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6.1.9 hemorrhage

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:  
- Tumor lesions of the lung with cavitations or tumor lesions which invade, encase, or about any major blood vessels; non-small cell lung cancer (NSCLC) with squamous cell differentiation is known for significant lung cavitations and centrally located tumors that may invade major blood vessels. The anatomic location and characteristics of tumor as well as the medical history should be carefully reviewed in the selection of subjects for treatment with cabozantinib.  
- Recent or concurrent radiation to the thoracic cavity - Active peptic ulcer disease, ulcerative colitis, and other inflammatory GI diseases - Underlying medical conditions which affect normal hemostasis (e.g., deficiencies in clotting factors and/or platelet function, or thrombocytopenia)
- Concomitant medication with anticoagulants or other drugs which affect normal hemostasis - 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, if it does not meet DLT criteria as defined in Section 5.4, may be restarted after the cause of hemorrhage has been identified and the risk of bleeding has subsided. 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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6.1.10 rectal and perirectal abscesses

These should be treated with appropriate local care and antibiotic therapy. Cabozantinib should be held until adequate healing has taken place unless ≥ grade 3 and occurring in the first 2 cycles in which case cabozantinib should be permanently discontinued.
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6.1.11 gastrointestinal perforation and gi

Complete healing following abdominal surgery or resolution of intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib. Discontinue cabozantinib and initiate appropriate management in subjects who have been diagnosed with GI perforation or fistula.
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6.1.12 wound healing and surgery

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 meeting DLT criteria as defined in Section 5.4. 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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6.1.13 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 life-threatening endocrine dysfunction.
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6.1.14 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. Study treatment may be reinitiated if it does not meet DLT criteria as defined in section **5.4;** however, reinitiation must be discussed with and approved by the Sponsor on a case by case basis.
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6.1.15 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  
- Treatment with other drugs associated with QTc prolongation (see http://www.qtdrugs.org).  
- Treatment with CYP 3A4 inhibitors (which may increase cabozantinib drug levels) - Electrolyte changes (hypokalemia, hypocalcemia, hypomagnesemia).  
- 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 permanently withheld if this occurs during the DLT evaluation period. Otherwise, the following actions should be taken:  
- Check electrolytes, especially potassium, magnesium and calcium. Correct abnormalities as clinically indicated.  
- If possible, discontinue any QTc-prolonging concomitant medications. - 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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6.1.16 additional information for dose

Dose delays for reason(s) other than AEs related to cabozantinib, such as surgical procedures with no anticancer therapy intent, may be allowed with investigator approval. The acceptable length of interruption will be determined by the investigator.
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6.2 docetaxel dose modifications

Patients should have an ANC 1500 cells/mm3, a platelet count  75,000 cells/mm3(grade 1 hematologic toxicity) and resolution of any grade 3 or higher non-hematologic toxicity to < grade 1 or baseline in order to initiate another treatment cycle of docetaxel. For febrile neutropenia developed within a prior cycle, docetaxel can be continued during future cycles at a dosage decreased by 25% and if indicated, with the addition of filgrastim support. For grade 4 neutropenia lasting greater than 5 days docetaxel will be held and patients will be treated with filgrastim support. Docetaxel will be resumed at the same dose once neutropenia has resolved to ≤ grade 1 or baseline.  
| When Neutrophils fall to      | for a Duration of   | Recommended Course                                                                                                                                                                                    |
|-------------------------------|---------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| <1000 but ≥ 500/mcL (Grade 3) | Any length of time  | No dose reduction for future cycles.                                                                                                                                                                  |
| <500/mcL (Grade 4)            | ≤ 5days             | No dose reduction for future cycles.                                                                                                                                                                  |
| <500/mcL (Grade 4)            | > 5 days            | No dose reduction. DOCETAXEL will be held  and patients will be treated with filgrastim support. DOCETAXEL will be resumed at the  same dose once neutropenia has resolved to ≤  grade 1 or baseline. |  
For grade 3 constipation or grade 3 fatigue, treatment can resume with a 25% dose reduction after resolution of toxicity to < grade 1 or baseline. Patients will be allowed to continue docetaxel treatment at successively reduced doses as long as they do not have progressive disease, regardless of the time required for recovery from ADEs. For dose-limiting toxicities related to docetaxel that lead to withholding docetaxel temporarily, cabozantinib may be withheld along with docetaxel at the discretion of the investigators for the best interest and safety of patients. However, prednisone should not be interrupted.  
59 CTEP Study \#: 9243
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6.3 study drug dose holidays

Patients may receive treatment indefinitely, but may have the doses of one or all drugs (docetaxel, cabozantinib or prednisone) withheld temporarily for resolution of toxicities or taking drug holidays, and potentially resume treatment as long as they do not fulfill the criteria for removal from protocol therapy outlined in section **5.9.1.** The determination of a drug holiday will be at the discretion of the investigator.
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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 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 2438 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.  
| Adverse Events with Possible                                                   |                                                               |                        |
|--------------------------------------------------------------------------------|---------------------------------------------------------------|------------------------|
| Relationship to XL184 (Cabozantinib) (CTCAE 4.0 Term) [n= 2438]                | 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)                                               |                        |  
**Version 2.3, October 4, 2016**1
60 CTEP Study \#: 9243  
| Adverse Events with Possible                                                                                                                                                                                            |                                                               |                        |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|------------------------|
| Relationship to XL184 (Cabozantinib) (CTCAE 4.0 Term) [n= 2438]                                                                                                                                                         | Specific Protocol Exceptions  to Expedited Reporting  (SPEER) |                        |
| Likely (>20%)                                                                                                                                                                                                           | Less Likely (<=20%)                                           | Rare but Serious (<3%) |
| Dry mouth                                                                                                                                                                                                               | Dry mouth (Gr 2)                                              |                        |
| Dyspepsia                                                                                                                                                                                                               | Dyspepsia (Gr 2)                                              |                        |
| 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                                                                        | Alanine aminotransferase                                      |                        |
| increased                                                                                                                                                                                                               | increased (Gr 3)                                              |                        |
| Aspartate aminotransferase                                                                                                                                                                                              | Aspartate aminotransferase                                    |                        |
| increased                                                                                                                                                                                                               | increased (Gr 3)                                              |                        |
| Lipase increased                                                                                                                                                                                                        | Lipase increased (Gr 4)                                       |                        |
| Platelet count decreased                                                                                                                                                                                                | Platelet count decreased (Gr 3)                               |                        |
| Weight loss                                                                                                                                                                                                             | Weight loss (Gr 3)                                            |                        |
| METABOLISM AND NUTRITION DISORDERS Anorexia                                                                                                                                                                             | Anorexia (Gr 3)                                               |                        |
| Dehydration Hypocalcemia Hypokalemia Hypomagnesemia                                                                                                                                                                     |                                                               |                        |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia Musculoskeletal and  connective tissue disorders - Other (muscle spasms) Osteonecrosis of jaw Pain in extremity NERVOUS SYSTEM DISORDERS Dizziness Dysgeusia | Dysgeusia (Gr 2)                                              |                        |
| Headache                                                                                                                                                                                                                | Reversible posterior  leukoencephalopathy  syndrome           |                        |  
| Adverse Events with Possible                                                                                                              |                                                                              |                        |
|-------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|------------------------|
| Relationship to XL184 (Cabozantinib) (CTCAE 4.0 Term) [n= 2438]                                                                           | Specific Protocol Exceptions  to Expedited Reporting  (SPEER)                |                        |
| Likely (>20%)                                                                                                                             | Less Likely (<=20%)                                                          | Rare but Serious (<3%) |
| RENAL AND URINARY DISORDERS Acute kidney injury                                                                                           | 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)                                                              |                        |
| Palmar-plantar                                                                                                                            | Palmar-plantar                                                               |                        |
| erythrodysesthesia syndrome                                                                                                               | erythrodysesthesia syndrome  (Gr 3)                                          |                        |
| Rash maculo-papular                                                                                                                       | Rash maculo-papular (Gr 3)                                                   |                        |
| Skin and subcutaneous tissue  disorders - Other (hair color  changes)                                                                     | Skin and subcutaneous tissue  disorders - Other (hair color  changes) (Gr 2) |                        |
| VASCULAR DISORDERS Hypertension                                                                                                           | Hypertension (Gr 3)                                                          |                        |
| Thromboembolic event9                                                                                                                     |                                                                              |                        |
| 1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal                 |                                                                              |                        |  
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, Enterovesical fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS SOC.  
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC.  
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC.  
5Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 6Pneumothorax has been observed at a higher than expected frequency (15-20%) in a study treating patients with relapsed Ewing sarcoma and osteosarcoma all of whom had pulmonary metastases.  
62 CTEP Study \#: 9243 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, 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 s-malate) trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that XL184 (Cabozantinib s-malate) caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other
(pancytopenia); Disseminated intravascular coagulation; Febrile neutropenia; Hemolytic uremic syndrome CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; Left ventricular systolic dysfunction; Myocardial infarction; Myocarditis; Supraventricular tachycardia EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo ENDOCRINE DISORDERS - Endocrine disorders - Other (autoimmune thyroiditis); Endocrine disorders - Other (hypopituitarism); Endocrine disorders - Other (thyroiditis); Endocrine disorders - Other (thyrotoxicosis); Hyperthyroidism EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other (corneal epithelium defect) GASTROINTESTINAL DISORDERS - Abdominal distension; Anal pain; Anal ulcer; Cheilitis; Colitis; Colonic obstruction; Duodenal ulcer; Dysphagia; Enterocolitis; Esophageal ulcer; Esophagitis; Flatulence; Gastric ulcer; Gastrointestinal disorders - Other (anal fissure); Gastrointestinal disorders - Other (gastroenteritis); Gastrointestinal disorders - Other (glossitis); Gastrointestinal disorders - Other (pneumoperitoneum); Hemorrhoids; Ileus; Pancreatitis; Rectal pain; Rectal ulcer GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Fever; Gait disturbance; General disorders and administration site conditions - Other (implant site inflammation); Malaise; Multi-organ failure; Non-cardiac chest pain; Pain HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other (cholelithiasis);
Hepatobiliary disorders - Other (hepatic cirrhosis); Hepatobiliary disorders - Other (hepatitis toxic); 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; CPK increased; Cardiac troponin I increased; Creatinine increased; Electrocardiogram QT corrected interval prolonged; GGT increased; Investigations - Other (blood lactate dehydrogenase increased); Investigations - Other (D-dimer); Investigations -
Other (eosinophil count increased); Investigations - Other (glucose urine present); Investigations - Other (urine ketone body present); Lymphocyte count decreased; Neutrophil count decreased; Serum amylase increased; White blood cell decreased METABOLISM AND NUTRITION DISORDERS - Glucose intolerance; Hyperglycemia; Hypernatremia; Hyperuricemia; Hypoalbuminemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other
(failure to thrive); Metabolism and nutrition disorders - Other (hypoproteinemia) MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Buttock pain; Flank pain; Generalized muscle weakness; Muscle weakness lower limb; Musculoskeletal and connective tissue disorders -
Other (muscle hemorrhage); Musculoskeletal and connective tissue disorders - Other (osteonecrosis); Musculoskeletal and connective tissue disorders - Other (rhabdomyolysis); Myalgia; Neck pain; Osteoporosis 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); Neoplasms benign, 63 CTEP Study \#: 9243 malignant and unspecified (incl cysts and polyps) - Other (tumor hemorrhage); Tumor pain NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Concentration impairment; Dysarthria; Dysesthesia; Encephalopathy; Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; Memory impairment; Nervous system disorders - Other (cerebral hematoma); Nervous system disorders - Other (hemiparesis); Nervous system disorders - Other (spinal cord compression); Nervous system disorders - Other (vocal cord paralysis); Peripheral motor neuropathy; Peripheral sensory neuropathy; Presyncope; Seizure; Somnolence; Stroke; Syncope; Transient ischemic attacks PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; Insomnia; Psychiatric disorders - Other (mental status changes) RENAL AND URINARY DISORDERS - Chronic kidney disease; Hematuria; Renal and urinary disorders - Other
(azotemia); Renal and urinary disorders - Other (hemorrhage urinary tract); Urinary tract obstruction REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast disorders - Other (scrotal ulcer/erythema/edema); Vaginal fistula RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; Allergic rhinitis; Aspiration; Atelectasis; Hypoxia; Laryngeal edema; 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 (oropharyngeal pain); Respiratory, thoracic and mediastinal disorders - Other (pneumomediastinum); Respiratory, thoracic and mediastinal disorders - Other (rales); Sore throat SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (pain, sloughing of skin and erythema); Skin and subcutaneous tissue disorders - Other (psoriasis); Skin and subcutaneous tissue disorders - Other (splinter hemorrhages); 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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7.1.1 adverse event list(s) for

(See package insert for complete list of side effects) The most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia
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7.1.1.2 prednisone

(See package insert for complete list of side effects) Serious side effects of prednisone include hypertension, hyperglycemia, infections, ruptured tendons, psychotic reactions, glaucoma, severe edema, gastrointestinal bleeding and allergic reactions. Short term side effects may include headaches and insomnia while long term side effects may cause weight gain, exopthalmos, osteoporosis, acne and truncal fat distribution.
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cardiovascular system

bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, ECG changes caused by potassium deficiency, edema, fat embolism, hypertension or aggravation of hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction, necrotizing angiitis, pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis.
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dermatologic

acne, acneiform eruptions, allergic dermatitis, alopecia, angioedema, angioneurotic edema, atrophy and thinning of skin, dry scaly skin, ecchymoses and petechiae (bruising), erythema, facial edema, hirsutism, impaired wound healing, increased sweating, Karposi's sarcoma, lupus erythematosus-like lesions, perineal irritation, purpura, rash, striae, subcutaneous fat atrophy, suppression of reactions to skin tests, striae, telangiectasis, thin fragile skin, thinning scalp hair, urticaria.
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endocrine

Adrenal insufficiency-greatest potential caused by high potency glucocorticoids with long duration of action (associated symptoms include; arthralgias, buffalo hump, dizziness, lifethreatening hypotension, nausea, severe tiredness or weakness), amenorrhea, postmenopausal bleeding or other menstrual irregularities, decreased carbohydrate and glucose tolerance, development of cushingoid state, diabetes mellitus (new onset or manifestations of latent), glycosuria, hyperglycemia, hypertrichosis, hyperthyroidism, hypothyroidism, increased requirements for insulin or oral hypoglycemic agents in diabetics, lipids abnormal, moon face, negative nitrogen balance caused by protein catabolism, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery or illness), suppression of growth in pediatric patients.
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fluid and electrolyte disturbances

congestive heart failure in susceptible patients, fluid retention, hypokalemia, hypokalemic alkalosis, metabolic alkalosis, hypotension or shock-like reaction, potassium loss, sodium retention with resulting edema.
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gastrointestinal

abdominal distention, abdominal pain,anorexia which may result in weight loss, constipation, diarrhea, elevation in serum liver enzyme levels (usually reversible upon discontinuation), gastric irritation, hepatomegaly, increased appetite and weight gain, nausea, oropharyngeal candidiasis, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis, vomiting.
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hematologic

anemia, neutropenia (including febrile neutropenia). Metabolic negative nitrogen balance due to protein catabolism.
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musculoskeletal

arthralgias, aseptic necrosis of femoral and humeral heads, increase risk of fracture, loss of muscle mass, muscle weakness, myalgias, osteopenia, osteoporosis, pathologic fracture of long bones, steroid myopathy, tendon rupture (particularly of the Achilles tendon), vertebral compression fractures.
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neurological/psychiatric

amnesia, anxiety, benign intracranial hypertension, convulsions, delirium, dementia (characterized by deficits in memory retention, attention, concentration, mental speed and efficiency, and occupational performance), depression, dizziness, EEG abnormalities, emotional instability and irritability, euphoria, hallucinations, headache, impaired cognition, incidence of severe psychiatric symptoms, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, increased motor activity, insomnia, ischemic neuropathy, long-term memory loss, mania, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychiatric disorders including steroid psychoses or aggravation of pre-existing psychiatric conditions, restlessness, schizophrenia, verbal memory loss, vertigo, withdrawn behavior.
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ophthalmic

blurred vision, cataracts (including posterior subcapsular cataracts), central serous chorioretinopathy, establishment of secondary bacterial, fungal and viral infections, exophthalmos, glaucoma, increased intraocular pressure, optic nerve damage, papilledema.
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other

abnormal fat deposits, aggravation/masking of infections, decreased resistance to infection, hiccups, immunosuppresion, increased or decreased motility and number of spermatozoa, malaise, insomnia, moon face, pyrexia.
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7.2 definitions 7.2.1 adverse event

An adverse event is defined as any reaction, side effect, or untoward event that occurs during the course of the clinical trial associated with the use of a drug in humans, whether or not the event is considered related to the treatment or clinically significant. For this study, AEs will include events reported by the patient, as well as clinically significant abnormal findings on physical examination or laboratory evaluation. A new illness, symptom, sign or clinically significant laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an AE. All AEs must be recorded on the AE case report form unless otherwise noted. An abnormal laboratory value will be considered an AE if the laboratory abnormality is characterized by any of the following:  
- Results in discontinuation from the study - Is associated with clinical signs or symptoms - Requires treatment or any other therapeutic intervention - Is associated with death or another serious adverse event, including hospitalization. - Is judged by the Investigator to be of significant clinical impact - If any abnormal laboratory result is considered clinically significant, the investigator will provide details about the action taken with respect to the test drug and about the patient's outcome.
7.2.1.1 Adverse Event Characteristics:  
- **CTCAE term (AE description) and grade:** The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
- For expedited reporting purposes only:  
o AEs for the agent that are *bold and italicized* in the CAEPR (*i.e.*, those listed in the SPEER column, Section Error! Reference source not found.) should be reported through CTEP-AERS only if the grade is above the grade provided in the SPEER.  
- **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:
- Death,  
- A life-threatening adverse drug experience - Inpatient hospitalization or prolongation of existing hospitalization - Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
- A congenital anomaly/birth defect - 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.
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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7.2.8 protocol deviation (nih definition)

Any change, divergence, or departure from the IRB approved research protocol.
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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:
- 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  
- Is related or possibly related to participation in the research; AND
- 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 **7.3.4**).
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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 multi-institutional studies

CTEP-AERS is programmed for automatic electronic distribution of reports to the following individuals: Study Coordinator of the Lead Organization, Principal Investigator, and the local treating physician. CTEP-AERS provides a copy feature for other e-mail recipients.
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7.3.4 expedited reporting guidelines

Use the CC 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 (incl 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.  
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention 1, 2 FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
```
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are
considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1) Death
2) A life-threatening adverse event
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions

```  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH
E2A and ICH E6).
ALL **SERIOUS** adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS
within the timeframes detailed in the table below.  
| Grade 3-5        |                                |                  |
|------------------|--------------------------------|------------------|
| Hospitalization  | Grade 1 and Grade 2 Timeframes | Timeframes       |
| Resulting in     |                                |                  |
| Hospitalization  | ≥                              | 10 Calendar Days |
| 24 hrs           | 24-Hour 5 Calendar Days        |                  |
| Not resulting in |                                |                  |
| Hospitalization  | ≥                              | Not required     |
| 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:
- All Grade 3, 4, and Grade 5 AEs
Expedited 10 calendar day reports for:
- Grade 2 AEs resulting in hospitalization or prolongation of hospitalization
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded
UP to the nearest whole day, after the agent/intervention was last administered. Footnote "1" above applies after this
reporting period.
Effective Date: May 5, 2011







```
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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 nhlbi irb and nhlbi

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

The protocol PI will report to the NHLBI-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:
- All Grade 2 **unexpected** events that are possibly, probably or definitely related to the research;
- All Grade 3 and 4 events that are possibly, probably or definitely related to the research;
- All Grade 5 events regardless of attribution; - All Serious Events regardless of attribution.
NOTE: Grade 1 events are not required to be reported.
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7.5.3 nhlbi-irb reporting of ind

Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported to the NHLBI IRB.
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7.5.4 nci guidance for reporting

The site PI must immediately report to the coordinating center PI any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the drug caused the event within 48 hours of PI awareness of the event. The Site PI must also report any protocol deviations to the coordinating center PI within 7 days of PI awareness. Participating centers must also submit the report to their IRB in accordance with their institutional policies. A
blank participating site problem form can be found in Appendix F.
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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:  
- Leukemia secondary to oncology chemotherapy (*e.g.*, acute myelocytic leukemia [AML])
- Myelodysplastic syndrome (MDS)
- Treatment-related secondary malignancy
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via the routine reporting mechanisms outlined in each protocol.
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7.7 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 and violations will be immediately reported to the IRB using iRIS and if applicable to the Sponsor.  
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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7.8.2 sponsor monitoring plan please

Cabozantinib is an investigational agent supplied to investigators by the Division of Cancer Treatment and Diagnosis (DCTD), NCI.
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8.1.3 formulation and preparation

Cabozantinib is supplied by Exelixis and distributed by the DCTD. Cabozantinib is available in 20 mg and 60 mg tablets. The tablets are yellow film coated containing cabozantinib malate equivalent to 20 mg and 60 mg of cabozantinib. The 20 mg tablets have a round shape and the 60 mg tablets have an oval shape, and they are packaged as 30 tablets per bottle. Cabozantinib should be dispensed in its original container; however, cabozantinib tablets can be dispensed in a pill cup with an expiration date not to exceed 24 hours. It can also be repackaged in a pharmacy dispensing bottle with expiration date not to exceed 7 days. The components of the tablets are listed the table below.  
| 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    |
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cabozantinib tablet components and composition

Store intact bottles of cabozantinib at controlled room temperature, 20° to 25°C.
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8.1.5 stability

Stability testing of the intact bottles is on-going. XL184 is stable up to 24 hours when dispensed in an open container such as a pill cup, and up to 7 days when dispensed in a closed container such as a pharmacy bottle other than the original container.
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8.1.7 incompatibilities

Potential Drug Interactions: XL184 is a substrate of CYP3A4. Coadministration of XL184 with medications that are strong inhibitors/inducers of CYP3A4 should be avoided. Strong CYP3A4 inducers are rifampin, carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, St. John's wort, and troglitazone. Strong CYP3A4 inhibitors include ketoconazole, itraconazole, clarithroumycin, indinavir, nefazodone, nelfinavir, and ritonavir. (See the frequently updated http://medicine.iupui.edu/clinpharm/ddis/ for current list agents that interact with CYP3A4). Use alternative medications. Avoid grapefruit/ grapefruit juice and Seville oranges while participating in this trial.  
In-vitro data indicate that XL184 is unlikely to be a substrate for P-glycoprotein, but it does appear to have the potential to inhibit the P-glycoprotein transport activity. Additional details related to these overall conclusions can be found in the investigator brochure. XL184 is highly protein bound, 99.9%. Use caution when coadministering 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.
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potential food effect

The effect of food on the bioavailability of cabozantinib was evaluated in healthy adult subjects in a Phase 1, open-label, randomized, single-dose, two-treatment, two way crossover study (Study XL184-004). Based on the preliminary PK data, a high fat meal did not appear to alter the terminal t1/2. but significantly increased the median tmax to 6 hours from 4 hours (fasted). The high fat meal also significantly increased both the cabozantinib Cmax and AUC values by 41% and 57%, respectively. Based on this result, cabozantinib should be taken on an empty stomach (fasting is required 2 hours before and 1 hour after each cabozantinib dose).  
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. Do not use cimetidine for dyspepsia or indigestion.
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molecular weight 635.6

Chemical Name: N-[4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl]-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate Molecular Formula: C28H24FN3O5·C4H6O5  
  
Cabozantinib is a tyrosine kinase inhibitor. It inhibits multiple RTKs implicated in tumor growth, metastasis, and angiogenesis, and targets primarily MET and VEGFR2. Other targets are RET, AXL, KIT, TIE-2, and FLT-3.
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8.1.8 agent ordering and agent

8.1.8.1 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.  
8.1.8.2 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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8.2 commercial agents 8.2.1 docetaxel

(Please see package insert for complete drug information)
8.2.1.1 Source Docetaxel will be obtained from commercial sources by the local site pharmacy. 8.2.1.2 Toxicity: See section 7.1.1.1 8.2.1.3 Formulation and Preparation 8.2.1.3.1 Formulation TAXOTERE® (docetaxel) Injection Concentrate, Intravenous infusion (IV) is a sterile, nonpyrogenic, pale yellow to brownish-yellow, non-aqueous solution in single-use vials containing 20 mg docetaxel (anhydrous), 0.54 grams polysorbate 80 and 0.395 grams dehydrated alcohol solution per milliliter in two presentations:  
1. TAXOTERE® (docetaxel) Injection Concentrate 20 mg docetaxel in 1 mL in 50/50 (v/v)
ratio polysorbate 80/dehydrated alcohol in a blister pack in one carton (NDC 0075-800301)
2. TAXOTERE® (docetaxel) Injection Concentrate 80 mg docetaxel in 4 mL in 50/50 (v/v)
ratio polysorbate 80/dehydrated alcohol in a blister pack in one carton (NDC 0075-800404)
8.2.1.3.2 Preparation Dilute the concentrated drug product:
1. After removing Taxotere® from refrigeration, allow them to stand at room temperature approximately 5 minutes before proceeding 2. Use only a 21-Gauge needle to withdraw the drug product from a vial
- Larger bore needles (e.g., 18 and 19 gauge) may result in stopper coring and introduce particulate matter into the drug product 3. Aseptically withdraw the amount of concentrated docetaxel solution required for a patient's dose with a calibrated syringe and transfer it into an appropriate parenteral product bag or bottle containing a volume of either 0.9% NS or D5W sufficient to produce a final docetaxel concentration within the range 0.3 - 0.74 mg/mL
- Product concentrations must not exceed 0.74 mg docetaxel per milliliter
- To minimize patient exposure to phthalate plasticizers (e.g., DEHP), which may be leached from PVC containers, prepare and store docetaxel injection for administration to patients in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin)
4. Thoroughly mix the admixture by manual rotation and by gently inverting the product container
8.2.1.4 Storage and Stability Store between 2°C and 25°C. Retain in the original package to protect from bright light. Freezing does not adversely affect the product.  
Confidential
- When prepared as described and stored between 2° - 25°C, docetaxel solutions are stable for 4 hours 8.2.1.5 Administration Procedures See section **5.3.2**. To minimize patient exposure to phthalate plasticizers (e.g., DEHP), which may be leached from PVC containers and administration sets, administer docetaxel only through polyethylene-lined administration sets 8.2.1.6 Incompatibilities  
- Hypersensitivity to docetaxal or polysorbate 80; neutrophil counts of <1500/µL. - Cytochrome P450 3A4 inducers, inhibitors, or substrates: May alter docetaxel metabolism.
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8.2.2 prednisone

(Please see package insert for complete drug information)
8.2.2.1 Source: For patient administration oral tablets will be purchased by the local site pharmacy from commercial sources. 8.2.2.2 Toxicity: See section 7.1.1.2 8.2.2.3 Formulation and preparation:
Prednisone is supplied as 5 mg tablets.  
8.2.2.4 Stability and storage:
Store at 15 - 30˚C, protected from moisture and light.  
8.2.2.5 Administration procedures: See section **5.3.3**. 8.2.2.6 Incompatibilities:
Systemic fungal infections and known hypersensitivity to components.
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9 pharmacokinetic biomarker correlative and

All patients enrolling at NCI on phase I (dose-escalation) and on the cabozantinib arm in the dose expansion will have blood samples drawn for PK studies. All patients enrolling at NCI will have samples collected for the other studies as described below. Samples will not be collected on patients enrolled outside NCI.
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9.1 pharmacokinetic studies

Blood samples for determination of plasma levels of cabozantinib and docetaxel will be obtained from each patient on Day 1 of Cycles 1 and 2 (C1D1, C2D1) at the following time points: before infusion, at approximately 5 minutes prior to the end of docetaxel infusion, 15 minutes, 30 minutes, 3h, 6h, 12h and 24h after the end of docetaxel infusion. The first dose of cabozantinib has to be administered on Day 2 of Cycle 1 after blood collection of the last time point (24h) to compare docetaxel exposure on C1D1 to C2D1, with and without XL184. XL184 should be taken at the beginning of the docetaxel infusion, prior to drawing PK blood samples on day 1 of cycle 2. The plasma concentration-time data will be analyzed using WinNonlin software (Pharsight, Mountain View, CA). The maximum concentration, time to maximum concentration, the area under the curve extrapolated to infinity, and clearance will be calculated. An assessment of a PK interaction of cabozantinib with docetaxel will be made by comparison of the derived PK parameters of cabozantinib in this study to those for historical data when cabozantinib was given alone. These assessments will be conducted according to the assay technology SOP utilized and validated by Exelixis and shared with Dr. Figg's laboratory for the purpose of conducting this study.
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9.1.1 collection of specimens

One 6mL sodium heparin tube (BD, Franklin Lakes, NJ) is collected from each patient on Day 1 of Cycles 1 and 2 (C1D1, C2D1) at the following time points: before drug administration, at approximately 5 minutes prior to the end of docetaxel infusion, and at 15 minutes, 30 minutes, 3h, 6h, 12h and 24h after the end of docetaxel infusion.
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9.1.2 handling and processing of

The samples will be placed immediately on wet ice and refrigerated. The date and exact time of each blood draw should be recorded on the sample tube and the PK sheet. Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@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 Julie Barnes by e-mail or at 240-760-6044. Upon arrival in the Blood Processing Core (BPC), samples will be centrifuged, and the plasma transferred into cryovials for storage at -80C until the time of analysis. In addition, samples will be barcoded as described in section **9.3.1**.
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9.1.3 site performing the study

The pharmacokinetic analysis will be performed on a research basis in the BPC.
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9.2 biomarker studies 9.2.1 genetic

Dr. Figg's laboratory has extensive experience and expertise in performing pharmacogenetic analyses of genes involved in angiogenesis and drug metabolism pathways. Towards this end, polymerase-chain reaction (PCR) followed by either restriction fragment length polymorphism (RFLP), direct sequencing, or gene array analysis will be used to genotype the single nucleotide polymorphisms. 9.2.1.1 Collection of Specimen(s) One 6ml EDTA tube (BD, Franklin Lakes, NJ) will be collected from patients at baseline (after consent, prior to treatment initiation).  
9.2.1.2 Handling and Processing of Specimens(s)
Immediately after collection, invert the blood tube 8-10 times. Place the tube on wet ice and then store at 4˚C in the refrigerator. The date and exact time of each blood draw should be recorded on the tube. Please page 102-11964 for immediate pick-up. Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@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 Julie Barnes by e-mail or at 240-760-6044. Upon arrival in the BPC, genomic DNA will be extracted and analyzed for genetic polymorphisms. 9.2.1.3 Site(s) Performing Correlative Study The genotyping will be performed on a research basis in the Molecular Pharmacology Section.
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9.2.2 pharmacodynamic biomarkers

The analyses will be performed with assays developed and validated in Dr. Liang Cao's laboratory using electrochemiluminescence technology that provides ultra-high sensitivity and very large signal dynamic range. The c-met assay utilized by Dr. Don Bottaro has been previously validated in his laboratory and published in studies54,56. Purified protein standards will be used for generating standard curves for concentration determination.
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9.2.2.1 collection of specimens

Plasma levels of VEGF, PlGF, HGF: One 5mL EDTA plasma tube (BD, Franklin Lakes, NJ) is collected from each patient prior to drug administration on C1D1 (baseline), C2D1, C3D1 to measure VEGF and PlGF for antiVEGFR2 activity and HGF for anti-c-MET activity.  
Immediately after collection, invert the blood tube 8-10 times. Place the tube on wet ice and then store at 4C in the refrigerator. The date and exact time of each blood draw should be recorded on the tube.  
79 CTEP Study \#: 9243 Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@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 Julie Barnes by e-mail or at 240-760-6044.
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plasma and urinary levels of

One 5mL EDTA plasma tube (BD, Franklin Lakes, NJ) is collected from each patient prior to drug administration on C1D1 (baseline), C2D1, C3D1 to measure soluble c-met. Immediately after collection, invert the blood tube 8-10 times. Place the tube on wet ice and then store at 4C
in the refrigerator. The date and exact time of each blood draw should be recorded on the tube.  
Urine samples (at least 5 mL) will be collected prior to drug administration on C1D1 (baseline), C2D1, and C3D1 to measure soluble met. Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@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 Julie Barnes by e-mail or at 240-760-6044.
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9.2.2.2 sample processing

Plasma levels of VEGF, PlGF, HGF:
Upon arrival in the BPC, blood samples will be centrifuged for 5 minutes at 1200 x g at 4C.  
Plasma will be aliquoted into 2 cryovials and stored at -80C until the time of analysis. The samples will be transferred to Dr. Liang Cao's lab at Bldg 37/Rm6134 (301-435-9039) for analysis. Plasma and urinary levels of soluble met:
Upon arrival in the BPC, blood samples will be centrifuged for 10 minutes at 1300 x g at RT.  
Plasma will be aliquoted into 2 cryovials and stored at -80C until the time of analysis.  
Urine samples will be adjusted to pH 7.5 with Trizma-HCl (Sigma, St. Louis, MO), 2 mol/L, pH 7.5 using 50 microliters per 2 ml urine volume. 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) at -80C. Determine urine creatinine value per standard clinical laboratory testing protocol for every sample collected prior to freezing and storage. The samples will be transferred to Dr. Don Bottaro's lab at Bldg 10/Rm 1W-5832 (301-402-0922) for analysis. 9.2.2.3 Site Performing the Assay The pharmacodynamic biomarker analysis studies will be performed on a research basis in the laboratories of Dr. Liang Cao (Bldg 37/Room 6134) and Dr. Don Bottaro at Bldg 10/Room 1W5832.
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9.2.3 markers for bone activities

Samples will be collected as part of the routine laboratory testing to measure the levels of total ALP and bone-specific ALP, and urine samples will be collected to measure uNTx prior to drug administration on C1D1 (baseline), C2D1, C3D1, and C5D1 (week 12). Blood will be collected in a 4 mL SST tube and urine will be collected in a 5 mL urine tube. Please request these assessments in CRIS by checking the box "Other Mayo" and listing the test names (Alkaline Phosphatase, Bone specific; NTx-Telopeptide, Urine) in the description box.  
9.2.3.2 Sample Processing The processing will be performed by the Clinical Center Laboratory.  
9.2.3.3 Site Performing the Assay The analysis will be performed by the Clinical Center Laboratory.
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9.2.4 circulating tumor cells ctc

CTCs will be investigated using immunofluorescence techniques and CTC identification by positive expression of epithelial markers and a viability marker and negative expression of hematopoietic markers. Jane Trepel has extensive experience in working with CTC technology and has developed a platform for accurate detection of CTC enumeration. The Veridex CTC analysis is an FDA-approved platform for the capture, analysis, and enumeration of CTCs in monitoring metastatic prostate cancer.
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ar analysis in ctc

Dr. Liang Cao has expertise in developing new CTC technologies capable of isolating live CTCs for molecular analyses. CTCs will be isolated using a novel and patented CTC microchip-based technology. The purified CTC will be used for the analysis of androgen receptor expression and activity. All the downstream molecular analytic assays have been established and validated. 9.2.4.1 Collection of Specimen(s) CTC enumeration: Two 7cc lavender top tubes for flow-based CTC analysis will be collected at C1D1 pre and C5D1 pre (week 12). Up to nine patients may have peripheral blood collected at the same time points (C1D1 pre and C5D1 pre) in one 7.5cc CellSave Preservative Tube for Veridex CTC analysis. AR analysis in CTCs: One 5 ml K2ETDA tube will be collected at pre-drug on C1D1 (baseline) and forward to Dr. Liang Cao's laboratory within two hours. CTCs will be isolated using a novel and patented CTC microchip-based technology. The purified CTC will be used for the analysis of androgen receptor expression and activity. All the downstream molecular analytic assays have been established and validated. These studies will be performed by Liang Cao, Head of Molecular Targets Core. 9.2.4.2 Handling and Processing of Specimens(s) CTC enumeration: As soon as possible after the patient is scheduled please send email notification to the Trepel lab: Jane Trepel at trepel@helix.nih.gov; Min-Jung Lee at leemin@mail.nih.gov that the sample is scheduled. After the sample is drawn please call the Trepel lab at 301-496-1547 to communicate that the sample is ready. Keep the sample on the unit at room temperature. The sample will be picked up by the lab and processed for CTC enumeration. AR analysis in CTCs: As soon as possible after the patient is scheduled please send email notification to the Cao lab: Liang Cao at caoli@helix.nih.gov that the sample is scheduled. After the sample is drawn please call the Cao lab (Mr. Yunkai Yu at 301.443.2799) to communicate that the sample is ready. Keep the sample on the unit at room temperature. The sample needs to be picked up by the lab within 2 hours. The blood will be processed for CTC isolation.
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9.2.4.3 site(s) performing correlative study

The flow cytometric analyses will be performed by the Trepel laboratory. The Trepel lab will deliver CellSave tubes to the research nursing staff and arrange for sending the tubes for Veridex analysis.  
AR analysis in CTCs will be performed by Dr. Liang Cao's laboratory in the Molecular Targets Core, Genetics Branch, Building 37, Room 6134.
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9.3 sample storage tracking and

Samples will be ordered and tracked through the CRIS Screens. Should a CRIS screen not be available, the NIH form 2803-1 will be completed and will accompany the specimen and be filed in the medical record. 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)

All samples 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.).  
Bar-coded samples are stored in bar-coded boxes in a locked freezer at either -20 or -80C
according to stability requirements. These freezers are located onsite in the BPC and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be accompanied by laboratory staff at all times. Access to stored clinical samples is restricted. Samples will be stored until requested by a researcher named on the protocol. All requests are monitored and tracked in the 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. It is the responsibility of the NCI Principal Investigator to ensure that the samples requested are being used in a manner consistent with IRB approval. 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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9.3.2 handling and storage for

Using a secure laboratory computerized database and a backup hardcopy process, all specimen collection and processing steps are documented and the specific location of each specimen is tracked. Each new specimen collected is assigned a unique 2D barcode identifier that can be linked to the original specimen collected and other relevant information within the inventory system. To ensure patient confidentiality, only containers used for the initial specimen collections will be labeled with patient identifiers. De-identified labels will be applied to all subsequent specimen containers. When specimens are processed and aliquoted, no patient information will be included on the new containers. Original specimen containers will be discarded. Only de-linked specimens will be stored. The inventory process contains other security provisions sufficient to safeguard patient privacy and confidentiality. Access to the inventory system and associated documents is restricted to appropriate personnel only. SOPs ensure that any changes in the 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 are trained to adhere to SOPs and are monitored for high-quality performance.
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9.3.3 molecular targets core (dr.

Biospecimens will be collected and processed using validated SOPs that will ensure both specimen quality and patient confidentiality pursuant to informed consent provisions. To ensure patient confidentiality, only containers used for the initial specimen collections will be labeled with patient identifiers. De-identified labels will be applied to all subsequent specimen containers. When specimens are processed and aliquoted, no patient information will be included on the new containers. Samples are labeled with printed consecutive numbers, frozen on dry ice, and stored in a -80°C freezer located at the NCI Research Facility, Building 37. The freezer is locked and monitored 24/7 for temperature control. Samples will be tracked using a limited access Excel database. Access to the inventory system and associated documents will be restricted to appropriate personnel only. Requests to use specimens stored in the repository must be approved by the IRB. SOPs ensure that any changes in the 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. The PI will submit a report to the IRB in the event that samples are lost or destroyed.  
| 10                                                                                                            | STUDY CALENDAR                  | Screening/Eligibility (Timepoints relative to   | Study Treatment Period   | End of   |
|---------------------------------------------------------------------------------------------------------------|---------------------------------|-------------------------------------------------|--------------------------|----------|
| enrollment)                                                                                                   | (1 cycle = 3 weeks)             | Treatment                                       |                          |          |
| Protocol Activities                                                                                           | Within 30 days after  last dose |                                                 |                          |          |
| ≤4 weeks                                                                                                      | ≤ 16 days                       | ≤ 1 week                                        |                          |          |
| prior                                                                                                         | prior                           | prior                                           | Day 1 of every cycle     |          |
| Informed consent                                                                                              | X                               |                                                 |                          |          |
| Demographics                                                                                                  | X                               |                                                 |                          |          |
| Medical & Oncology                                                                                            | X                               | X                                               |                          |          |
| History  Dental Examination 1                                                                                 | X                               |                                                 |                          |          |
| Physical examination5                                                                                         | X                               | X                                               | X                        |          |
| Weight                                                                                                        | X                               | X                                               | X                        |          |
| Vital signs                                                                                                   | X                               | X                                               | X                        |          |
| ECOG performance status                                                                                       | X                               | X                                               | X                        |          |
| Clinical laboratory tests2                                                                                    | X                               | X                                               | X                        |          |
| Urinalysis and UPCR                                                                                           | X                               | X                                               | X                        |          |
| PSA                                                                                                           | X                               | X2                                              | X                        |          |
| PT/INR and PTT                                                                                                | X                               | X                                               |                          |          |
| Thyroid Function tests                                                                                        | X                               | X                                               |                          |          |
| Serum testosterone                                                                                            | X                               |                                                 |                          |          |
| 12-lead ECG                                                                                                   | X                               | X                                               | X                        |          |
| Tumor assessment: CT  scan3 (chest, abdomen and  pelvis), 99Tc bone  scintigraphy                             | X                               |                                                 |                          |          |
| (every 3 cycles)                                                                                              |                                 |                                                 |                          |          |
| X                                                                                                             |                                 |                                                 |                          |          |
| Cabozantinib                                                                                                  | X                               |                                                 |                          |          |
| administration                                                                                                | (daily or every other day)      |                                                 |                          |          |
| Docetaxel administration                                                                                      | X                               |                                                 |                          |          |
| (day 1 of each cycle)                                                                                         |                                 |                                                 |                          |          |
| Prednisone administration                                                                                     | X                               |                                                 |                          |          |
| (twice daily)                                                                                                 |                                 |                                                 |                          |          |
| Pharmacokinetics7                                                                                             | Cycles 1 & 2 only               |                                                 |                          |          |
| Correlative studies                                                                                           | X4                              |                                                 |                          |          |
| Concomitant medications                                                                                       | Continuous                      | X                                               |                          |          |
| Adverse events                                                                                                | Continuous                      | X6                                              |                          |          |
| ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; UPCR, urine protein/urine  creatinine ratio |                                 |                                                 |                          |          |  
Concomitant medications Continuous X  
Adverse events Continuous X6  
ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; UPCR, urine protein/urine  
creatinine ratio  
1Dental examination required in patients that have been treated with or are currently taking  
bisphosphonates  
2Clinical laboratory tests include: CBC, acute care panel, mineral panel, hepatic panel, ionized calcium,  
amylase, lipase, LDH, total protein, GGT. Refer to section **5.6.4**. In the event the patient's condition is  
85 CTEP Study \#: 9243 deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of next cycle of therapy.  
3In order to minimize radiation exposure, if there is no evaluable soft tissue disease on baseline CT,
future CT scans will not be obtained unless clinically indicated.  
4Correlative blood and urine samples collected at baseline, C1D1, C2D1, C3D1 and C5D1. See section 9.2 for additional instructions.  
5Height does not need to be repeated unless there is a clinical indication6If treatment related toxicity is present, adverse event must be followed until resolution, stable or irreversible per investigator discretion.  
7NCI patients enrolled on phase I and on the cabozantinib arm of phase II. See section 9 for instructions.
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11 measurement of effect 11.1

Although response is not the primary endpoint of this trial, patients with metastatic disease will be assessed primarily by CT scan of the chest, abdomen and pelvis and by 99Tc bone scintigraphy. For the purposes of this study, patients should be re-evaluated every 3 cycles. 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)59 and Prostate Cancer Clinical Trials Working Group criteria (PCWG2)1. 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. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
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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 10 mm diameter as assessed using calipers
(*e.g.*, skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Conventional CT and MRI This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (*e.g.* for body scans).  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible. PET-CT At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed. Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, Laparoscopy The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint. 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-PET While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion.  
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDGPET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET 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

Partial Response (PR): At least a 30% decrease in the sum of the diameters of  
target lesions, taking as reference the baseline sum diameters.  
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.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.  
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 nonpathological in size (<10 mm short axis).  
| Note:                                                                                                                                                                                                                        | If tumor markers are initially above the upper                                                                      |    |     |    |      |     |         |        |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------|----|-----|----|------|-----|---------|--------|
| normal limit, they must normalize for a patient to be  considered in complete clinical response.                                                                                                                             |                                                                                                                     |    |     |    |      |     |         |        |
| Non-CR/Non-PD:                                                                                                                                                                                                               | Persistence of one or more non-target lesion(s) and/or  maintenance of tumor marker level above the normal  limits. |    |     |    |      |     |         |        |
| Progressive Disease (PD):                                                                                                                                                                                                    | Appearance                                                                                                          | of | one | or | more | new | lesions | and/or |
| unequivocal progression of existing non-target lesions.  Unequivocal progression should not normally trump  target lesion status. It must be representative of overall  disease status change, not a single lesion increase. |                                                                                                                     |    |     |    |      |     |         |        |  
Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator).
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11.1.4.3 metastatic bone lesions

Disease progression is considered if a minimum of two new lesions is observed on bone scan. New lesions seen by the end of cycle 3 or before cycle 4 (after the first staging bone scan) may represent disease that was not detected on the pre-study scan, and a confirmatory scan will be required in next scheduled staging bone scan unless clinically not indicated. If confirmed, progression should be dated by the initial time when the lesions are first detected. If new lesions are seen after cycle 3, but no additional lesions are seen on confirmatory scans, the scans from after cycle 3 would serve as the baseline scan to evaluate for disease progression1.
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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.  
| Target         | NonTarget                                                                                                                                                                                                                                                                                                                               |                                           |                                                    |              |      |          |    |         |
|----------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------|----------------------------------------------------|--------------|------|----------|----|---------|
| Lesions        | Lesions                                                                                                                                                                                                                                                                                                                       | New                                       | Overall                                            | Best Overall |      |          |    |         |
| Lesions        | Response                                                                                                                                                                                                                                                                                                                      | Response when  Confirmation is  Required* |                                                    |              |      |          |    |         |
| CR             | CR                                                                                                                                                                                                                                                                                                                            | No                                        | CR                                                 | >4 wks.      |      |          |    |         |
| Confirmation** |                                                                                                                                                                                                                                                                                                                               |                                           |                                                    |              |      |          |    |         |
| CR             | Non                                                                                                                                                                                                                                                                                                                               |                                           |                                                    |              |      |          |    |         |
| CR/NonPD                | No                                                                                                                                                                                                                                                                                                                            | PR                                        |                                                    |              |      |          |    |         |
| CR             | Not                                                                                                                                                                                                                                                                                                                           | No                                        | PR                                                 | >4 wks.      |      |          |    |         |
| evaluated      | Confirmation**                                                                                                                                                                                                                                                                                                                |                                           |                                                    |              |      |          |    |         |
| PR             | Non                                                                                                                                                                                                                                                                                                                               |                                           |                                                    |              |      |          |    |         |
| CR/NonPD/not  evaluated                | No                                                                                                                                                                                                                                                                                                                            | PR                                        |                                                    |              |      |          |    |         |
| SD             | Non                                                                                                                                                                                                                                                                                                                               |                                           |                                                    |              |      |          |    |         |
| CR/NonPD/not  evaluated                | No                                                                                                                                                                                                                                                                                                                            | SD                                        | Documented at least  once >4 wks. from  baseline** |              |      |          |    |         |
| PD             | Any                                                                                                                                                                                                                                                                                                                           | Yes or                                    | PD                                                 |              |      |          |    |         |
| No             |                                                                                                                                                                                                                                                                                                                               |                                           |                                                    |              |      |          |    |         |
| 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. |                                           |                                                    |              |      |          |    |         |  
For Patients with Measurable Disease (*i.e.***, Target Disease)**  
Confidential  
For Patients with Non-Measurable Disease (*i.e.***, Non-Target Disease)**  
| Non-Target Lesions                                                                                                                                      | New Lesions   | Overall Response   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|--------------------|
| CR                                                                                                                                                      | No            | CR                 |
| Non-CR/non-PD                                                                                                                                           | No            | Non-CR/non-PD*     |
| Not all evaluated                                                                                                                                       | No            | not evaluated      |
| Unequivocal PD                                                                                                                                          | Yes or No     | PD                 |
| Any                                                                                                                                                     | Yes           | PD                 |
| * 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease  since SD is increasingly used as an endpoint for assessment of efficacy in |               |                    |  
* '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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12 data collection / data

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7
(Adverse Events: List and Reporting Requirements).
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12.1 data collection

Data will be collected prospectively and entered into NCI CCR C3D database within 14 days of collection. The NCI principal investigator is responsible for the collection, maintenance and quality control of study data. 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:
- The patient met all eligibility criteria  
- Signed informed consent was obtained prior to treatment
- Treatment was given according to protocol (dated notes about doses given, complications, and clinical outcomes)
- Toxicity was assessed according to protocol (laboratory report slips, etc) - Response was assessed according to protocol (X-ray, scan, lab reports, date noted on clinical assessment, as appropriate)
The PI will be responsible for overseeing entry of data into an in-house password protected electronic system and ensuring data accuracy, consistency and timeliness. The principal investigator, associate investigators/research nurses and/or a contracted data manager will assist with the data management efforts. All data obtained during the conduct of the protocol will be kept in secure network drives or in approved alternative sites that comply with NIH security standards. Primary and final analyzed data will have identifiers so that research data can be attributed to an individual human subject participant. 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 breech in our plan to protect subject confidentiality and trial data has occurred, the IRB will be notified.
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12.2 data reporting 12.2.1 method

This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP on a quarterly basis, either by FTP burst of data or via the CDS web application. Reports are due January 31, April 30, July 31, and October 31. Instructions for submitting data using the CDUS can be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html).  
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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12.2.2 responsibility for data submission

Study participants are responsible for submitting CDUS data and/or data forms to either the Coordinating Center quarterly. The date for submission to the Coordinating Center will be set by them. CDUS does not accept data submissions from the participants on the study. When setting the dates, allow time for Coordinating Center compilation, Principal Investigator review, and timely submission to CTEP by the quarterly deadlines (see Section **12.2.1**).  
The Coordinating Center is responsible for compiling and submitting CDUS data to CTEP for all participants and for providing the data to the Principal Investigator for review.
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12.3 ctep multicenter guidelines

This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines. The specific responsibilities of the Principal Investigator and the Coordinating Center (Study Coordinator) and the procedures for auditing are presented in **Appendix E**.  
- The Principal Investigator/Coordinating Center is responsible for distributing all IND
Action Letters or Safety Reports received from CTEP to all participating institutions for submission to their individual IRBs for action as required.  
- Except in very unusual circumstances, each participating institution will order DCTDsupplied agents directly from CTEP. Agents may be ordered by a participating site only after the initial IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO (PIO@ctep.nci.nih.gov) except for Group studies.
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12.4 collaborative agreements language

The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) (hereinafter referred to as "Collaborator(s)") and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the "Intellectual Property Option to Collaborator" (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the terms of award, apply to the use of the Agent(s) in this study:  
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the investigators. The protocol documents for studies utilizing Agents contain confidential information and should not be shared or distributed without the permission of the NCI. If a copy of this protocol is requested by a patient or patient's family member participating on the study, the individual should sign a confidentiality agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov.  
2. For a clinical protocol where there is an investigational Agent used in combination with
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and use of data by each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data"):
a. NCI will provide all Collaborators with prior written notice regarding the existence and nature of any agreements governing their collaboration with NCI, the design of the proposed combination protocol, and the existence of any obligations that would tend to restrict NCI's participation in the proposed combination protocol.  
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any other Collaborator solely to the extent necessary to allow said 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 MultiParty 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.
Confidential other Collaborator to develop, obtain regulatory approval or commercialize its own Agent.  
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:
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email ncicteppubs@mail.nih.gov

The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of Collaborator's confidential/ proprietary information.
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13 statistical considerations 13.1 study

The single arm phase I study of fixed dose of docetaxel and prednisone in combination with cabozantinib will enroll patients at a maximum of three escalating doses using a standard 3 + 3 design. The primary objective is to determine the safety profile of cabozantinib in combination with docetaxel and prednisone, and to determine the maximal tolerated dose (MTD) as recommended phase II dose in combination with docetaxel. Once the MTD has been determined, 6 additional patients will be enrolled as an expansion at MTD level to further characterize the safety, toxicity and pharmacokinetics, as well as to obtain preliminary data on the efficacy of the combination treatment. After completing the phase I portion, a randomized phase II portion of the trial will be conducted to compare docetaxel, prednisone and cabozantinib at the MTD as compared to docetaxel and prednisone (standard of care) in mCRPC patients. Based upon results in the literature, patients who would be eligible to be randomized on this part of the trial would be expected to have an estimated 5 month median progression free survival from docetaxel and prednisone. The goal of this portion of the study will be to determine if the use of cabozantinib, docetaxel, and prednisone will result in patients having an improved progression free survival, with a 9 month median progression free survival. Kaplan-Meier curves and a two-tailed log-rank test will be the primary analysis methods. Assuming exponential progression free survival curves, the hazard rate for docetaxel and prednisone alone would be 0.1386, or approximately a 14% probability of progressing each month when the median PFS is approximately 5 months. If we assume that adding cabozantinib will increase the median progression free survival time to approximately 9 months, this corresponds to a hazard rate of 0.0770 and the resulting hazard ratio for the comparison of the two overall actuarial curves would be 1.80. Following the principles of a phase 2.5 design, to compare these curves and detect a difference with a 0.10 one-tailed log-rank test, a total of 29 evaluable subjects per arm (58 total) will need to be randomized over a two year period and followed for an additional 18 months from the date of entry of the last patient, with occurrence of 52 total progressions in both arms combined, in order to have 80% power to compare the curves. As a futility rule for early stopping, when 50% of the anticipated events have occurred (26 total progressions), the hazard ratio will be determined. If this hazard ratio favors docetaxel and prednisone, then no further patients will be randomized as soon as this has been determined.
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13.2 sample size/accrual rate

Up to 18 subjects may be required to reach the MTD, with an additional 6 subjects required for the expansion phase. Thus, an enrollment of up to 24 subjects is anticipated prior to the randomized portion. For the phase II portion, 58 patients will be enrolled with an additional 4 patients allowed for randomized patients who are not evaluable. Currently, we have 19 patients enrolled. If we enroll an additional 62, this will bring the total accrual required to 81. Based on previous efforts and experience in recruiting patients with this disease onto trials at the NCI, it is anticipated that 2 to 3 patients will be enrolled to this trial per month. Thus, it is expected that accrual for Phase I can be completed in approximately 1 year and the accrual of 62 patients for Phase II can be completed in 2 years. Men of all races will be eligible for this study. Prostate cancer is not present in women; therefore, they will be excluded from this study.  
| Accrual Targets                        |            |           |       |         |        |    |      |
|----------------------------------------|------------|-----------|-------|---------|--------|----|------|
| Ethnic Category                        | Sex/Gender |           |       |         |        |    |      |
| Females                                | Males      | Total     |       |         |        |    |      |
| Hispanic or Latino                     | 0          | +         | 4     | =       | 4      |    |      |
| Not Hispanic or Latino                 | 0          | +         | 77    | =       | 77     |    |      |
| Ethnic Category: Total of all subjects | 0          | (A1)      | +     | 81      | (B1) = | 81 | (C1) |
| Racial Category                        |            |           |       |         |        |    |      |
| American Indian or Alaskan Native      | 0          | +         | =     |         |        |    |      |
| Asian                                  | 0          | +         | 4     | =       | 4      |    |      |
| Black or African American              | 0          | +         | 35    | =       | 35     |    |      |
| Native                                 | Hawaiian   | or        | other | Pacific | 0      | +  | =    |
| Islander White                         | 0          | +         | 42    | =       | 42     |    |      |
| Racial Category: Total of all subjects | 0          | (A2)      | +     | 81      | (B2) = | 81 | (C2) |
| (A1 = A2)                              | (B1 = B2)  | (C1 = C2) |       |         |        |    |      |
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13.3 analysis of secondary endpoints

Secondary objectives include: assessment of pharmacokinetics of each agents during combination therapy; evaluation of antitumor activities of combination therapy via measurable disease as determined by Response Evaluation Criteria in Solid Tumors (RECIST); assessment of changes in molecular biomarkers in the pathways of receptor tyrosine kinases and angiogenesis, as well as the biomarkers for bone metabolism.
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14 human subjects protections 14.1

Subjects treated on this study, will be individuals with metastatic prostate cancer, which has recurred (or persisted) after appropriate standard treatment. 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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14.1.1 nhlbi irb multi-institutional guidelines

The PI will provide the NHLBI IRB and Central Registration Office with a copy of the participating institution's approved yearly continuing review. Registration will be halted at any participating institution in which a current continuing approval is not on file at the NHLBI IRB.  
14.1.1.2 Amendments and Consents The CCR PI will provide the NHLBI IRB with copies of all amendments, consents and approvals from each participating institution.
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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 prostate cancer, and because of unknown toxicities of cabozantinib in combination with docetaxel and prednisone 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 for evaluation. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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14.4 evaluation of benefits and

The potential benefit to a patient that goes onto study is a reduction in the bulk of their tumor and improvement in their bony lesions, which may or may not have favorable impact on symptoms and/or survival. Potential risks include the possible occurrence of any of a range of side effects which are listed in the Consent Document. The procedure for protecting against or minimizing risks will be to medically evaluate patients on a regular basis.
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14.5 risks/benefits analysis

For patients with castrate-resistant prostate cancer, median survival is in the range of 12-18 months. Potential risks include the possible occurrence of any of a range of side effects listed in section 7. Although no compensation is available, any injury will be fully evaluated and treated in keeping with the benefits or care to which patients are entitled under applicable regulations.
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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 in the medical record that informed consent has been obtained.
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14.6.1 telephone re-consent procedure

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. A witness to the subject's signature will sign and date the 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. A copy of the informed consent document will be kept in the subject's research record.
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14.6.2 informed consent of non-english

If there is an unexpected enrollment of a research participant for whom there is no translated extant IRB approved consent document, the principal investigator and/or those authorized to obtain informed consent will use the Short Form Oral Consent Process as described in MAS Policy M77-2, OSHRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2). The summary that will be used is the English version of the extant IRB approved consent document.  
Signed copies of both the English version of the consent and the translated short form will be given to the subject or their legally authorized representative and the signed original will be filed in the medical record. Unless the PI is fluent in the prospective subject's language, an interpreter will be present to facilitate the conversation. Preferably someone who is independent of the subject (i.e., not a family member) will assist in presenting information and obtaining consent. Whenever possible, interpreters will be provided copies of the relevant consent documents well before the consent conversation with the subject (24 to 48 hours if possible). We will request prospective IRB approval of the use of the short form for up to a maximum of 5 participants in a given language and will notify the IRB at the time of continuing review of the frequency of the use of the Short Form. Should we reach the threshold of 5, we will notify the IRB of the need for an additional use of the Short Form and that we will have that consent document translated into the given inherent language.
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15 publication of data and

The Principal Investigator (Protocol Chair) holds the primary responsibility for publication of the study results; provided that the PI will provide any such publication to Exelixis, Inc. for review at least sixty (60) days prior to submission and also comply with any provisions regarding publication as are agreed to between the PI's institution (National Cancer Institute) and Exelixis, Inc. in the Clinical Trial Agreement related to this study. The results will be made public within 24 months of the end of data collection. However, if a report is planned to be published in a peerreviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. In any event, a full report of the outcomes should be made public no later than three (3) years after the end of data collection. Authorship for abstracts and manuscripts resulting from this study will be determined according to guidelines established by the International Committee of Medical Journal Editors.
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16 references

1. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. *Journal of clinical oncology : official* journal of the American Society of Clinical Oncology. 2008;26(7):1148-1159.  
2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. *CA: a cancer journal for* clinicians. 2010;60(5):277-300.  
3. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. The New England journal of medicine. 2004;351(15):1513-1520.  
4. Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26(2):242-245.  
5. Galsky MD, Vogelzang NJ. Docetaxel-based combination therapy for castration-resistant prostate cancer. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2010;21(11):2135-2144.  
6. Serpa Neto A, Tobias-Machado M, Kaliks R, Wroclawski ML, Pompeo AC, Del Giglio A. Ten Years Of Docetaxel-Based Therapies in Prostate Adenocarcinoma: A Systematic Review and Meta-Analysis of 2244 Patients in 12 Randomized Clinical Trials. *Clinical* genitourinary cancer. 2011.  
7. Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. *Am J Pathol.* 1993;143(2):401409.  
8. Duque JL, Loughlin KR, Adam RM, Kantoff PW, Zurakowski D, Freeman MR. Plasma levels of vascular endothelial growth factor are increased in patients with metastatic prostate cancer. *Urology.* 1999;54(3):523-527.  
9. George DJ, Halabi S, Shepard TF, et al. Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480. Clinical cancer research : an *official* journal of the American Association for Cancer Research. 2001;7(7):1932-1936.  
10. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. *Nature.* 2005;438(7070):967974.  
11. Kelly WK HS, Carducci MA, et al. . A randomized, double-blind, placebo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castration-resistant prostate cancer (mCRPC): Survival results of CALGB 90401. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010 (suppl; abstr LBA4511);28:344s.  
12. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis.  
Nature. 2011;473(7347):298-307.  
13. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. *Nat Rev Cancer.*
2008;8(8):592-603.  
14. Ning YM, Gulley JL, Arlen PM, et al. Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(12):2070-2076.  
15. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM.  
Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. *Cancer cell.* 2003;3(4):347-361.  
16. Humphrey PA, Zhu X, Zarnegar R, et al. Hepatocyte growth factor and its receptor (cMET) in prostatic carcinoma. *Am J Pathol.* 1995;147(2):386-396.  
17. Knudsen BS, Gmyrek GA, Inra J, et al. High expression of the Met receptor in prostate cancer metastasis to bone. *Urology.* 2002;60(6):1113-1117.  
18. Verras M, Lee J, Xue H, Li TH, Wang Y, Sun Z. The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression. *Cancer research.* 2007;67(3):967-975.  
19. Paez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. *Cancer cell.* 2009;15(3):220-231.  
20. Sennino B, Naylor RM, Tabruyn SP, You W-K, Aftab DT, McDonald DM. Abstract A13: Reduction of tumor invasiveness and metastasis and prolongation of survival of RIP-Tag2 mice after inhibition of VEGFR plus c-Met by XL184. *Mol Cancer Ther.* 2009;8(12 (Suppl)):A13.  
21. You WK, Sennino B, Williamson CW, et al. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. *Cancer research.* 2011;71(14):47584768.  
22. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011:Sep 16 [Epub ahead of print].  
23. Zhang S, Zhau HE, Osunkoya AO, et al. Vascular endothelial growth factor regulates myeloid cell leukemia-1 expression through neuropilin-1-dependent activation of c-MET signaling in human prostate cancer cells. *Molecular cancer.* 2010;9:9.  
24. Investigator's Brochure. *Investigator's Brochure for Cabozantinib (XL184).* South San Francisco, CA: Exelixis, Inc.; 09 August 2011 2011.  
25. Investigator's Brochure. *Investigator's Brochure for XL184.* South San Francisco, CA:
Exelixis, Inc.; 29 July 2010 2010.  
26. Kurzrock R, Sherman SI, Ball DW, et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(19):2660-2666.  
27. *Cabozantinib (XL184) in Chemotherapy-Pretreated Metastatic Castration Resistant* Prostate Cancer (mCRPC): Results from a Phase 2 Non-Randomized Expansion Cohort (Abstract \#4513 presentation) 2012.  
28. Lee RJ, Dror Michaelson M, Saylor PJ, et al. Investigator-sponsored trial of efficacy and tolerability of cabozantinib (cabo) at lower dose: A dose-finding study in men with castration-resistant prostate cancer (CRPC) and bone metastases. *Journal of clinical* oncology : official journal of the American Society of Clinical Oncology. 2012;30(Supplement):4566.  
29. Exelixis Announces Results from the COMET-1 Phase 3 Pivotal Trial of Cabozantinib in Men with Metastatic Castration-Resistant Prostate Cancer. 2014.  
30. Basch ES, M; De Bono, J.S; Vogelzang, N.J; De Souza, P.L; et al. Final analysis of COMET-2: Cabozantinib (Cabo) versus mitoxantrone/prednisone (MP) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with moderate to severe pain who were previously treated with docetaxel (D) and abiraterone (A) and/or enzalutamide
(E). . *Journal of Clinical Oncology.* 2015;33.  
31. van Soest RJ, van Royen ME, de Morree ES, et al. Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer. *Eur J Cancer.* 2013;49(18):3821-3830.  
32. Mackler NJ, Pienta KJ. Drug insight: Use of docetaxel in prostate and urothelial cancers.  
Nat Clin Pract Urol. 2005;2(2):92-100; quiz 101 p following 112.  
33. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. *The New England journal of medicine.*
2004;351(15):1502-1512.  
34. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. *Lancet.* 2010;376(9747):1147-1154.  
35. Beer TM, Garzotto M, Henner WD, Eilers KM, Wersinger EM. Intermittent chemotherapy in metastatic androgen-independent prostate cancer. British journal of cancer. 2003;89(6):968-970.  
36. Beer TM, Garzotto M, Henner WD, Eilers KM, Wersinger EM. Multiple cycles of intermittent chemotherapy in metastatic androgen-independent prostate cancer. *British* journal of cancer. 2004;91(8):1425-1427.  
37. Soga N, Kato M, Nishikawa K, et al. Intermittent docetaxel therapy with estramustine for hormone-refractory prostate cancer in Japanese patients. International journal of clinical oncology. 2009;14(2):130-135.  
38. Beer TM, Ryan CW, Venner PM, et al. Intermittent chemotherapy in patients with metastatic androgen-independent prostate cancer: results from ASCENT, a doubleblinded, randomized comparison of high-dose calcitriol plus docetaxel with placebo plus docetaxel. *Cancer.* 2008;112(2):326-330.  
39. Gordon MS VN, Schoffski P, Daud A, Spira AI, O'Keeffe BA, et al. Activity of cabozantinib (XL184) in soft tissue and bone: Results of a phase II randomized discontinuation trial (RDT) in patients (pts) with advanced solid tumors [abstract]. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(suppl; abstr 3010).  
40. Hussain M SM, Sweeney C, Corn PG, Elfiky A, Gordon MS, et al. Cabozantinib
(XL184) in metastatic castration-resistant prostate cancer (mCRPC): Results from a phase II randomized discontinuation trial [abstract]. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29:suppl; abstr 4516 41. Mezynski J, Pezaro C, Bianchini D, et al. Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance? Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2012;23(11):2943-2947.  
42. Aggarwal R, Harris A, Formaker C, et al. Response to Subsequent Docetaxel in a Patient Cohort With Metastatic Castration-Resistant Prostate Cancer After Abiraterone Acetate Treatment. *Clinical genitourinary cancer.* 2014.  
43. Schweizer MT, Zhou XC, Wang H, et al. The Influence of Prior Abiraterone Treatment on the Clinical Activity of Docetaxel in Men with Metastatic Castration-resistant Prostate Cancer. *European urology.* 2014.  
44. Sweeney CC, Y. H.; Carducci, M; Liu, G; . CHAARTED: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer.  
ASCO abstract \#2. 2014.  
45. Jain L, Sissung TM, Danesi R, et al. Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib.  
J Exp Clin Cancer Res. 2010;29:95.  
46. Rajpar S, Massard C, Laplanche A, et al. Urinary N-telopeptide (uNTx) is an independent prognostic factor for overall survival in patients with bone metastases from castrationresistant prostate cancer. *Annals of oncology : official journal of the European Society for* Medical Oncology / ESMO. 2010;21(9):1864-1869.  
47. Benson AB, 3rd, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. *Journal of clinical oncology : official* journal of the American Society of Clinical Oncology. 2004;22(14):2918-2926.  
48. Hesketh PJ. Chemotherapy-induced nausea and vomiting. The New England journal of medicine. 2008;358(23):2482-2494.  
49. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006;24(18):2932-2947.  
50. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. *Annals of oncology : official journal of the European* Society for Medical Oncology / ESMO. 2010;21 Suppl 5:v232-243.  
51. Choueiri TK, Vaishampayan U, Rosenberg JE, et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;31(2):181-186.  
52. Dharmawardana PG, Giubellino A, Bottaro DP. Hereditary papillary renal carcinoma type I. *Current molecular medicine.* 2004;4(8):855-868.  
53. Bottaro DP, Rubin JS, Faletto DL, et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. *Science.* 1991;251(4995):802-804.  
54. Athauda G, Giubellino A, Coleman JA, et al. c-Met ectodomain shedding rate correlates with malignant potential. *Clinical cancer research : an official journal of the American* Association for Cancer Research. 2006;12(14 Pt 1):4154-4162.  
55. Cecchi F, Liu Y, Gagnon R, et al. Shed MET (sMET), VEGFA, and sVEGFR2 are markers of foretinib treatment in metastatic gastric cancer patients *Mol Cancer Ther.* 2009;8(12, Supplement 1):Abstract B210.  
56. Russo AL, Jedlicka K, Wernick M, et al. Urine analysis and protein networking identify met as a marker of metastatic prostate cancer. *Clinical cancer research : an official* journal of the American Association for Cancer Research. 2009;15(13):4292-4298.  
57. Zhu M, Tang R, Doshi S, et al. Exposure-response (E-R) analysis of rilotumumab (R,
AMG 102) plus epirubicin/cisplatin/capecitabine (ECX) in patients (pts) with locally advanced or metastatic gastric or esophagogastric junction (G/EGJ) cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30:suppl abstract 2535.  
58. Spigel DR, Edelman MJ, Mok T, et al. The MetLUNG study: A randomized, doubleblind, phase III study of onartuzumab (MetMAb) plus erlotinib versus placebo plus erlotinib in patients with advanced, MET-positive non-small cell lung cancer (NSCLC). Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30:suppl abstract TPS7616.  
59. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). *Eur J Cancer.* 2009;45(2):228-247.
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17 appendices

| 17.1                                                                                                                                                            | APPENDIX A: PERFORMANCE STATUS CRITERIA 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. Requires occasional assistance, but |             |                 |             |
| 60                                                                                                                                                              | is able to care for most of his/her  needs.                             |                                                                                                               |             |                 |             |
| In                                                                                                                                                              | bed                                                                     | <50%                                                                                                          | of          | the             | time.       |
| Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                            |                                                                         |                                                                                                               |             |                 |             |
| 2                                                                                                                                                               | 50                                                                      | Requires considerable assistance and  frequent medical care.                                                  |             |                 |             |
| 40                                                                                                                                                              | Disabled, requires special care and  assistance.                        |                                                                                                               |             |                 |             |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                          |                                                                         |                                                                                                               |             |                 |             |
| 3                                                                                                                                                               | 30                                                                      | Severely                                                                                                      | disabled,   | hospitalization |             |
| indicated. Death not imminent.                                                                                                                                  |                                                                         |                                                                                                               |             |                 |             |
| 100%                                                                                                                                                            | bedridden.                                                              | Completely                                                                                                    |             |                 |             |
| disabled.                                                                                                                                                       | Cannot carry on any                                                     |                                                                                                               |             |                 |             |
| self-care. Totally confined to bed  or chair.                                                                                                                   | 20                                                                      | Very sick, hospitalization indicated.  Death not imminent.                                                    |             |                 |             |
| 4                                                                                                                                                               | 10                                                                      | Moribund,                                                                                                     | fatal       | processes       |             |
| progressing rapidly.                                                                                                                                            |                                                                         |                                                                                                               |             |                 |             |
| 5                                                                                                                                                               | Dead.                                                                   | 0                                                                                                             | Dead.       |                 |             |
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17.2 appendix b patient information

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.  
- The enzyme(s) in question is **CYP3A4**. This enzyme breaks down cabozantinib, gradually reducing the level of the active drug in your system.  
- 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.  
- You and healthcare providers who prescribe drugs for you must be careful about adding or removing any drug in this category.  
- Before you start the study, your study doctor will work with your regular prescriber to switch any medicines that are considered "strong inducers/inhibitors or substrates of CYP3A4."
- Your 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.  
- 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.  
- Be careful:  
Confidential 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: 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 If you take medications used to treat indigestion, you should avoid using drugs such as cimetidine, ranitidine, famotidine, nizatidine omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, and rabeprazole. Instead, you should take antacids for the initial treatment of indigestion. If antacids are not adequate, please contact a member of the research team before taking any other medications.
Other medicines can be a problem with your study drugs.  
- You should check with your doctor or pharmacist whenever you need to use an over-the-counter medicine or herbal supplement.  
- Your regular prescriber should check a medical reference or call your study doctor before prescribing any new medicine for you. Your study doctor's name is **Dr. William Dahut** and he can be contacted at **301 435** 8183.
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:
➢ Tell your doctors if you stop taking regular medicine or if you start taking a new medicine.  
➢ Tell all of your prescribers (doctor, physicians' assistant, nurse practitioner, pharmacist) that you are taking part in a clinical trial.  
➢ Check with your doctor or pharmacist whenever you need to use an over-the-counter medicine or herbal supplement.  
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:
➢ Tell your doctors if you stop taking regular medicine or if you start taking a new medicine.  
➢ Tell all of your prescribers (doctor, physicians' assistant, nurse practitioner, pharmacist) that you are taking part in a clinical trial.  
➢ Check with your doctor or pharmacist whenever you need to use an over-the-counter medicine or herbal supplement.  
109 CTEP Study \#: 9243 17.3 APPENDIX C: GUIDELINES FOR PROPHYLAXIS AND TREATMENT FOR HYPERSENSITIVITY REACTIONS (HSR) A**SSOCIATED**
WITH D**OCETAXEL**  
| HSR Interventions                                                                                      |                                                                                                                 |                                                                                                                                                                                                                                             |            |                   |     |
|--------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|-------------------|-----|
| Initial Regimen                                                                                        | HSR Interventions                                                                                               | HSR Interventions                                                                                                                                                                                                                           |            |                   |     |
| Step 1                                                                                                 | Step 2                                                                                                          | Step 3                                                                                                                                                                                                                                      |            |                   |     |
| For                                                                                                    | ALL                                                                                                             | patients                                                                                                                                                                                                                                    | who        | have              | not |
| experienced                                                                                            | an                                                                                                              | HSR                                                                                                                                                                                                                                         | associated | with              |     |
| Docetaxel                                                                                              | For pts with a H/O a                                                                                            | For pts who experience a HSR                                                                                                                                                                                                                |            |                   |     |
| single HSR episode                                                                                     | after                                                                                                           | implementing                                                                                                                                                                                                                                | Step 1     |                   |     |
| interventions                                                                                          | For pts with severe or repeated HSR  episodes after implementing Steps 1 & 2  interventions PREMEDICATION WITH: |                                                                                                                                                                                                                                             |            |                   |     |
| PREMEDICATION WITH:                                                                                    | Dexamethasone 8 - 20 mg PO for 2 doses  between 24 - 36 h and at 12 hours before  starting docetaxel            |                                                                                                                                                                                                                                             |            |                   |     |
| Dexamethasone 8 mg PO for 2 doses at 12 h & 3 h before  starting docetaxel                             |                                                                                                                 |                                                                                                                                                                                                                                             |            |                   |     |
| PREMEDICATION WITH: Dexamethasone 8 mg PO for 3 doses at 12 h,  3 h, & 1 h before starting docetaxel   | +                                                                                                               | +                                                                                                                                                                                                                                           |            |                   |     |
| Dexamethasone 8 mg IV 30 - 60 min before starting  docetaxel                                           | Dexamethasone 20 mg IV 30 - 60 min before  starting docetaxel                                                   |                                                                                                                                                                                                                                             |            |                   |     |
| OR                                                                                                     |                                                                                                                 |                                                                                                                                                                                                                                             |            |                   |     |
| Dexamethasone 8 mg IV 30 - 60 min before  docetaxel for patients who miss ≥1 oral  dexamethasone doses | +                                                                                                               | +                                                                                                                                                                                                                                           |            |                   |     |
| Diphenhydramine 50 mg IV push 15 - 30 min before  starting docetaxel                                   | Diphenhydramine 50 - 150 mg IV push 15 - 30 min before starting docetaxel                                       |                                                                                                                                                                                                                                             |            |                   |     |
| -                                                                                                      | Reference: study protocol, Section 5.3.2                                                                        | +                                                                                                                                                                                                                                           | +          |                   |     |
| Ranitidine                                                                                             | 50 mg IV infusion 30 min before starting                                                                        |                                                                                                                                                                                                                                             |            |                   |     |
| docetaxel                                                                                              | Ranitidine 50 mg IV infusion 15 - 30 min  before starting docetaxel                                             |                                                                                                                                                                                                                                             |            |                   |     |
| Docetaxel 75 mg/m2* IV over 60 minutes†                                                                | Docetaxel                                                                                                       | 75 mg/m2*                                                                                                                                                                                                                                   | Docetaxel  | 75 mg/m2* IV over |     |
| IV over 1 - 2 hours†                                                                                   | 4 hours                                                                                                         | Docetaxel 75 mg/m2* IV - Given in three portions‡, as follows: 1. Docetaxel 5 mg in 10 mL IV via syringe  pump over 60 min, followed immediately  afterward by: 2. Docetaxel 25 mg in 50 mL IV over  60 min, followed immediately afterward |            |                   |     |
| -                                                                                                      | Given in two portions‡, as: Docetaxel 37.5 mg/m2 IV over  2 hours, q.2 h for 2 doses                            |                                                                                                                                                                                                                                             |            |                   |     |  
110 CTEP Study \#: 9243  
Confidential  
Initial Regimen  
HSR Interventions  
| HSR Interventions   |                                                                                                                                                      |                              |            |      |     |
|---------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|------------|------|-----|
| Initial Regimen     | HSR Interventions                                                                                                                                    | HSR Interventions            |            |      |     |
| Step 1              | Step 2                                                                                                                                               | Step 3                       |            |      |     |
| For                 | ALL                                                                                                                                                  | patients                     | who        | have | not |
| experienced         | an                                                                                                                                                   | HSR                          | associated | with |     |
| Docetaxel           | For pts with a H/O a                                                                                                                                 | For pts who experience a HSR |            |      |     |
| single HSR episode  | after                                                                                                                                                | implementing                 | Step 1     |      |     |
| interventions       | For pts with severe or repeated HSR  episodes after implementing Steps 1 & 2  interventions by: 3. Docetaxel 75 mg/m2 (minus 30 mg) IV  over 120 min |                              |            |      |     |
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prn orders

Hydrocortisone 100 mg IV push q.15 min for 2 doses, PRN docetaxel reaction  
| +                                                                                                                                                                                                                                                                                                                                                                                                                   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Diphenhydramine 50 mg IV push q.15 min for 2 doses, PRN docetaxel reaction + Ranitidine 50 mg IV, PRN docetaxel reaction + Hydromorphone 1 mg IV push q.15 min for 4 doses, PRN pain with docetaxel reaction + Aluminum Hydroxide 200 mg + Magnesium Hydroxide 200 mg + Simethicone 20 mg chewable tablet 1 - 2 tablets q.3 hours, PRN epigastric discomfort (drug name in CRIS is cross-referenced with "Mylanta") |  
* Initial (unmodified) docetaxel dosage is identified. Consult the study protocol or a medically responsible investigator to determine whether docetaxel dose/dosage modification is indicated.  
111 CTEP Study \#: 9243
† For each docetaxel product, drug delivery will be attempted over the administration period indicated, but rate titration is permitted. If rate titration is needed to accommodate patient tolerance, the following escalation scheme is recommended:  
  
‡ Docetaxel stability is concentration dependent. All docetaxel products diluted within the range 0.3 - 0.74 mg/mL are labeled to expire 4 hours after preparation was completed.  
112 CTEP Study \#: 9243