A Randomized, Double-blind Study To Evaluate the Efficacy and
Safety of Cabozantinib (XL184) at 60 mg/Day Compared to
140 mg/Day in Progressive, Metastatic Medullary Thyroid
Cancer Patients

1. The subject has a histologically confirmed diagnosis of MTC.
2. Availability of tumor tissue for shipment to the central laboratory
according to prior determination of RET mutation status:
a. For subjects lacking evidence of a RET of RAS mutation, a recent tumor tissue
sample (defined as collected within 6 months prior to randomization) will be
required. Tissue shall come from a progressive tumor location,
preferably from the most recently progressed metastatic site if feasible.
If a recent tumor sample is not available, a tumor biopsy will be
obtained during screening.
b. Subjects with documentation of a RET or RAS mutation found in tumor tissue
will not be required to submit a recent tumor tissue sample; however,
the report demonstrating the subject's RET or RAS mutation must be reviewed
and approved by the sponsor prior to subject randomization.
c. For subjects with documentation of a hereditary RET mutation (ie,
pathology report showing presence of a specific RET mutation identified
in a blood sample), a tumor sample will not be required. Review and
approval of the RET mutation report by the sponsor is required prior to
randomization of the subject.
3. The subject has MTC that is metastatic as determined by the investigator based upon computerized tomography (CT), magnetic
resonance imaging (MRI), bone scan, PET scan, or X-ray taken within 28
days before randomization.
4. The subject has disease that is measurable per RECIST 1.1 as
determined by the investigator based upon CT or MRI images taken
within 28 days before randomization.
5. The subject has documented progressive disease (PD) on CT, MRI, PET
scan, bone scan, or X-ray as determined by the investigator per RECIST
1.1 on qualifying screening images taken within 4 months prior to
randomization as compared to previous images taken within 14 months
before the qualifying screening images.
a. PET scan can only be used to establish PD by the presence of new
lesions (not to document increases in target or non-target lesions).
b. Bone scan or x-ray, can only be used to establish PD by the presence
of new lesions in bone (not to document increases in target or nontarget
lesions).
6. The subject has recovered to baseline or CTCAE v4.0 (Common
Terminology Criteria for Adverse Events, version 4.0) * Grade 1 from
toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant
and/or stable on supportive therapy.
7. The subject is * 18 years old on the day of consent.
8. The subject has an ECOG (Eastern Cooperative Oncology Group) status
* 1 at screening
9. The subject has adequate organ and marrow function, based upon the
following laboratory criteria from assessments performed within 28 days
before randomization
a. Absolute neutrophil count (ANC) * 1500/mm3
b. Platelets * 100,000/mm3
c. Hemoglobin * 9 g/dL
d. Total bilirubin * 1.5 x the upper limit of normal (ULN). For subjects
with known Gilbert's disease, total bilirubin * 3.0 mg/dL.
e. Alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) < 3.0 x ULN
f. Serum creatinine * 1.5 x ULN or creatinine clearance * 50 mL/min
(using the Cockcroft-Gault equation: CrCl (mL/min) <= (140 * age) x wt
(kg) / (serum creatinine [mg/dL] x 72); for females multiply by 0.85
g. Urine protein/creatinine ratio (UPCR) * 1 mg/mg (* 113.1 mg/mmol)
or 24-hour urine protein < 1 g
h. The subject has prothrombin time (PT)/INR or partial thromboplastin
time (PTT) test results at screening * 1.3 x the laboratory ULN
10. The subject is capable of understanding and complying with the
protocol requirements and has signed the informed consent document.
11. Sexually active fertile subjects and their partners must agree to use
medically accepted methods of contraception (defined in appendix E of the protocol) during the
course of the study and for 4 months after the last dose of study
treatment
12. Female subjects of childbearing potential must not be pregnant at
screening. Females of childbearing potential are defined as
premenopausal females capable of becoming pregnant (ie, females who
have had any evidence of menses in the past 12 months, with the
exception of those who had prior hysterectomy). However, 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, or ovarian suppression or other reasons.

1. The subject has previously received cabozantinib
2. The subject has received prior treatment with a small molecule kinase
inhibitor or a hormonal therapy (including investigational kinase
inhibitors or hormones) within 28 days or five half-lives of the compound
or active metabolites, whichever is shorter before randomization or at any time
after the date of the qualifying images used to document PD for
eligibility
3. The subject has received prior systemic anti-tumor therapy (eg,
chemotherapy, biologic modifiers, or anti-angiogenic therapy) within 28
days of randomization (42 days for nitrosoureas or/ mitomycin C) or at any time
after the date of the qualifying images used to document PD for
eligibility
4. The subject has received any other type of investigational agent
within 28 days before randomization or at any time
after the date of the qualifying images used to document PD for
eligibility
5. The subject has received radiation therapy within 28 days (14 days for
radiation for bone metastases) or radionuclide treatment within 42 days
of randomization. Subject is ineligible if there are any clinically relevant
ongoing complications from prior radiation therapy
6. The subject has untreated and/or active (progressing or requiring
anticonvulsants or corticosteroids for symptomatic control) central
nervous system (CNS) metastasis. Must have completed radiation
therapy * 28 days prior to randomization and stable without
corticosteroids or anti-convulsant treatment for * 10 days
7. Concomitant anticoagulation at therapeutic doses with oral
anticoagulants or platelet inhibitors
8. The subject has uncontrolled, significant intercurrent or recent illness
including, but not limited to, the following conditions:
a. Cardiovascular disorders including
i. Symptomatic congestive heart failure, unstable angina pectoris, or
serious cardiac arrhythmias
ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg
systolic, or > 100 mm Hg diastolic despite optimal antihypertensive
treatment
iii. Stroke (including transient ischemic attack [TIA]), myocardial
infarction, or other ischemic event within 6 months before
randomization
iv. Thromboembolic event within 3 months before randomization.
b. Gastrointestinal (GI) disorders including those associated with a high
risk of perforation or fistula formation:
i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory
bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or
appendicitis, acute pancreatitis or acute obstruction of the pancreatic
duct or common bile duct, or gastric outlet obstruction
ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal
abscess within 6 months before randomization,
Note: Complete healing must be confirmed prior to randomization,
including radiographic evidence of complete resolution of abdominal
abscess
c. Major surgery (eg, open surgery of the chest or abdominal cavity,
surgery involving the viscera or removal of a large amount of tissue,
removal or biopsy of brain metastasis) within 2 months before
randomization. Complete healing from major surgery must have
occurred 1 month before randomization. Complete healing from minor
surgery must have occurred at least 7 days before randomization.
Subjects with clinically relevant complications from prior surgery are not
eligible
d. Cavitating pulmonary lesion(s) or endobronchial disease
e. Lesion invading a major blood vessel (eg, pulmonary artery, aorta,
carotid artery, or vena cava)
f. Clinically significant bleeding risk including the following within 3
months of randomization: hematuria, hematemesis, hemoptysis of >0.5
teaspoon (>2.5 mL) of red blood, or other signs indicative of pulmonary
hemorrhage, or history of other significant bleeding if not due to
reversible external factors
g. Other clinically significant disorders such as: i. Active infection requiring systemic treatment, known infection with
human immunodeficiency virus (HIV) or known acquired
immunodeficiency syndrome (AIDS)-related illness
ii. Serious non-healing wound/ulcer/bone fracture
iii. Malabsorption syndrome
iv. Uncompensated/symptomatic hypothyroidism
v. History of solid organ transplantation
9. Corrected QT interval calculated by the Fridericia formula (QTcF) >
500 ms within 28 days before randomization. Note: If the QTcF is >500
ms in the first ECG, a total of three ECGs should be performed. If the
average of these three consecutive results for QTcF is * 500 ms, the
subject meets eligibility in this regard.
10. The subject is unable to swallow multiple tablets or capsules
11. The subject has a previously identified allergy or hypersensitivity to
components of the study treatment formulation
12. The subject is pregnant or breastfeeding
13. The subject has had a diagnosis of another malignancy within 2
years before randomization, except for superficial scan cancers, or
localized, low grade tumors deemed cured and not treated with systemic
therapy