A Phase 2 Study of Cabozantinib (XL184), a Dual Inhibitor of MET and VEGFR, in Patients With Metastatic Refractory Soft Tissue Sarcoma

Inclusion Criteria

- INCLUSION CRITERIA:

- Patients must have histologically or cytologically confirmed soft tissue sarcoma that
is metastatic or unresectable and for which standard treatment that prolongs survival
does not exist or is no longer effective.

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as > 20 mm with conventional
techniques or as > 10 mm with spiral CT scan, MRI, or calipers by clinical exam.

- Patients are allowed prior VEGFR-TKI therapy, which should have been completed at
least 3 months prior to enrollment. Patients will be stratified based on prior
VEGFR-TKI therapy.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of cabozantinib in patients < 18 years of age,
children are excluded from this study.

- ECOG performance status less than or equal to 1 (Karnofsky > 70%).

- Life expectancy > 3 months.

- Patients must have normal organ and marrow function as defined below:

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,500/mcL

- platelets greater than or equal to 100,000/mcL

- total bilirubin less than or equal to 1.5 times ULN

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of
normal creatinine within normal institutional limits

OR

- creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with
creatinine levels above institutional normal.

- hemoglobin greater than or equal to 9 g/dL

- serum albumin greater than or equal to 2.8g/dL

- lipase < 2.0 times ULN and no radiologic or clinical evidence of pancreatitis

- urine protein/creatinine ratio (UPCR) less than or equal to 1

- serum phosphorus calcium, magnesium and potassium greater than or equal to LLN

- (PT)/ International Normalized Ratio (INR) or partial thromboplastin time

- (PTT) test < 1.3 times the laboratory ULN

- Subjects must have blood pressure (BP) no greater than 140 mmHg (systolic) and
90 mmHg (diastolic) for eligibility. Initiation or adjustment of BP medication
is permitted prior to study entry provided that the average of three BP readings
at the time of enrollment is less than or equal to 140/90 mmHg

- Patients must be able to swallow whole tablets. Tablets must not be crushed or
chewed.

- The effects of cabozantinib on the developing human fetus are unknown. For this
reason and because receptor tyrosine kinases are known to be teratogenic, women
of child-bearing potential and men must agree to use adequate contraception. 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).

Sexually active subjects (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.

-Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

- Patients who have had anticancer therapy, including kinase inhibitors, within 4 weeks
(6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who
have not recovered to baseline from adverse events (except alopecia and other
non-clinically significant AEs) due to agents administered more than 4 weeks earlier.
Prior VEGFR therapy should have been completed at least 3 months prior to enrollment.
Patients who have received prior cabozantinib or inhibitors of c-MET or HGF are
ineligible.

- Patients who are receiving any other investigational agents within 28 days before the
first dose of the study treatment.

- The subject has received radionuclide treatment within 6 weeks of the first dose of
study treatment

- The subject has received radiation therapy:

- to the thoracic cavity, abdomen, or pelvis within 3 months before the first dose
of study treatment, or has ongoing complications, or is without complete
recovery and healing from prior radiation therapy.

- to bone or brain metastasis within 14 days before the first dose of study
treatment

- to any other site(s) within 28 days before the first dose of study treatment.

- Patients with active brain metastases or carcinomatous meningitis or epidural disease
are excluded from this clinical trial. Subjects with brain metastases previously
treated with whole brain radiation or radiosurgery or subjects with epidural disease
previously treated with radiation who are asymptomatic and have remained stable for 4
weeks and do not require steroid treatment for at least 2 weeks before starting study
treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy
is permitted if completed at least 3 months before starting study treatment. Baseline
brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain
metastases is required to confirm eligibility.

- Eligibility of subjects receiving any medications or substances known to affect or
with the potential to affect the activity of cabozantinib will be determined
following review of their cases by the Principal Investigator. Patients who are
taking enzyme-inducing anticonvulsant agents are not eligible.

- Patients with refractory nausea and vomiting, chronic gastrointestinal diseases
(e.g., inflammatory bowel disease), or significant bowel resection that could
interfere with absorption.

- Uncontrolled intercurrent illness including, but not limited to symptomatic
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements.

- Pregnant women are excluded from this study because cabozantinib has the potential
for teratogenic or abortifacient effects. Because there is an unknown but potential
risk for adverse events in nursing infants secondary to treatment of the mother with
cabozantinib, breastfeeding should be discontinued if the mother is treated with
cabozantinib.

- Strong inhibitors and inducers of CYP3A4 can affect levels of cabozantinib and should
be avoided whenever possible or switched to alternatives. Subjects requiring chronic
concomitant treatment of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin,
carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort)
are not eligible for this study. Because the lists of these agents are constantly
changing, it is important to regularly consult a frequently-updated list such as
http://medicine.iupui.edu/clinpharm/ddis/; medical reference texts such as the
Physicians' Desk Reference may also provide this information. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new overthe-counter medicine or herbal
product.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with cabozantinib. Appropriate studies
will be undertaken in patients receiving combination antiretroviral therapy when
indicated.

- The subject has PT/INR or PTT test greater than or equal to 1.3 times the laboratory
ULN within 7 days before the first dose of study treatment.

- 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 (e.g., clopidogrel). Low dose aspirin (less than
or equal to 81 mg/day), low-dose warfarin (less than or equal to 1 mg/day), and
prophylactic low molecular weight heparin (LMWH) are permitted.

- The subject has experienced any of the following

- clinically-significant gastrointestinal bleeding within 6 months before the
first dose of study treatment

- hemoptysis of greater than or equal to 0.5 teaspoon (2.5 mL) of red blood within
3 months before the first dose of study treatment

- any other signs indicative of pulmonary hemorrhage within 3 months before the
first dose of study treatment

- The subject has radiographic evidence of cavitating pulmonary lesion(s).

- The subject has tumor in contact with, invading, or encasing any major blood vessels

- The subject has 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

- The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:

1. Cardiovascular disorders including:

1. Congestive heart failure (CHF): New York Heart Association (NYHA) Class III
(moderate) or Class IV (severe) at the time of screening

2. Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg
systolic, or > 90 mm Hg diastolic despite optimal antihypertensive
treatment within 7 days of the first dose of study treatment

3. Any history of congenital long QT syndrome

4. 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

- thromboembolic event requiring therapeutic anticoagulation (Note:
subjects with a venous filter (e.g. vena cava filter) are not eligible
for this study)

2. Gastrointestinal disorders particularly those associated with a high risk of
perforation or fistula formation including:

1. 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,

- inflammatory bowel disease (including ulcerative colitis and Crohn's
disease), diverticulitis, cholecystitis, symptomatic cholangitis or
appendicitis

- malabsorption syndrome

2. 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 that 6
months before the first dose of study treatment.

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

4. Other clinically significant disorders such as:

1. serious non-healing wound/ulcer/bone fracture within 28 days before the
first dose of study treatment

2. history of organ transplant, including allogeneic bone marrow transplant

3. concurrent uncompensated hypothyroidism or thyroid dysfunction within 7
days before the first dose of study treatment

4. history of major surgery as follows:

i. Major surgery within 3 months of the first dose of cabozantinib if there were
no wound healing complications or within 6 months of the first dose of
cabozantinib if there were wound complications

ii. Minor surgery within 1 months of the first dose of cabozantinib if there
were no wound healing complications or within 3 months of the first dose of
cabozantinib if there were wound complications In addition, complete wound
healing from prior surgery must be confirmed at least 28 days before the first
dose of cabozantinib irrespective of the time from surgery

- The subject is unable to swallow tablets

- The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >
500 ms within 28 days before enrollment. Note: if initial QTcF is found to be > 500
ms, two additional EKGs separated by at least 3 minutes should be performed. If the
average of these three consecutive results for QTcF is less than or equal to 500 ms,
the subject meets eligibility in this regard.

- The subject is unable or unwilling to abide by the study protocol or cooperate fully
with the investigator or designee.

- The subject has had evidence within 2 years of the start of study treatment of
another malignancy which required systemic treatment.

- Patients should not have any clinical evidence of an active infection at the time of
enrollment. Patients with a history of infection within 28 days prior to enrollment
should have completed their course of systemic therapy.

INCLUSION OF WOMEN AND MINORITIES:

Both men and women of all races and ethnic groups are eligible for this trial.