Study to Evaluate the Effects of Cabozantinib in Patients With Unresectable Metastatic Pheochromocytomas and Paragangliomas

Study Drug Administration:

If you are found to be eligible to take part in this study, you will take cabozantinib
tablets by mouth 1 time each day. You should take your dose of study drug at about the same
time each day, at least 1 hour before and 2 hours after eating a meal, with about a cup (8
ounces) of water. Do not crush the tablets.

If you forget to take your dose of cabozantinib and it has been less than 12 hours since the
scheduled dose time, take your dose as soon as you remember. If it has been more than 12
hours, do not take the drug that day, and wait for your next scheduled dose.

Study Visits:

On Day -4 (4 days before you start taking the study drug):

- You will have a physical exam.

- Blood (about 2 teaspoons) and urine will be collected for routine tests.This routine
blood draw may include a pregnancy test if you can become pregnant.

- You will have an EKG.

- You will answer 1 questionnaire about any symptoms you may be having. It should take
about 10 minutes to complete. You will complete this questionnaire 1 time every week
after you start the study drug . The study staff will tell you how to complete this
questionnaire.

- If you can become pregnant, urine may be collected for a pregnancy test.

On Day 1 of Weeks 3, 5, 7, 9, and then every 4 weeks after that until Week 24 (Weeks 13, 17,
21, and 24) and then every 8 weeks after that:

- You will have a physical exam.

- Blood (about 3 teaspoons) and urine will be collected for routine tests. This routine
blood draw may include a pregnancy test if you can become pregnant.

- If you can become pregnant, urine may be collected for a pregnancy test.

Every 4 weeks until Week 24 and then every 8 weeks after that, you will have an EKG.

Every 8 weeks:

- You will have an MRI, CT, or PET scan to check the status of the disease.

- Blood (about 2 teaspoons) will be drawn for biomarker testing.

- If the doctor thinks it is needed, you may have a bone scan and/or a
fluorodeoxyglucose-PET (FDG-PET) scan to check the status of the disease.

Starting after Week 24, you will be called by the research nurse every 8 weeks (at the 4-week
midpoint between your every 8-week study visits) to ask about any symptoms you may have and
if you have started any new medications. This call should last about 15 minutes.

During the study, leftover tissue from a previous biopsy or surgery will be collected for
biomarker testing.

If the study doctor thinks it is needed, you will have photographs taken of any skin lesions
or rashes you may develop during the study. Your private areas will be covered (as much as
possible), and a picture of your face will not be taken unless there are lesions on your
face.

Length of Treatment:

You may continue taking the study drug for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drug if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions. If the
disease appears to get worse, but the study doctor and those who monitor the safety of this
study think you are still receiving benefit from the study drug, you may be able to continue
to receive the drug. This will be discussed with you.

Your participation on the study will be over after the follow-up visit.

Follow-Up Visit:

About 30-37 days after your last dose of study drug, you will have a follow-up visit. At this
visit:

- You will have a physical exam.

- Blood (about 2 teaspoons) and urine will be collected for routine tests.

- You will have an EKG.

- If you can become pregnant, blood (about 1 teaspoon) or urine will be collected for a
pregnancy test.

If you are having side effects at the follow-up visit, you may have additional follow-up
visits until the side effects get better or the doctor thinks you no longer need them.

Inclusion Criteria:

1. 18 years of age or older

2. Histological confirmation of PH/PG

3. Locally advanced or metastatic disease not amenable to surgery

4. Patients enrolled in the main branch should have measurable disease. Patients with a
predominance of bone disease who have small, non-measurable or small measurable
lesions other than bone, may be included per the Principal Investigator's discretion,
in the exploratory branch of the study for patients with bone metastases only.

5. Progressive disease per RECIST 1.1 as determined by the investigator within the 12
months preceding study enrollment

6. Assessment of all known disease sites, eg, by CT scan, MRI, bone scan as appropriate,
and/or FDG-PET scan within 28 days before the first dose of cabozantinib

7. Eastern Cooperative Oncology Group (ECOG) performance status <=2

8. Life expectancy of at least 3 months

9. Organ and marrow function and laboratory values as follows within 4 days prior to the
first dose of cabozantinib: a. Absolute neutrophil count (ANC) >/= 1500/mm^3 without
colony stimulating factor support, b. Platelets >/= 100,000/mm^3, c. Hemoglobin >/= 9
g/dL d. Bilirubin Gilbert's disease, bilirubin /= 2.8 g/dl, f. Serum
creatinine /= 50 mL/min (For creatinine
clearance estimation, the Cockcroft and Gault equation should be used: Male: CrCl
(mL/min)=(140 - age)×weight (kg) / (serum creatinine × 72); Female: Multiply above
result by 0.85, g. Alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) pancreatitis, i.Urine protein/creatinine ratio (UPCR) calcium, potassium >/= lower limit of normal (LLN) and magnesium >/= 1.2 mg/dL.

10. Capable of understanding and complying with the protocol requirements and has signed
the informed consent document

11. Sexually active patients (men and women) must agree to use medically accepted barrier
methods of contraception (e.g., male or female condom) during the course of the study
and for 4 months after the last dose of study drug(s), even if oral contraceptives are
also used. All subjects of reproductive potential must agree to use both a barrier
method and a second method of birth control during the course of the study and for 4
months after the last dose of study drug(s).

12. Women of childbearing potential must have a negative pregnancy test at screening.
Women of childbearing potential include women who have experienced menarche and who
have not undergone successful surgical sterilization (hysterectomy, bilateral tubal
ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopause is
defined as amenorrhea >/= 12 consecutive months. Note: women who have been amenorrheic
for 12 or more months are still considered to be of childbearing potential if the
amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression
or any other reversible reason.

Exclusion Criteria:

1. Received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or
biologic agents (eg, cytokines or antibodies) within 3 weeks, or nitrosoureas/
mitomycin C within 6 weeks before the first dose of study treatment.

2. Prior treatment with cabozantinib

3. Radiation therapy for bone metastasis within 2 weeks, or any other external radiation
therapy within 4 weeks before the first dose of study treatment. Subjects with
clinically relevant ongoing complications from prior radiation therapy are not
eligible.

4. Received radionuclide treatment (i.e. I-131 meta-iodo- benzyl guanidine) within 6
months of the first dose of study treatment

5. Receipt of any type of small molecule kinase inhibitor (including investigational
kinase inhibitor) within 14 days before the first dose of study treatment.

6. Receipt of any other type of investigational agent within 28 days before the first
dose of study treatment.

7. The subject has not recovered to baseline or CTCAE all prior therapies except alopecia and other non-clinically significant AEs.

8. Prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin
time (PTT) test >/= 1.3 x the laboratory ULN within 7 days before the first dose of
study treatment.

9. The subject requires concomitant treatment, in therapeutic doses, with anticoagulants
such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa
inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin ( mg/day), low-dose warfarin ( heparin (LMWH) are permitted.

10. The subject requires chronic concomitant treatment of strong CYP3A4 inducers (eg,
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine,
phenobarbital, and St. John's Wort).

11. The subject has experienced any of the following: a. clinically-significant
gastrointestinal bleeding within 6 months before the first dose of study treatment, b.
hemoptysis of >/= 0.5 teaspoon (2.5ml) of red blood within 3 months before the first
dose of study treatment, c. any other signs indicative of pulmonary hemorrhage within
3 months before the first dose of study treatment

12. Radiographic evidence of cavitating pulmonary lesion(s)

13. Tumor invading or encasing any major blood vessels

14. Evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel,
rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days
before the first dose of cabozantinib.

15. Uncontrolled, significant intercurrent or recent illness including, but not limited
to, the following conditions: a. Cardiovascular disorders including: i. Congestive
heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class
IV (severe) at the time of screening, ii. Concurrent uncontrolled hypertension defined
as sustained blood pressure > 150 mm Hg systolic, or > 90 mm Hg diastolic despite
optimal antihypertensive treatment within 7 days of the first dose of study treatment,
iii. Any history of congenital long QT syndrome, or iv. Any of the following within 6
months before the first dose of study treatment: unstable angina pectoris,
clinically-significant cardiac arrhythmias, stroke (including TIA, or other ischemic
event), myocardial infarction, or thromboembolic event requiring therapeutic
anticoagulation (Note: subjects with a venous filter (e.g. vena cava filter) are not
eligible for this study); CONTINUED BELOW

16. b. Gastrointestinal disorders, particularly those associated with a high risk of
perforation or fistula formation, including: i. Any of the following within 28 days
before the first dose of study treatment: intra-abdominal tumor/metastases invading GI
mucosa, active peptic ulcer disease (patients must be completely recovered),
inflammatory bowel disease (including ulcerative colitis and Crohn's disease),
diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis (patient must
be completely recovered from these conditions), malabsorption syndrome; ii. Any of the
following within 6 months before the first dose of study treatment: abdominal fistula,
gastrointestinal perforation, bowel obstruction or gastric outlet obstruction, or
intra-abdominal abscess. (Complete resolution of an intra-abdominal abscess must be
confirmed prior to initiating treatment with cabozantinib even if the abscess occurred
more that 6 months before the first dose of study treatment.); CONTINUED BELOW

17. c. Other disorders associated with a high risk of fistula formation including PEG tube
placement within 3 months before the first dose of study therapy, or CONTINUED BELOW

18. d. Other clinically significant disorders such as: i. active infection requiring
systemic treatment within 28 days before the first dose of study treatment, ii.
serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of
study treatment, iii. history of organ transplant, iv. concurrent uncompensated
hypothyroidism or thyroid dysfunction within 7 days before the first dose of study
treatment, or v. Major surgery within 12 weeks before the first dose of study
treatment. Complete wound healing from major surgery must have occurred 1 month before
the first dose of study treatment. Minor surgery within 28 days before the first dose
of study treatment with complete wound healing at least 10 days before the first dose
of study treatment. Subjects with clinically relevant ongoing complications from prior
surgery are not eligible.

19. Unable to swallow tablets

20. A corrected QT interval calculated by the Fridericia formula (QTcF) >500 ms within 28
days before first dose of study treatment . Three ECGs must be performed. If the
average of these three consecutive results for QTcF is eligibility in this regard.

21. Pregnant or breastfeeding.

22. A previously identified allergy or hypersensitivity to components of the study
treatment formulation.

23. Unable or unwilling to abide by the study protocol or cooperate fully with the
investigator or designee.

24. Evidence within 2 years of the start of study treatment of another malignancy which
required systemic treatment except for cured nonmelanoma skin cancer or cured in situ
cervical carcinoma

25. Any other severe acute or chronic medical or psychiatric condition or laboratory
abnormality which, in the judgment of the investigator, would have made the patient
inappropriate for entry into this study.