Cabozantinib in Unresectable/Metastatic Adrenocortical Carcinoma

Study Drug Administration:

If participant is are found to be eligible to take part in this study, participant will take
cabozantinib tablets by mouth 1 time each day. Participant should take participant's dose of
study drug at about the same time each day with about a cup (8 ounces) of water. Participant
should not eat for at least 2 hours before and at least 1 hour after taking participant's
dose of study drug. Participant should not crush the tablets.

If participant forgets to take participant's dose of cabozantinib and it has been less than
12 hours since the scheduled dose time, participant should take participant's dose as soon as
participant remembers. If it has been more than 12 hours, participant should not take the
drug that day, and wait for participant's next scheduled dose.

Length of Study:

Participant may continue to receive cabozantinib for as long as the study doctor thinks it is
in participant's best interest. Participant will no longer be able to take the study drug if
the disease gets worse, if intolerable side effects occur, or if participant is unable to
follow study directions.

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

Study Visits:

On Day 1:

- Blood (about 3 tablespoons) will be drawn for pharmacokinetic (PK) testing. PK testing
measures the amount of study drug in the body at different time points.

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

On Day 1 of Weeks 3 and 5 and then every 4 weeks after that:

- Participant will have a physical exam.

- Blood (about 3-4 teaspoons) and urine will be collected for routine tests.

- Participant will have an EKG. After Week 12, this will be performed every 8 weeks.

- If participant can become pregnant, urine or part of the above blood sample will be
collected for a pregnancy test. After Week 12, this pregnancy test will be performed
every 8 weeks.

On Day 29, blood (about 3 tablespoons), and then every 12 weeks after that, blood (about 2
teaspoons), will be drawn for PK testing.

On Day 1 of Week 9, blood (about 3 tablespoons) will be drawn for immune system testing.

Every 8 weeks:

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

- If the doctor thinks it is needed, blood (about 3-4 teaspoons) will be drawn to measure
participant's hormone levels.

If at any point the disease appears to get worse, blood (about 3 tablespoons) will be drawn
for immune system testing.

Follow-Up Visit:

About 30-37 days after participant's last dose of study drug:

- Participant will have a physical exam.

- Blood (about 3-4 teaspoons) and urine will be collected for routine tests. If
participant can become pregnant, part of this urine or blood sample may be used for a
pregnancy test.

- You will have an EKG.

Inclusion Criteria:

1. The subject is >= 18 years old on the day of consent

2. Histological confirmation of ACC based on either: i). Weiss Score of >= 3 in patients
who had earlier surgical resection OR ii). biopsy results compatible with ACC in the
context of clinical setting highly suggestive of ACC (adrenal mass > 4 cm invading
surrounding organs or associated with distant metastases).

3. Locally advanced or metastatic disease not amenable to surgery with curative intent
with measurable disease per RECIST 1.1 (9) as determined by the investigator based on
an assessment of all known disease sites by computerized tomography (CT) scan or
magnetic resonance imaging (MRI) of chest/abdomen/pelvis within 28 days before the
first dose of cabozantinib. In patients with IV contrast allergy or borderline renal
function, CT without IV contrast or 18 FDG PET CT may be used as clinically indicated.

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

5. Recovery to baseline or <= Grade 1 CTCAE v.4.0 from toxicities related to any prior
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive
therapy

6. Life expectancy of at least 3 months

7. Organ and marrow function and laboratory values as follows within 28 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 <= 1.5 × the upper limit of normal (ULN). For subjects with known
Gilbert's disease, bilirubin <= 3.0 mg/dL e. Serum albumin >= 2.8 g/dl f. Serum
creatinine <= 1.5 × ULN or creatinine clearance (CrCl) >= 50 mL/min. For creatinine
clearance estimation, the Cockcroft and Gault equation should be used: Male: CrCl
(mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72). Female: Multiply above
result by 0.85 g. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
<= 3.0 × ULN h. Lipase<=2.0 x the upper limit of normal and no radiologic or clinical
evidence of pancreatitis i. Urine protein/creatinine ratio (UPCR) <= 1 j. Serum
phosphorus>=2.5mg/dl,calcium>=8mg/dL,magnesium>=1.2mg/dL and potassium>= 3.0meq/L

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

9. 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 sexually active 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).

10. 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, anti-estrogens, ovarian suppression
or any other reversible reason.

Exclusion Criteria:

1. Received cytotoxic chemotherapy, radiation therapy, or targeted therapy (including
investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or
antibodies) within 28 days of study enrollment.

2. For patients who received mitotane within 6 months of consenting, mitotane should have
been stopped at least 28 days prior to study enrollment AND to have mitotane serum
level of < 2 mg/L

3. Prior treatment with cabozantinib or other cMET inhibitors

4. Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
before the first dose of study treatment. Eligible subjects must be neurologically
asymptomatic and without corticosteroid treatment at the time of the start of study
treatment

5. The subject has not recovered to baseline or CTCAE <= Grade 1 from toxicity due to all
prior therapies except alopecia and other non-clinically significant AEs.

6. Prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin
time (PTT) test >= 1.3 × the laboratory ULN within 28 days before the first dose of
study treatment

7. Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin
and Factor Xa inhibitors), platelet inhibitors (e.g., clopidogrel) or therapeutic
doses of low molecular weight heparins (LMWH). Low dose aspirin for cardioprotection
(per local applicable guidelines) and low-dose LMWH are permitted. Anticoagulation
with therapeutic doses of LMWH is allowed in subjects who are on a stable dose of LMWH
for at least 6 weeks before the first dose of study treatment, and who have had no
clinically significant hemorrhagic complications from the anticoagulation regimen or
the tumor.

8. Severe and uncontrolled Cushing syndrome despite medical management (e.g., systolic
blood pressure >160mmHg or hyperglycemia with fasting glucose above 300mg/dL).

9. The use of strong CYP3A4 inhibitor (with the exception of ketoconazole).

10. 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>= 0.5 teaspoon(2.5 mL) 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. Tumor invading any major blood vessel
at the time of study enrollment.

11. 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, or the subject with radiographic evidence of
cavitating pulmonary lesion(s); or subjects with tumor invading or encasing any major
blood vessels.

12. Uncontrolled, significant concurrent 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 BP > 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) within 90 days of the first dose of study treatment • myocardial infarction •
clinically significant thromboembolic event within 42 days of randomization requiring
therapeutic anticoagulation.

13. (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this
study) 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), acute
pancreatitis, pancreatic duct or common bile duct obstruction, acute diverticulitis,
acute cholecystitis, symptomatic cholangitis or recent appendicitis within 1 month of
first dose of cabozantinib; patients must be completely recovered from these
conditions • clinically significant malabsorption syndrome, c. Endocrine disorders,
uncontrolled Cushing syndrome despite of adequate medical therapy

14. Any of the following within 6 months before the first dose of study treatment: •
abdominal fistula • gastrointestinal perforation •bowel obstruction or gastric outlet
obstruction •intra-abdominal abscess. Note: Complete resolution of an intra-abdominal
abscess must be confirmed prior to initiating treatment with cabozantinib even if the
abscess occurred more than 6 months before the first dose of study treatment. . •Other
disorders associated with a high risk of fistula formation including PEG tube
placement within 90 days before the first dose of study therapy

15. Other clinically significant disorders such as: i. active infection requiring systemic
antibiotic treatment within 14 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 (TSH above 10) within 28 days before the first
dose of study treatment 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.

16. Unable to swallow tablets

17. A corrected QT interval calculated by the Fridericia formula (QTcF) >500 milliseconds
within 28 days before first dose of study treatment. Three ECGs must be performed for
eligibility determination. If the average of these three consecutive results for QTcF
is <= 500 milliseconds, the subject will be eligible.

18. Pregnant or breastfeeding.

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

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

21. Evidence within 2 years of the start of study treatment of another malignancy which
required systemic treatment except for breast ductal carcinoma-in situ, cured
non-melanoma skin cancer, or cured in situ cervical carcinoma

22. 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.