For Patients with Measurable Disease (i.e., Target Disease) Target  NonTarget  Lesions  Lesions  New  Overall  Best Overall  Lesions  Response  Response when  Confirmation is  Required*  CR CR No CR >4 wks.  Confirmation** CR NonCR/NonPD No PR  CR Not  No PR  >4 wks.  evaluated  Confirmation** PR NonCR/NonPD/not  evaluated  No PR  SD NonCR/NonPD/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 nontarget lesions may be accepted as disease progression.  Note: Patients with a global deterioration of health status requiring  discontinuation of treatment without objective evidence of disease  progression at that time should be reported as "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 |               |                    |
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11.1.5 duration of response

Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease or death 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.
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11.1.6 progression free survival

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

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 0 (Adverse Events: List and Reporting Requirements).
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12.1 data collection

The PI will be responsible for overseeing entry of data into an in-house password protected electronic system NCI CCR C3D database within 14 days of collection and ensuring data accuracy, consistency and timeliness. The principal investigator, associate investigators/research nurses and/or a contracted data manager will assist with the data management efforts. All data obtained during the conduct of the protocol will be kept in secure network drives or in approved alternative sites that comply with NIH security standards. Primary and final analyzed data will have identifiers so that research data can be attributed to an individual human subject participant. All adverse events, including clinically significant abnormal findings on laboratory evaluations, regardless of severity, will be followed until return to baseline or stabilization of event. Patients will be followed for adverse events for a minimum of 30 days after removal from study treatment or until off-study, whichever comes first. An abnormal laboratory value will be considered an AE if the laboratory abnormality is characterized by any of the following:  
x Results in discontinuation from the study x Is associated with clinical signs or symptoms x Requires treatment or any other therapeutic intervention x Is associated with death or another serious adverse event, including hospitalization. x Is judged by the Investigator to be of significant clinical impact x If any abnormal laboratory result is considered clinically significant, the investigator will provide details about the action taken with respect to the test drug and about the patient's outcome.
Quality assurance complete records must be maintained on each patient treated on the protocol. These records should include primary documentation (e.g.: laboratory report slips, X-ray reports, scan reports, pathology reports, physician notes, etc.) which confirm that:
x The patient met all eligibility criteria  
x Signed informed consent was obtained prior to treatment
x Treatment was given according to protocol (dated notes about doses given, complications, and clinical outcomes)  
x Toxicity was assessed according to protocol (laboratory report slips, etc.) x Response was assessed according to protocol (X-ray, scan, lab reports, date noted on clinical assessment, as appropriate)
All data will be kept secure. Personal identifiers will not be used when collecting and storing data. An enrollment log will be maintained in the regulatory binder/file which is the only location of personal identifiers with unique subject identification number. End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH Intramural Records Retention Schedule as applicable. Loss or destruction of data: Should we become aware that a major breach in our plan to protect subject confidentiality and trial data has occurred, the IRB will be notified.
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12.2 genomic data sharing plan

Unlinked genomic data will be deposited in public genomic databases such as dbGaP in compliance with the NIH Genomic Data Sharing Policy.
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12.3 data reporting 12.3.1 method

This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. The C3D data management system will be used to capture data and report to the clinical data update system (CDUS). 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: If your study has been assigned to CDUS-Complete reporting, all adverse events (both routine and expedited) that have occurred on the study and meet the mandatory CDUS reporting guidelines must be reported via the monitoring method identified above. If your study has been assigned to CDUS-Abbreviated reporting, no adverse event reporting (routine or expedited) is required to be reported via CDUS.
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12.4 ctep multicenter guidelines n/a

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 nonCooperative 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.
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12.6 material transfer agreement (mta)

An MTA is to be filed for samples to be sent to HTG Molecular as outlined in section **9.1.11**.
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12.7 mta for samples sent

An MTA for samples to be sent to Nagireddy Putluri Ph.D at Baylor College as outlined in section 9.1.12, will be finalized upon approval of the amendment O dated 11/08/2017.
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13 statistical considerations 13.1 study

The primary objective of this study is to determine if patients with advanced or metastatic bladder cancer will exhibit responses to XL184. The study will be conducted as an optimal two-stage phase II trial (Simon R, Controlled Clinical Trials 10:1-10, 1989), in order to rule out an unacceptably low 5% overall response rate (ORR; p0=0.05), in favor of a modest response rate of 20% (p1=0.20). With alpha=0.05 (probability of accepting a poor treatment=0.05) and beta = 0.10 (probability of rejecting a good treatment=0.10), the study will initially enroll 21 evaluable patients and if 0 to 1 of the 21 have a response by RECIST version 1.1, then no further patients will be accrued. If 2 or more the first 21 have a response, then accrual would continue until a total of 41 patients have enrolled. As it may take several weeks to determine if a patient has experienced a response, a temporary pause in the accrual to the trial may be necessary to ensure that enrollment to the second stage is warranted. If there are 2 to 4 responses in 41 patients, this would be an uninterestingly low response rate, while if there were 5 or more responses in 41patients, then this would be sufficiently interesting to warrant further study in later trials. Under the null hypothesis (5% response rate), the probability of early termination is 72%. Patients with bone-only disease will be accrued and evaluated separately from all other patients, as they cannot be evaluated with the same methods or same degree of accuracy as all other patients with this disease. It is expected that only 15-20% of all patients enrolling on the trial will have bone-only disease. The patients which would be expected to enroll while awaiting enrollment of the main set of 41 patients will be considered a hypothesis generating cohort to determine if any patients show some evidence of avoiding worsening disease while receiving XL184. They will be evaluated using Na18F PET CT scans in addition to standard CT CAP (or MRI) and FDG PET and will be considered to have favorable results if additional lesions are not noted compared to baseline. As this is a small set of patients, the results will be used to determine if a more definitive subsequent study in these patients would be warranted. Patients with non transitional cell carcinoma will be accrued and evaluated separately from all other patients. Because no data for an expected response rate for comparison currently exist with regard to this group of patients, this will be an exploratory study. The patients which would be expected to enroll while awaiting enrollment of the main set of 41 patients will be considered a hypothesis generating cohort to determine if any patients show some evidence of avoiding worsening disease while receiving XL184. They will be evaluated using standard CT CAP (or MRI) and FDG PET and will be considered to have favorable results if additional lesions are not noted compared to baseline. As this is a small set of patients, the results will be used to determine if a more definitive subsequent study in these patients would be warranted.
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13.2 sample size/accrual rate

In order to allow for up to 41 evaluable patients plus up to 21 patients with either bone only or non TCC bladder, urethra, ureter, or renal pelvis cancer who will be evaluated in separate cohorts, the accrual ceiling will be 71 patients. This will allow enrollment of up to 8-9 patients who may be considered inevaluable. It is anticipated that 2-3 patients per month may enroll on this trial; thus, 2 to 3 years is anticipated as the accrual period for this study. Subjects will be accrued into the exploratory cohorts (cohorts 2 and 3) for only as long as subjects are being accrued onto the hypothesis generating cohort (cohort 1).
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13.3 stratification factors n/a 13.4

The secondary endpoint of progression free survival and survival will also be analyzed via a Kaplan-Meier curve. This latter, secondary, evaluation will be based on all patients who are able to be assessed in either the first (retrospectively) or second stage of accrual. The secondary endpoint of the assessment of non RECIST imaging criteria and association with treatment response (RECIST) will be analyzed via appropriate non-parametric methods, such as a Wilcoxon rank sum test to compare parameters between responders and non-responders. Toxicity and safety are also a primary consideration for use of this agent in this population. The worst grade of each type of toxicity noted per patient will be tabulated and reported according to the NCI Common Toxicity Criteria, version 4.0. Evaluations of any laboratory and correlative parameters obtained will be done using exploratory techniques. Comparisons of parameters between patients who do and do not respond to therapy will be done using non-parametric methods such as a Wilcoxon rank sum test. The results will be reported without any formal adjustment for multiple comparisons. For the secondary objective of FDG PET scan evaluation we will examine the change of uptake of FDG over time and explore its relationship with response to therapy. Descriptive statistics such as percent changes of FDG over time and its overall trend in relation to the clinical endpoints will be reported. The data obtained from this study will be used for hypothesis generating and sample size planning for the main study.
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13.5 reporting and exclusions 13.5.1

All patients will be evaluable for toxicity from the time of their first treatment with cabozantinib.
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13.5.2 evaluation of response

All patients included in the study must be assessed for response to treatment, even if there are major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). [Note: By arbitrary convention, category 9 usually designates the "unknown" status of any type of data in a clinical database.] All of the patients who met the eligibility criteria (with the possible exception of those who received no study medication) should be included in the main analysis of the response rate. Patients in response categories 4-9 should be considered to have a treatment failure (disease progression). Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the analysis of the response rate. Precise definitions for categories 4-9 will be protocol specific. All conclusions should be based on all eligible patients. Subanalyses may then be performed on the basis of a subset of patients, excluding those for whom major protocol deviations have been identified (*e.g.*, early death due to other reasons, early discontinuation of treatment, major protocol violations, etc.). However, these subanalyses may not serve as the basis for drawing conclusions concerning treatment efficacy, and the reasons for excluding patients from the analysis should be clearly reported. The 95% confidence intervals should also be provided.
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14 human subjects protections 14.1

Subjects with progressive urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis will be eligible for participation in this study. Individuals of any race or ethnic group will be eligible for this study. Eligibility assessment will be based solely on the patient's medical status. Recruitment of patients onto this study will be through standard CCR mechanisms. No special recruitment efforts will be conducted.
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14.2 participation of children

Individuals under the age of 18 will not be eligible to participate in this study because they are unlikely to have urothelial cancer, and because of unknown toxicities of this agent in the pediatric patient.
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14.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (section **14.4**), all subjects ≥ age 18 will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment of whether an individual has the capacity to provide consent; assistance in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint a surrogate. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E 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.
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14.4 evaluation of benefits and

The potential benefit to a patient on this study is a reduction in the bulk of their tumor and improvement in cancer lesions, which may or may not have favorable impact on symptoms and/or survival.
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14.4.2 risks radiation risks

Undergoing the research FDG PET CT scans will cause subjects to be exposed to approximately 3.2 rem which is below the guideline of 5 rem per year allowed for adult research subjects by the NIH Radiation Safety Committee.
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other risks

Additional risks include the possible occurrence of any of a range of side effects which are listed in the Consent Document. Frequent monitoring for adverse effects will help to minimize the risks associated with administration of cabozantinib.
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14.5 risks/benefits analysis

Although urothelial cancer is a chemosensitive malignancy with response proportions of over 50% with conventional cytotoxic regimens, the response durations are short and the median survival of patients with metastatic disease is approximately 14 months. There is no FDA-approved second line drug for metastatic urothelial cancer. Inhibition of angiogenesis has demonstrated antitumor efficacy in patients with metastatic UC. Cabozantinib inhibits multiple receptor kinases with growth promoting and angiogenic properties, including MET and VEGF, which are known to be over-expressed in bladder cancer. The use of cabozantinib as a second line agent in metastatic urothelial cancer has the potential to improve outcomes in this patient population. Given the efforts to minimize risk with the administration of this combination, this protocol involves greater than minimal risk, but presents the potential for direct benefit to individual subjects.
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14.6 consent and assent process

The principal investigator or a designee will obtain written informed consent from each subject participating in this study after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study. In the case where the subject is unable to read, an impartial witness will be present during the entire informed consent discussion. After the subject has orally consented to participation in the trial, the witness's signature on the form will attest that the information in the consent form was accurately explained and understood. If new safety information results in significant changes in the risk/ benefit assessment, the consent form will be reviewed and updated as necessary. All subjects (including those already being treated) will be informed of the new information, be given a copy of the revised form, and be asked give their consent to continue in the study. It will be documented on the case report form that informed consent has been obtained.
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14.6.1 telephone re-consent

Reconsent on this study may be obtained via telephone according to the following procedure: the informed consent document will be sent to the subject. An explanation of the study will be provided over the telephone after the subject has had the opportunity to read the consent form. The subject will sign and date the informed consent. The original informed consent document will be sent back to the consenting investigator who will sign and date the consent form with the date the consent was obtained via telephone. A fully executed copy will be returned via mail for the subject's records. The informed consent process will be documented in the medical record.
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16 appendices 16.1 appendix a

| ECOG Performance Status Scale                                                                                                                                   | Karnofsky Performance Scale                                |                                                                                 |             |                 |             |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|---------------------------------------------------------------------------------|-------------|-----------------|-------------|
| Grade                                                                                                                                                           | Descriptions                                               | Percent                                                                         | Description |                 |             |
| 100                                                                                                                                                             | Normal, no complaints, no evidence  of disease.            |                                                                                 |             |                 |             |
| Normal activity. Fully active, able                                                                                                                             |                                                            |                                                                                 |             |                 |             |
| 0                                                                                                                                                               | to                                                         | carry                                                                           | on          | all             | pre-disease |
| performance without restriction.                                                                                                                                | 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 selfcare, 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. |             |                 |             |
| 2                                                                                                                                                               | 50                                                         | Requires considerable assistance and  frequent medical care.                    |             |                 |             |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                          | 40                                                         | Disabled, requires special care and  assistance.                                |             |                 |             |
| 3                                                                                                                                                               | 30                                                         | Severely                                                                        | disabled,   | hospitalization |             |
| indicated. Death not imminent.                                                                                                                                  |                                                            |                                                                                 |             |                 |             |
| 20                                                                                                                                                              | Very sick, hospitalization indicated.  Death not imminent. |                                                                                 |             |                 |             |
| 100%                                                                                                                                                            | bedridden.                                                 | Completely                                                                      |             |                 |             |
| disabled. Cannot carry on any selfcare. Totally confined to bed or  chair.                                                                                                                                                                 |                                                            |                                                                                 |             |                 |             |
| 4                                                                                                                                                               | 10                                                         | Moribund,                                                                       | fatal       | processes       |             |
| progressing rapidly.                                                                                                                                            |                                                            |                                                                                 |             |                 |             |
| 5                                                                                                                                                               | Dead.                                                      | 0                                                                               | Dead.       |                 |             |
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information on possible interactions with

The patient ____________________________ is enrolled on a clinical trial using the experimental **cabozantinib***. This clinical trial is sponsored by the National Cancer Institute. This* form is addressed to the patient, but includes important information for others who care for this patient. Cabozantinib interacts with many drugs that are processed by your liver. Because of this, it is very important to tell your study doctors about all of your medicine before you start this study. It is also very important to tell them if you stop taking any regular medicine, or if you start taking a new medicine while you take part in this study. When you talk about your medicine with your study doctor, include medicine you buy without a prescription at the drug store (over-the-counter remedy), or herbal supplements such as St. John's wort. Many health care prescribers can write prescriptions. You must also tell your other prescribers (doctors, physicians' assistants or nurse practitioners) that you are taking part in a clinical trial. Bring this paper with you and keep the attached information card in your wallet. These are the things that you and they need to know: Cabozantinib interacts with (a) certain specific enzyme(s) in your liver.  
x The enzyme(s) in question is **CYP3A4**. This enzyme breaks down cabozantinib, gradually reducing the level of the active drug in your system.  
x Other medicines may affect the activity of the enzyme. Cabozantinib must be used very carefully with these medicines, or you may need to switch to alternate medications.  
o Substances that increase the enzyme's activity ("inducers") could reduce the effectiveness of the drug, while substances that decrease the enzyme's activity ("inhibitors") could result in high levels of the active drug, increasing the chance of harmful side effects.  
x You and healthcare providers who prescribe drugs for you must be careful about adding or removing any drug in this category.  
x Before you start the study, your study doctor will work with your regular prescriber to switch any medicines that are considered "strong inducers/inhibitors or substrates of CYP3A4."
x Your prescribers should look at this web site http://medicine.iupui.edu/clinpharm/ddis/ or consult a medical reference to see if any medicine they want to prescribe is on a list of drugs to avoid.  
x Please be very careful! Over-the-counter drugs have a brand name on the label—it's usually big and catches your eye. They also have a generic name—it's usually small and located above or below the brand name, and printed in the ingredient list. Find the generic name and determine, with the pharmacist's help, whether there could be an adverse interaction.  
x Be careful:
o If you take acetaminophen regularly: You should not take more than 4 grams a day if you are an adult or 2.4 grams a day if you are older than 65 years of age. Read labels carefully! Acetaminophen is an ingredient in many medicines for pain, flu, and cold.  
o If you drink grapefruit juice or eat grapefruit or Seville orange: Avoid these until the study is over.  
o If you take herbal medicine regularly: You should not take St. John's wort while you are taking cabozantinib o For indigestion, take antacid at least 2 hours (preferably 4 hours) after taking cabozantinib and at least 14 hours before the next dose of cabozantinib if possible. Avoid using ranitidine, famotidine, omeprazole, lansoprazole, rabeprazole, pantoprazole, or esomeprazole. If antacids are not adequate, please contact the research team member before taking any other medications.  
Other medicines can be a problem with your study drugs.  
x You should check with your doctor or pharmacist whenever you need to use an over-the-counter medicine or herbal supplement.  
x Your regular prescriber should check a medical reference or call your study doctor before prescribing any new medicine for you. Your study doctor's name is **Dr. Andrea Apolo** and she can be contacted at 301-4800536.  
| INFORMATION ON POSSIBLE DRUG INTERACTIONS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                           |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------|
| You are enrolled on a clinical trial using the experimental agent XL184  (cabozantinib). This clinical trial is sponsored by the NCI. XL184  (cabozantinib) interacts with drugs that are processed by your liver.  Because of this, it is very important to:  ¾ Tell your doctors if you stop taking regular medicine or if you start  taking a new medicine.  ¾ Tell all of your prescribers (doctor, physicians' assistant, nurse  practitioner, pharmacist) that you are taking part in a clinical trial. ¾ Check with your doctor or pharmacist whenever you need to use  an over-the-counter medicine or herbal supplement. | INFORMATION ON POSSIBLE DRUG INTERACTIONS |
| You are enrolled on a clinical trial using the experimental agent XL184  (cabozantinib). This clinical trial is sponsored by the NCI. XL184  (cabozantinib) interacts with drugs that are processed by your liver.  Because of this, it is very important to:  ¾ Tell your doctors if you stop taking regular medicine or if you start  taking a new medicine.  ¾ Tell all of your prescribers (doctor, physicians' assistant, nurse  practitioner, pharmacist) that you are taking part in a clinical trial. ¾ Check with your doctor or pharmacist whenever you need to use  an over-the-counter medicine or herbal supplement. |                                           |