| Eligibility |
Inclusion Criteria:
1. The subject has a histologic or cytologic diagnosis of a variant histology renal cell
carcinoma including papillary, chromophobe, Xp.11 translocation, undifferentiated, or
unclassified which is treatment naïve or has previously been treated with one systemic
treatment line not containing any vascular endothelial growth factor antibody or
vascular endothelial growth factor receptor tyrosine kinase inhibitors. The patient
may have received treatment with immune checkpoint therapy including nivolumab as a
single agent or nivolumab plus ipilimumab in combination. Previous treatment with
mammalian target of rapamycin agents such as temsirolimus or everolimus is acceptable.
2. Measurable disease per RECIST v1.1 as determined by the investigator.
3. The subject has had an assessment of all known disease sites eg, by computerized
tomography (CT) scan, magnetic resonance imaging (MRI), bone scan as appropriate,
within 28 days before the first dose of cabozantinib or sunitinib.
4. The subject is >/=18 years old on the day of consent;
5. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of
</=2.
6. 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;
7. The subject has organ and marrow function and laboratory values as follows within 4
days before the first dose of cabozantinib or sunitinib: a.The ANC >/= 1500/mm^3
without colony stimulating factor support; b.White blood cell count >/= 2500/mm^3 (>/=
2.5 GI/L). c.Platelets >/=100,000/mm^3; d.Hemoglobin >/= 9 g/dL; e. Bilirubin </= 1.5
x the ULN. For subjects with known Gilbert's disease, bilirubin </= 3.0 mg/dL; f.Serum
albumin >/= 2.8 g/dl g.Serum creatinine </= 2.0 X ULN or calculated creatinine
clearance >/= 30 mL/min (>/= 0.5 mL/sec) using the Cockcroft-Gault equation: Males:
(140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72) Females: [(140 - age) x
weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85 h.Alanine aminotransferase (ALT),
aspartate aminotransferase (AST), and alkaline phosphatase (ALP) </= 3 X upper limit
of normal (ULN). ALP </= 5 X ULN with documented bone metastases. i.Urine
protein/creatinine ratio (UPCR) </= 1 mg/mg (</= 113.2 mg/mmol);
8. The subject is capable of understanding and complying with the protocol requirements
and has signed the informed consent document;
9. Sexually active subjects (men and women) must agree to use medically accepted barrier
methods of contraception (eg, 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);
10. 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, low body
weight, ovarian suppression or other reasons.
Exclusion Criteria:
1. The subject has a variant histology that includes renal medullary carcinoma or
collecting duct renal cell carcinoma. Any clear cell component in the tumor will lead
to exclusion.
2. The subject has received any previous anti-angiogenic agent. Prior treatment with
cabozantinib.
3. Radiation therapy for bone metastasis within 2 weeks, any other external radiation
therapy within 4 weeks before the first dose of study treatment. Systemic treatment
with radionuclides within 6 weeks before the first dose of study treatment. Subjects
with clinically relevant ongoing complications from prior radiation therapy are not
eligible;
4. The subject has received any other type of investigational agent within 28 days before
the first dose of study treatment;
5. 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;
6. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin
and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel). Allowed
anticoagulants are the following: o Low-dose aspirin for cardioprotection (per local
applicable guidelines) is permitted. o Low-dose low molecular weight heparins (LMWH)
are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects
without known brain metastases who are on a stable dose of LMWH for at least 6 weeks
before first dose of study treatment, and who have had no clinically significant
hemorrhagic complications from the anticoagulation regimen or the tumor.
7. The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT)
tes>/=1.3 X the laboratory ULN within 7 days before the first dose of study treatment.
8. The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions: Cardiovascular disorders: a.Congestive
heart failure New York Heart Association Class 3 or 4, unstable angina pectoris,
serious cardiac arrhythmias. b.Uncontrolled hypertension defined as sustained blood
pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal
antihypertensive treatment. c.Stroke (including transient ischemic attack [TIA]),
myocardial infarction (MI), or other ischemic event, or thromboembolic event (eg, deep
venous thrombosis, pulmonary embolism) within 6 months before first dose.
9. Continuation of 8:Gastrointestinal (GI) disorders including those associated with a
high risk of perforation or fistula formation: The subject has evidence of tumor
invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg,
Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or
appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common
bile duct, or gastric outlet obstruction. Abdominal fistula, GI perforation, bowel
obstruction, or intra-abdominal abscess within 6 months before first dose.
10. Continuation of 8: Clinically significant hematuria, hematemesis, or hemoptysis of >
0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (eg,
pulmonary hemorrhage) within 12 weeks before first dose. Cavitating pulmonary
lesion(s) or known endotracheal or endobronchial disease manifestation. Lesions
invading or encasing any major blood vessels. Other clinically significant disorders
that would preclude safe study participation. Serious non-healing wound/ulcer/bone
fracture. Uncompensated/symptomatic hypothyroidism. Moderate to severe hepatic
impairment (Child-Pugh B or C).
11. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks
before first dose of study treatment. Complete wound healing from major surgery must
have occurred 1 month before first dose and from minor surgery (eg, simple excision,
tooth extraction) at least 10 days before first dose. Subjects with clinically
relevant ongoing complications from prior surgery are not eligible.
12. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
electrocardiogram (ECG) within 28 days before first dose of study treatment
13. Pregnant or lactating females.
14. Inability to swallow tablets
15. Previously identified allergy or hypersensitivity to components of the study treatment
formulations.
16. Diagnosis of another malignancy within 2 years before first dose of study treatment,
except for superficial skin cancers, or localized, low grade tumors deemed cured and
not treated with systemic therapy. Patients with Gleason 6 (3+3) prostate cancer with
previous treatment or on active surveillance may also be allowed on protocol.
17. The subject requires chronic concomitant treatment with strong CYP3A4 inducers (eg,
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine,
phenobarbital, and St. John's Wort).
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